2.Major pathological processes in disease

Just as physiology is the study of the way in which the body works, pathology is the scientific study of abnormal physiology, i.e. disease.

  There are many ways in which physiological processes can be upset, and knowledge of the aetiology of a disease may give valuable clues to diagnosis and management. The physician will rely on the signs and symptoms resulting from the derangement of normal physiology to reach these decisions. In this chapter we will examine how physiological processes common to all body systems are altered by disease. Aspects of pathology specific to individual diseases are dealt with in Part 2, in the chapters dealing with the various disease states

Introduction

Physiological processes are delicately balanced to 

maintain a stable internal body environment, a 

process known as homeostasis. This includes, 

for instance, maintaining a constant tempera-

ture and blood pressure, ensuring that the body 

is  properly  hydrated  and  adjusting  levels  of 

electrolytes and blood cells. Homeostasis is a 

dynamic system involving complex inter-related 

positive and negative feedback signals. It is the 

mechanism by which the body defends itself 

against   a   changing   and   sometimes   hostile environment.   A   knowledge   of   homeostatic 

mechanisms is key to understanding pathology

One    reason    why    physiology    becomes 

abnormal is that the various homeostatic mech-

anisms have been overwhelmed, e.g. a severe 

infection may swamp all of the various physio-

logical   responses   to   injury,   including   the 

immune system. However, this explains only a 

relatively small number of diseases. Most appear 

to be due to excessive defective adaptive mecha-

nisms (defensive or homeostatic) that, instead of 

maintaining stability, actually disrupt normal 

function. Table 2.1 lists some general causes of 

disease and how they can give rise to four major pathological processes: inflammation, degeneration, neoplastic change and inherited disease. 

Running through each of these is the recurrent 

theme   of   failure   in   adaptive   mechanisms 

(maladaptation). For example, in infection or 

allergy, it is the response of the body in trying to 

eliminate the foreign agent rather than its pres-

ence   that   may   cause   the   major   problem. 

Immunological processes themselves can some-

times be more harmful than beneficial, e.g. a 

severe allergic reaction. In autoimmune disease 

antibodies  and  cells  of  the  immune  system 

attack the body’s own tissues

   However   a   tissue   is   damaged,   the   body attempts to remove the source of the injury and repair damaged tissue. The fundamental tissue response to injury is inflammation (p. 46), but if that response is excessive it may do more 

damage than the original injury. The conse-

quences of inflammation are far-reaching and underlie many different disease states. Conse-

quently much of this chapter is devoted to a 

consideration of inflammation and the closely related immunological processes

   Degeneration is another major pathological process and represents a cellular response to 

injury. Toxins, infections, immunological reactions, ischaemia and radiation may all lead to 

cellular damage, degeneration and eventually tissue death (necrosis). In some circumstances, 

e.g. exposure to tumour necrosis factor alpha 

(TNFa) and irreparable DNA damage by radiation 

and cytotoxic drugs (see Chapter 10), cells can 

initiate programmed self-destruction, a process 

called apoptosis

  Unlike necrosis, which causes local inflamma-

tion by releasing intercellular enzymes, apop-

tosis is a normal physiological function that is 

integral to growth and development and so is 

not proinflammatory. The 26S proteasome is a 

multienzyme organelle that catabolizes proteins 

that are involved in regulating cell growth and 

reproduction. Abnormal enzymes that promote 

uncontrolled reproduction of tumour cells, e.g. 

tyrosine  kinase,  belong  to  an  enzyme  group 

called the Janus kinases, which underlie some 

monoclonal diseases that are characterized by 

uncontrolled haemopoietic stem cell proliferation. The name comes from the Roman god 

Janus,  represented  as  having  two  faces,  one 

looking back and one forward - the gatekeeper, 

and hence January. The enzyme Janus kinase 2 

(JAK2)  is  a  signal  transducer  for  a  range  of 

cytokines, i.e. mostly small proteins that are 

produced by effector cells to signal other cells to 

respond (see  Table 2.2),  and  causes  chronic 

myeloid leukaemia (CML) and other haemopoi-

etic neoplasms. Thus digestion of JAK2 by the 

26S proteasome inhibits abnormal cell prolifera-

tion and may abort such diseases. The mono-

clonal antibody imatinib is a JAK2 inhibitor that 

has revolutionized CML treatment in patients 

who are unsuitable for bone marrow transplan-

tation, in whom other treatments have failed 

or  whose  disease  is  in  an  aggressive  state. 

Conversely, inhibition of the proteasome by the 

new   monoclonal   agent,   bortezomib,   induces 

apoptosis of the abnormal proliferating cells. 

The combination of bortezomib  with corticos-

teroids produces synergism and is reported to 

double the response rate to corticosteroids alone 

in the treatment of refractory myeloma

  JAK3  deficiency  is  involved  in  the  severe combined immunodeficiency syndrome, which affects both B and T cell lines (see below)

  Many conditions are caused by cardiovascular 

problems, e.g. if blood loss is very severe, circu-

latory collapse (shock) may result. Conversely, if 

a  thrombus  (blood  clot)  is  large  enough  to 

impede   the   circulation   or   block   a   vessel 

completely, this can be viewed as a defect in the 

homeostatic mechanisms that normally prevent 

blood loss. The results of thrombosis, shock and 

related phenomena can all lead to a reduction in 

blood flow to an area of tissue, i.e. ischaemia 

(literally ‘blocking  blood’),  which  may  cause degeneration or necrosis of the tissue supplied 

(ischaemia is discussed on p. 58)

In  some  cases  a  combination  of  disease 

processes may lead to further damage, e.g. the 

inflammatory response evoked by a widespread 

burn will lead to a large exudation of protein-rich 

fluid from the bloodstream, causing a fall in the 

oncotic pressure of the plasma and a flow of fluid 

into the tissues, producing oedema. Further, the 

resulting low blood pressure (shock) may cause 

kidney  ischaemia  leading  to  degeneration  of 

kidney nephrons and, if the number of functioning nephrons falls below a critical level, renal 

failure will follow. Shock will also have more 

generalized effects throughout the body - the 

heart, lungs and CNS being especially vulnerable

Immunology

Specific and non-specific (innate) immunity

There are three general lines of defence against a hostile environment:

•  The simple mechanical barriers provided by the skin and mucous membranes

•  The complex but non-specific innate defence mechanisms, including the inflammatory reaction, the functions of the white cells and the complement system of the blood

•  The   specific   acquired   immune   defence mechanisms

We concentrate here on the last two of these, 

using  the  theme  of  microbial  infection  to 

illustrate how they work together

  Following exposure to infection, a reaction 

will develop against the organism concerned and 

the chance of re-infection with the same species 

is  usually  slight.  This  reaction  is  known  as 

specific acquired immunity, which may be due 

to circulating antibodies (humoral immunity) 

or   to   specific   sensitized   cells(CMI,   cell-

mediated immunity) or both. A similar reaction 

occurs when other foreign compounds or tissues, 

e.g. some drugs, or a transplant, comes into 

contact with the blood

  There  are  also  systems  of  innate  non-

specific immunity, which do not depend on 

contact with a foreign organism, protein, etc. 

The key cells here are certain white blood cells 

(WBCs, leucocytes), especially the neutrophils 

and  macrophages,  which  engulf  and  digest  any  microbe  or  foreign  material  with  which 

they come into contact, regardless of whether  

or  not  it  has  previously  encountered  the 

immune system. However, the action of these 

cell types is greatly enhanced if the body has 

developed acquired immunity to the organism 

or  material.  Additionally,  the  complement 

system (p. 35)  provides  non-specific  defence and  also  acts  to  potentiate  acquired  specific immunity

  It is becoming clear that cell adhesion mole-

cules  are important in the function of many 

cell-cell and cell-membrane interactions, which 

may  be  important  in  normal  physiological 

processes and pathological ones. These include, 

for example, beta-1 integrin, which is essential 

to the correct morphogenesis and differentiation 

of mammary glands, and blood platelet surface 

receptors,  e.g.  glycoprotein 1a,  which  enable 

platelet binding to collagen, and glycoprotein 

1b, which binds to von Willebrand factor, both 

essential  in  blood  clotting (see  Chapter 11). 

Bacterial pili contain surface lectins that recog-

nize specific sugar residues in cell walls and this 

explains   the   selectivity   of   certain   bacterial 

strains or species for specific tissues, e.g. the 

strains of Escherichia coli that produce intestinal 

and urinary-tract infections are demonstrably 

different

Antigens and immunoglobulins

An antigen is any foreign substance, of whatever 

origin, that is capable of initiating the production 

of a specific blood protein called an immunoglob-

ulin (Ig, older term is antibody) that will act 

against it. The Igs so formed will react specifically 

with  that  particular  antigen,  neutralizing  its 

biological effect. Thus antigens are sometimes 

referred to as immunogens. However, other anti-

gens possessing a sufficiently similar chemical 

structure  may  cross-react  with  the  Ig  because 

antigen-antibody reactions involve close inter-

molecular binding and depend on a ‘lock and key’ 

steric fit, similar to the binding of drugs to recep-

tors and enzymes to substrates. We sometimes 

make use of this ability to cross-react, e.g. in the 

old  Wasserman  test  for  syphilis  antibody,  an 

indicator of past or current infection, but now 

replaced  by  an  enzyme  immunoassay.  The 

Wasserman  reaction  does  not  use  Treponema 

pallidum spirochaetes, which are difficult to grow 

and  manipulate,  but  an  artificial  antigen 

prepared from beef hearts that reacts similarly

  Most antigens are proteins. Once these have 

been recognized by the immune system as ‘non-

self’ (foreign), an immune response is initiated.

Microorganisms always express several antigenic groupings  (determinants,   epitopes)   on   their 

surface, so a number of different Igs may be 

produced against a particular organism. A vast 

number of non-microbial proteins are capable of 

stimulating antibody production, including the 

numerous  substances  to  which  allergies  are 

developed. Macromolecules other than proteins 

can also lead to the production of antibodies, 

e.g. lipopolysaccharides. Smaller molecules or 

ions, e.g. penicillins and heavy metals, may act 

as antigenic determinants if they combine with 

‘self’ (non-antigenic) proteins or cells in an indi-

vidual,  causing  the  modified  protein  or  cell 

surface  to  be  recognized  as  foreign  by  that 

person’s immune system. These small molecules 

or  ions,  which  cannot  themselves  elicit  the 

production of an Ig but will react with it when it 

has   been   formed   in   response   to   the 

protein-small molecule complex, or a similar cell 

complex, are termed haptens

Cell types involved in the immune system

The chief components of the immune system are 

three  classes  of  leucocytes (Figure 2.1),  i.e. 

lymphocytes, monocytes and neutrophils. All of 

these   are   derived   from   common   precursor 

pluripotent  stem  cells  in  the  bone  marrow, 

which have the capacity to replicate indefinitely 

and are the precursors of all blood cells.

Two  lineages  of  leucocytes  are  derived  via 

intermediate lymphoid and myeloid stem cells. 

The lymphoid intermediate stem cells give rise 

to the lymphocytes (B cells and T cells) and the 

myeloid stem cells to the granulocytes, the cyto-

plasm of which contains numerous granules. 

The   granulocytes   comprise   the   neutrophils, 

eosinophils and basophils, which are recognized 

by the staining character of their granules and 

the shapes of their nuclei

B-lymphocytes (B cells)

Mature B cells produce Igs and so are responsible 

for humoral immunity. They originate in the 

bone marrow and, after activation by contact 

with  antigen,  undergo  clonal  expansion  and 

mature into plasma cells, which produce an Ig that will react specifically with the same priming 

antigen. They are capable of producing Igs only 

when mature. The plasma cells are stored mainly 

in the cortical regions of lymph nodes, only about 0.1% of B cells being found in 

the  bloodstream.  Plasma  cells  are  terminally 

differentiated, i.e. each clone can carry out only 

the single function of producing one Ig, and 

have a short half-life of about 5 days. However, a 

small number of activated B cells do not differ-

entiate  to  produce  Ig,  but  are  processed  in 

germinal centres in lymph nodes to become memory cells able to respond rapidly to   a   subsequent   challenge   with   the   same antigen. This memory function is a crucial prop-

erty of the immune system because it protects against infection, perhaps many decades after an initial infection, e.g. second attacks of measles and whooping cough are rare

T-lymphocytes (T cells, thymocytes)

These mature within the thymus gland, located 

behind the upper sternum, and are stored in the 

paracortical areas of lymph nodes. They have 

two important roles: cell-mediated immunity (CMI), directed against certain types of micro-

organisms and organ grafts, and regulation of the activity of B cells. There are four important classes of T cells:

•  T helper cells (TH), which up-regulate B cells to become plasma cells

•  T suppressor cells (TS), which down-regulate the immune system

•  Cytotoxic T cells (TC), which identify and eliminate virus-infected host cells, malignant

cells and certain bacteria

•  Memory   T   cells,   which   are   primed   to respond rapidly when the priming antigen is

re-encountered

Undifferentiated TH  cells are designated TH0. 

These are stimulated to differentiate into one of 

two subclasses by their cytokine environment 

(see Table 2.2). If interferon gamma (IFN gamma) 

predominates, the TH0 cells become TH1 cells, 

whereas  if  interleukin-4 (IL-4)  predominates, 

they become TH2 cells. TH  cells are CD4÷ (see 

below and p. 33) able to recruit TC cells, and they 

can also stimulate B cells to form antibodies. TH 

cells also perform these functions through the 

production of cytokines, some of which are stim-

ulatory and others inhibitory to lymphocytes. 

The T suppressor cells (TS) are CD8÷ and have a 

general inhibitory function

  Different types of T cell can be distinguished by 

the  use  of  monoclonal  antibodies  (p. 33)  to 

distinguish specific groups of cell surface anti-

gens, identified by their cluster of differentiation (CD) number. The CD antigens are specified by genes of the major histocompatibility complex (MHC, p. 44). All T cells have CD3 and a T cell receptor surface molecule. TC cells are CD8÷ and  are able to bind with MHC class I molecules, thus identifying cells that have been infected by a virus, and TH  cells (CD4÷) are able to bind to MHC class II molecules on the surface of antigen-presenting  cells  (APCs).  Over  30  CD  antigen clusters have been identified on a wide variety of cells from platelets to macrophages. A further type of cell is the natural killer (NK) cell; these are CD34÷ and are produced from CD3÷ T precursor cells. They are non-specific cells that are neither B nor T cells. They recog nize  Igs  that  have  reacted  with  foreign  cell surfaces and cells that do not have the MHC 

class I molecules (see below) that characterize all ‘self’ cells and are thus ‘seen’ as foreign.

Monocytes

These  are  formed  in  the  bone  marrow  and 

migrate via the bloodstream to various body 

tissues, where they mature into macrophages. 

Some   macrophages   have   specific   names 

according to the particular tissue they inhabit, 

e.g. macrophages in the liver are called Kupffer 

cells. Macrophages are scavengers, capable of 

phagocytosing (engulfing)  a  wide  variety  of 

‘foreign’ matter, e.g. microorganisms, damaged 

cells and cell debris. A particle or organism is 

taken up by the macrophage in a phagosome, a 

cytoplasmic inclusion formed from the plasma 

membrane of the macrophage as it surrounds 

and ingests the foreign material. The phagosome 

then fuses with a lysosome, thus exposing it to 

the action of lysosomal enzymes and to superox-

ides and oxidizing free radicals, formed in a burst 

of   respiration,   which   together   destroy   the 

engulfed material. The phagolysosome provides 

an environment that protects the rest of the cell 

from its highly active interior. However, some 

microorganisms, notably Mycobacterium tubercu-

losis, some fungi and helminths, are able to with-

stand   the   normally   lethal   action   of   the 

phagolysosome and may survive for long periods 

within macrophages, which may then aggregate 

to form granulomas (see Figure 2.16) as part of 

the inflammatory process(see p.57).

  There has been great interest in the secretory 

function  of  macrophages,  particularly  of  the 

interleukin (IL) group of cytokines (Table 2.2). 

IL-1 and IL-6 are believed to play an important 

part in some of the generalized symptoms of 

systemic inflammatory reactions, e.g. fever and 

septic   shock(p.61).   Also,   the   role   of 

macrophages as APCs (see above) is partly facili-

tated by the action of interleukins. Many other 

substances are secreted by macrophages, some of 

which have an important role in chronic inflam-

mation (p. 56)

Granulocytes

Neutrophils

Neutrophils(polymorphonuclear   leucocytes, 

polymorphs) are so named because their large 

nuclei have two to five lobes and have a very 

variable appearance, even resembling a string of 

beads

  Their prime function is phagocytosis. Some 

common  causes  of  acquired  neutrophil  defi-

ciency (neutropenia),  i.e 1.5. 109/L, are given in Table 2.3, which shows that this is an important indicator of infection. Neutrophils are much   shorter-lived   than   macrophages   and persist in the peripheral blood for only 6-8 h. 

However,  like  macrophages  they  will  readily ingest microbial cells that have been opsonized, i.e. coated with Igs and complement compo-

nents (see Figure 2.6) that facilitate microbial attachment  to  phagocytic  leucocytes,  which then engulf and destroy them. Neutrophils are important in acute rather than chronic inflam-

mation and play no part in CMI 

Eosinophils

These usually have two-lobed nuclei and their 

cationic cytoplasmic granules stain bright red 

with eosin dye. They play a key role in the clear-

ance of damaged cells and in allergic reactions 

(p. 39) and are involved in defence against bac-

terial, fungal, helminth (worms) and protozoal 

infections

Basophils

Unlike  other  leucocytes,  basophils  are  non-

phagocytic. Their cytoplasmic granules contain 

histamine,   heparin   and   myeloperoxidases. 

Because they have high-affinity IgE receptors 

they play a role in anaphylactic-type allergic 

reactions (p. 39) and probably in anticoagula-

tion, due to the presence of heparin granules, 

in   responding   to   parasitic   diseases   and   in 

immunoregulation.   Basophils   will   not   be 

considered further here

Intercellular messengers: the cytokine network

The ways in which the various cells involved in 

the immune system are controlled and interact is 

currently of great interest. The principal cellular 

messengers   involved   comprise   the   cytokine 

network, which is being intensively researched 

to provide immunological treatments for a wide 

range of diseases

  Cytokines are produced by a range of leuco-

cytes  and  mediate  signalling  between  cells. Those produced by T cells are referred to as 

lymphokines,    those    by    monocytes    as 

monokines.  Those  cytokines  that  have  the 

particular property of inducing chemotaxis, the attraction of leucocytes to sites of inflammation, are sometimes called chemokines

  The numerous cytokines have a number of 

overlapping actions, and their exact roles in the 

immunological response are not easy to define, 

often depending on the initial reason for stimu-

lation. For instance, some cytokines produced by 

TH cells to stimulate macrophages will, in other 

circumstances, also inhibit B cell function. The 

most important cytokines are the interleukins, 

interferons,  colony-stimulating  factors  and 

tumour necrosis factors, some of which are 

listed in Table 2.2 with their cells of origin and 

range of actions. Some cytokines and cytokine 

inhibitors are already used in clinical practice:

•  Both  aldesleukin  (rh-interleukin-2)  and  IFN alfa  are used in the management of some neoplastic diseases (see Chapter 10).

• Peginterferon alfa-2a and -2b are licensed for the  treatment  of  chronic  hepatitis  C  (see

Chapter 3)

• The immunosuppressive effects of IFN beta are utilized in multiple sclerosis to reduce the

incidence    of    acute    attacks    in    the 

relapsing/remitting form of the disease

• Filgrastim(granulocyte-colony   stimulating factor,   rhG-CSF),   lenograstim  (glycosylated 

rhG-CSF)  and  pegfilgrastim (pegylated  rhG-

CSF) have been used to treat neutropenia and 

related conditions, especially as adjuncts to 

chemotherapy, to stimulate leucocyte produc-

tion after treatment with myelosuppressive 

(antineoplastic  and  bone  marrow  suppres-

sive) agents (see Chapter 10). Granulocyte-

macrophagecolony-stimulatingfactor 

(rhGM-CSF) is used similarly

• Inhibitors   of   interleukins   and   tumour necrosis factor are also being used in the

management of a variety of inflammatory 

autoimmune diseases, e.g. RA and ankylosing 

spondylitis (see Chapter 12), psoriasis (see 

Chapter 13) and inflammatory bowel disease 

(see Chapter 3). This group of apparently 

unrelated  diseases  share  a  common  final 

inflammatory pathway and have been called 

theimmune-mediated     inflammatory 

disorders (IMIDs)

Humoral immunity: antibody production

When antigens first appear in the body they are 

taken up by B cells, monocytes/macrophages, 

and Langerhans cells in the skin (see Chapter 13) 

and   the   antigens   are   processed   and   their 

epitopes expressed on their surfaces. All of these 

cells  are  then  APCs.  There  may  be  several 

epitopes (antigenic determinants) with complex 

antigens, e.g. bacteria and other cellular anti-

gens.  The  epitopes  of  immunogens  on  the 

surfaces of APCs, in combination with MHC 

class II molecules (see p. 44), can then be recog-

nized by complementary TH cells. These in turn 

produce interleukins, which stimulate the appro-

priate B cell clone to mature and produce Igs 

(Table 2.4 and Figure 2.3). Although most anti-

genic responses require this involvement of TH 

cells, some bacterial antigens, notably wall poly-

saccharides,  are  T  cell-independent  and  can 

stimulate B cell clones directly to produce the 

IgM type of Ig (see Table 2.4 and p. 35).

  A single B cell cannot produce all the varieties 

of Ig that may ever be required. At an early stage 

of human embryonic development, precursor B 

cells undergo extensive genetic rearrangement. 

There are three genetic regions: a variable region 

(V, between 25 and 100 genes), a diversity region 

(D, 10 genes) and a junctional region (J, 5-6 genes). Because genes from each region can be 

spliced to any genes from the other regions, there 

is a huge number of possible VDJ combinations 

capable of producing different Igs. These are suffi-

cient to meet a lifetime challenge of up to 109 

environmental  antigens.  The  plasma  cells  so 

produced  are  terminally  committed,  being 

capable of producing only a single Ig. This anti-

genic stimulation causes the correct complemen-

tary type of B cell to undergo clonal expansion 

under  the  influence  of  IL-4,  IL-5  and  IL-6  to 

produce a reservoir of plasma cells, all of which 

are capable of producing the same Ig against one 

antigenic determinant

  When  the  antigen  is  presented  to  B  cells 

belonging  to  the  correct  clone,  the  B  cells 

multiply and mature into plasma cells, which 

produce the appropriate Ig. Cells belonging to a 

particular   clone   can   recognize   the   specific 

antigen,  owing  to  the  presence  on  the  cell 

surface of the Ig that it will eventually synthe-

size, i.e. the Ig acts as a surface receptor, in addi-

tion to free circulation in the blood. Reaction 

between antigen and the Ig receptor acts as a 

signal for the clone to proliferate under the 

influence of a cytokine. A microorganism may 

activate  a  number  of  clones,  but  a  specific 

epitope of an antigen will only stimulate a single 

clone, to produce monoclonal antibodies. Puri-

fied preparations of the latter are an important 

research tool, e.g. as reagents for identifying 

microorganisms, proteins, types of cancer cell, 

etc. They also have useful clinical applications, 

such  as  immunosuppression  to  prevent  graft 

rejection,  where  the  monoclonal  humanized 

antibodies basiliximab and daclizumab (antilym-

phocyte globulins) have been raised against the 

T-lymphocytes causing graft rejection. The same 

principle is being investigated for the treatment 

of a variety of autoimmune diseases by using 

monoclonal antibodies against CD4 molecules, 

which are antigenic, to inhibit TH cell function.

  The  monoclonal  antibodies  rituximab  and 

alemtuzumab, which cause B cell lysis, are used 

to  treat  some  forms  of  lymphoma (B  cell 

malignancies)   and   leukaemia,   respectively. 

Further, the anti-interleukin 1 monoclonal anti-

body anakinra is being evaluated for the treat-

ment  of  refractory  RA (see  Chapter 12),  in 

association with methotrexate

 Fab fragments (see Figure 2.4 and below) of 

monoclonal   antibodies   that   can   complex 

digoxin, e.g. Digibind, have been used for some 

time to treat overdoses of this drug. The use of 

Fab fragments in the treatment of cancer has 

been less successful, because penetration of the 

antibody fragment into the tumour mass appears 

to be a limiting factor

  Ig production is modulated by TH and TS cells, 

which  respectively  promote  and  suppress  Ig 

production.  This  introduces  the  concept  of 

immune tolerance, i.e. when potentially anti-

genic material fails to elicit an immune response. 

Natural tolerance to host (self) tissues is acquired 

during fetal development. The mechanisms by 

which the immune system distinguishes between 

‘self’ and ‘non-self’ depend on the recognition of 

‘self’-defining CD clusters, which are HLA class I 

molecules  (see  p.  44).  Failure  of  the  body  to 

recognize  self-antigens  causes  a  variety  of 

autoimmune diseases. An acquired tolerance to 

other antigens can also be induced later in life 

if  the  body  is  subjected  to  carefully  graded, 

progressively larger doses of antigen. This is the 

basis of hyposensitization therapy for allergic 

diseases,  although  this  technique  has  limited 

therapeutic application because it is potentially 

hazardous. Hyposensitization therapy should be 

undertaken only when full resuscitation facilities, 

including adrenaline (epinephrine) injection, are available,   although   new,   less   hazardous approaches are being explored.

  Unfortunately,  tolerance  to  non-genetically 

identical organ transplants is never acquired, so 

recipients require life-long immunosuppression

Active and passive immunity

Antigenic material can make contact with the 

host defence system wherever lymphocytes are 

found, i.e. the bloodstream, lymphatic system 

and in epithelial tissues. Igs can be detected 

approximately 2 weeks after the first exposure to 

an antigen, corresponding to the time required 

for the B cells to multiply, differentiate into 

plasma cells and produce sufficient Ig to be 

capable   of   detection.   This   is   the   primary 

response. On subsequent contact 

with the same antigen, a secondary response 

occurs. Now the memory B cells are triggered to 

synthesize Igs almost immediately and in far 

higher concentrations than during the primary 

response,  thus  conferring  immunity.  This  is 

active immunity and provides the best form of prophylaxis against infection, primarily because of the memory functions of B and T cells. Active 

immunization is given to those at special risk 

from significant infections, e.g. elderly people (influenza and pneumonia), and healthcare workers who are likely to encounter infected patient

  However, if there is no time to provide active 

immunization in a non-immune person, passive 

immunization  may   be   appropriate. This   involves   giving   preformed   Igs 

against the potential risk. This is less satisfactory 

than active immunization because the protec-

tion lasts only about 30 days before they are 

eliminated,  and  there  is  no  memory  effect: 

another contact with the corresponding antigen 

or   microorganism   elicits   only   a   primary 

response

  Thus recently pregnant women who have not 

had German measles (rubella) as a child, or who 

have  not  been  immunized  against  German 

measles, and have been in contact with a case, 

would  be  given (human)  normal  immuno-

glubulin. This is derived from pooled plasma and contains  a  range  of  Igs.  Nowadays,  routine 

MMR vaccination should avoid this situation. 

People bitten by a suspected rabid animal are 

given  rabies  immunoglobulin  immediately,  to 

cover the period required for Ig production, and 

a course of rabies vaccine is started simultane-

ously.  Other  Igs  available  include  tetanus, 

hepatitis  B,  cytomegalovirus (a  herpes  virus) 

and   varicella-zoster,   the   chickenpox   and 

shingles virus

  Passive immunization may also be indicated in immunocompromized   individuals.   Newborn infants  are  naturally  passively  protected  by maternal  Igs  that  cross  the  placenta  or  are secreted in their mother’s milk, thus conferring resistance  to  infections  until  their  immune 

systems are sufficiently developed to produce their own active response 

The basic structure of Igs comprises two mole-

cules of two types of polypeptide chain (heavy 

and light), which together comprise a crystalliz-

able fragment  (Fc) and an antigen binding 

fragment (Fab). There are five groups of Igs (IgA, 

IgD, IgE, IgG and IgM), distinguished by the type 

of heavy chain. The general structure of IgG (also 

called gamma-globulin), of which there are at 

least 45 subclasses, is illustrated in Figure 2.4. The Fc portion is responsible for non-specific 

binding to macrophages or polymorphs and for 

binding complement (see below). The Fab frag-

ment binds to specific antigens and has the 

highly  variable  structure  responsible  for  the 

specificity of Igs. Each Fab fragment is a partic-

ular ‘lock’ that matches just one antigen ‘key’. Because there are two Fab fragments in each Ig 

molecule, each   Ig   molecule   can   crosslink 

common antigens, e.g the haemagglutinins or 

neuraminidases of influenza virus, neutralizing them, or between two red blood cells, causing clumping.

  Igs combine with the antigens, and possibly 

complement components (see below), a process 

that  opsonizes (coats)  the  antigen,  so  that 

phagocytosis can take place more readily. Some 

antibodies are also directly toxic to cells after 

subsequent combination with complement. The 

properties of the Igs are compared in Table 2.4

  All Igs, except IgM, have a similar basic struc-

ture to IgG. IgM is a pentamer of IgG, five mole-

cules of which are linked by joining chains. IgM is the first type of Ig to be formed after stimula-

tion and is believed to represent the most primi-

tive form. Because of its large size and multiple Fab  sites  it  is  very  efficient  at  causing  the clumping (agglutination) of bacteria and other foreign cells, e.g. erythrocytes 

The complement system

This  system  has  already  been  mentioned  in 

connection with opsonization and will also be 

encountered later in connection with inflamma-

tion. The complement system is part of the 

innate non-specific immune mechanisms (see 

above), and a similar process occurs regardless of 

the type of stimulus

  Some20-30   different,   naturally-occurring 

plasma  proteins  make  up  this  system  and  a 

simplified   outline   of   the   steps   involved 

following its activation is given in Figure 2.6. In 

practice,  the  individual  complement  compo-

nents, which are mostly enzymes, interact or 

combine with each other at various stages of the 

cascade.   Note   that   the   components   are 

numbered in the order of their discovery, not in 

the order in which they react

  C1 is activated by the presence of an immune 

complex, and then acts as an esterase to cleave 

C4 into C4a plus C4b, and C2 into C2a plus C2b. 

The C4b and C2a fragments then combine and 

cleave C3, which in turn cleaves C5, and the 

cascade continues as shown. Finally, C8 and C9 

bind with C5b67 to form a membrane attack 

complex, which forms an annular transmem-

brane pore, allowing cell contents to leak from 

the cell, thus producing cell lysis. This sequence 

of events is known as the classical pathway for 

complement activation

  Another initiator for the classical pathway is the interaction of mannose-binding lectin with mannose groups on bacterial surfaces. In certain situations, e.g. in some viral infections, the alter-

nate pathway may be invoked and C3 can be 

activated directly without the production of C3a and C3b by the C4b2a convertase

  Two  important  aspects  of  the  complement 

system should be noted. First, sequential activa-

tion results in amplification of the system. Thus 

one bimolecule of C3 convertase will produce many C3b molecules, and one molecule of C8 can bind up to six molecules of C9 

  Also, many of the individual components of the system have intrinsic immunological and 

inflammatory properties in their own right

Overall view of humoral immunity

We can now complete the picture of humoral 

immunity. After production by plasma cells, an 

Ig links to its specific antigen via the variable end

of the Fab moiety. These immune complexes 

then  bind  strongly  to  Fc  receptors  on  the 

surfaces of phagocytic cells and are then easily drawn into the cell where they can be destroyed in a phago-lysosome

  Antigenic determinants on the cell surfaces of 

bacteria and other small foreign cells also bind 

Igs. Complement then binds to the Fc fragments 

of the Igs, triggering the complement cascade. 

C3d  fragments  then  become  attached  to  the 

microbial  surface  and  the  microbe  is  now 

opsonized. This enables the Fc and C3d fragments 

to unite with their receptors on phagocytic cells, 

again facilitating engulfment and destruction

  Although opsonization is the primary mode of action  of  Igs,  they  can  also  act  directly  on bacteria and foreign erythrocytes, etc. by causing them to clump together(agglutinate), especially IgMs. Additionally, certain Igs (antitoxins) can neutralize bacterial toxins.

  The overall series of events is illustrated in 

Figures 2.3 and 2.5

Cell-mediated immunity

Bacterial, fungal and viral infections may also be combated via CMI, but it is slower-acting than humoral   immunity.   Even   the   secondary 

response (due to memory T cells) may take days to appear. The cells chiefly responsible for CMI are T cells and macrophages. CMI is comple-

mentary to humoral immunity. Whether one 

mechanism comes into play, or both, depends on the precise nature of the stimulus

  Initial contact between a lymphocyte and a 

cellular  antigen  causes  the  proliferation  of  a 

clone of sensitized T-lymphocytes similar to the 

process seen with B cells. Extremely long-lived 

memory T cells are also produced, ensuring that 

sensitized T cells are available on subsequent 

exposure to the same antigen. The initial recog-

nition of antigens by TH  cells is achieved by 

expression of the antigen by an APC, as previ-

ously described. CD8÷ T cells interact with MHC 

class I molecules on APCs and CD4÷ 

T cells with MHC class II molecules. Bacteria elic-

iting a CMI response are generally the larger 

ones, e.g. Mycobacterium tuberculosis, which tends 

to form filaments. Fungi such as Candida albicans are also dealt with via CMI. The process in 

summarized in Figure 2.8(a)

  CMI can also combat viral infections if the 

virus has altered the surface of the cell it has 

invaded, so as to confer new antigenic properties 

on the cell. This commonly occurs because the 

viral genome directs the production of new viral 

compounds   that   migrate   to   the   plasma 

membrane of the host cell, affecting its surface 

structures. The infected cell is then recognized as 

foreign via antigen-specific T cells interacting 

with MHC class I molecules on the infected host 

cell surface and is attacked by TC 

cells. Some cancer cells may be prevented simi-

larly from proliferation, or may be eliminated at 

a  very  early  stage,  if  the  neoplastic  change 

renders them recognizable as ‘foreign’ by the 

immune system

  Interleukins also play an important part in the process  of  stimulating  the  various  cell  types involved in CMI. For instance, IL-1 is released from APCs to stimulate TH cells to produce IL-2, which in turn stimulates TC cells. Furthermore, some cytokines produced by TH cells are able to stimulate and attract macrophages

Potential problems with the immune system (immunopathology)

If  part  of  the  immune  system  simply  fails  to 

work (immunodeficiency),  the  consequences 

may be disastrous. In rare cases, the failure is 

the  result  of  a  hereditary  lack  of  a  particular 

immunological   process   or   component.   In 

hypogammaglobulinaemia the patient fails to 

produce adequate levels of Igs because of B cell 

defects,  so  children  with  this  condition  will 

suffer recurrent bacterial and other infections. 

A  more   dramatic   example   of   hereditary 

immuno-deficiency  is  the  severe  combined 

immuno-deficiency   syndrome.   There   are 

several   variants,   e.g.   adenosine   deaminase 

deficiency,  purine  nucleoside  phosphorylase 

deficiency  and  the  production  of  a  common 

abnormal  receptor  for  interleukins.  Children 

born  with  these  serious  forms  will  fail  to 

thrive.  Although  Igs  can  be  given,  the  main 

problem is with the cell-mediated arm of the 

immune system because T-lymphocytes fail to produce  cytokines,  or  respond  to  them  and APCs.  The  only  remedy  is  to  maintain  the child  until  it  is  capable  of  undergoing  bone marrow transplantation

  Most  drugs  used  to  treat  cancer  suppress 

tumour growth by inhibiting cell division. An 

unfortunate  side-effect  of  this  is  the  suppres-

sion  of  the  immune  system  by  similarly 

affecting  the  bone  marrow.  This  leaves  the 

patient  very  susceptible  to  serious  infections, 

often by organisms that are not normally path-

ogenic,  e.g.  Pseudomonas,  Candida  or  Pneumo-

cystis. Some diseases may also 

cause immune suppression. The clinical conse-

quences of HIV infection are not only poten-

tially fatal infections but also the occurrence of 

certain   uncommon   tumours,   e.g.   Kaposi’s 

sarcoma, or infections, e.g. Pneumocystis jiroveci 

(formerly known as P. carinii). This emphasizes 

the  importance  of  T  cells  in  limiting  the 

growth of malignancies

  Much of immunopathology is concerned with 

an   inappropriate   or   maladaptive   immune 

response. For convenience, these have usually 

been divided into five classes, summarized in 

Figure 2.7.  In  each  class,  humoral  or  CMI 

responses (or  both)  that  have  already  been 

described are involved, but the responses are 

often out of proportion to the stimulus eliciting 

them.   Such   hypersensitivity   reactions  will 

result in inflammation, as they all involve some 

tissue damage, and other symptoms

  Although    hypersensitivity    is    sometimes 

described  as  an  inappropriate  or  exaggerated 

response  by  the  immune  system,  it  is  more 

correctly regarded as a normal immune reaction 

that happens to damage body tissue. The five 

classes of hypersensitivity are described below. 

However, a reaction to a particular stimulus may 

involve  more  than  one  of  these,  e.g.  serum 

sickness can involve both type I and type II 

reactions

Type I: (anaphylactoid) hypersensitivity

Many allergic  reactions involve the excessive

formation  of  IgE,  produced  in  response  to 

primary contact with an antigen, called in this 

case an allergen. This IgE response by plasma 

cells is driven by the secretion of IL-4 by TH2 

cells. The IgE binds strongly to mast cells by the 

Fc portion. Subsequent contact with the same 

allergen   results   in   a   reaction   between   the 

allergen and bound IgE on the cell surface. The 

crosslinking of IgE molecules by the allergen 

destabilizes the mast cell membrane and causes 

the release of histamine and other mediators 

from preformed granules within its cytoplasm 

and the production of bradykinin. These medi-

ators play an important part in the process of 

inflammation (see p. 46 and Table 2.7). The 

consequences of this mediator release can vary 

from  very  mild  reactions  to  life-threatening 

ones. The most extreme form is anaphylactic 

shock,  with  acute  bronchoconstriction,  rash, 

gastrointestinal disturbance, profound hypoten-

sion and collapse. Less dramatic anaphylactoid 

(anaphylactic-type)    reactions    are    asthma, 

hayfever and eczema. However, the link between 

these conditions and mast cell degranulation is 

not always clear

  Children sometimes experience one or more 

different anaphylactoid reactions, and such indi-

viduals are said to be atopic (out of place). There 

is usually a family history of other anaphylactoid 

conditions, e.g. hayfever and allergic eczema, 

and positive skin tests to a variety of allergens. 

Both the tendency to produce high levels of IgE 

and the presentation of symptoms are genetic-

ally determined. Many different allergens trigger 

this type of reaction, notably pollens and house 

dust mites. Various classes of drugs also act as 

haptens to induce type I hypersensitivity, e.g. 

penicillins and non-steroidal anti-inflammatory 

drugs (NSAIDs).

Type II: (cytotoxic) hypersensitivity

In   this   type   of   reaction,   antigens   become 

attached to or are part of cell surfaces. Subse-

quently, Igs react with the antigens and activate 

complement,   which   then   causes   cell   lysis. 

Complement components (C3a, C5a) may also attract phagocytes, which are unable to engulf

the  large  cells  of  the  body,  and  so  release enzymes that cause much of the damage. In 

addition,  the  NK (natural  killer)  cells  may 

have a cytotoxic action on tissue cells. NK cells 

belong to a group of lymphocytes that are non-

phagocytic and neither T nor B type, whose 

immunological role is to induce lysis or apop-

tosis (programmed cell death) of virus-infected or 

otherwise abnormal cells, e.g. cells undergoing 

neoplastic change

  If the reaction involves red blood cells (RBCs), 

autoantibodies  directed  against  the  red  cell 

surface may cause a haemolytic anaemia (see 

Chapter 11), possibly due to the binding of a 

foreign molecule to the RBC surface, conferring 

new antigenic properties on it. Methyldopa is well 

known to be likely to cause the formation of 

such  autoantibodies,  which  can  be  detected, 

although a positive test for these does not always 

mean that haemolytic anaemia will occur.

Transfusion reactions

These are one form of type II reaction. All RBCs 

carry A, B or both antigens on their surfaces and 

the  alternative  natural  anti-B  or  anti-A  anti-

bodies are in the plasma. Unusu-

ally for immunological reactions, the Igs against 

blood group antigens are present from birth, 

even though individuals have not been previ-

ously exposed to the foreign blood group, so a 

reaction will occur on a first transfusion. If a type 

A individual were to be transfused with whole 

blood from a type B or type O donor, the anti-A 

antibodies   in   the   donated   blood   would 

haemolyse some of the recipient’s red cells. More 

importantly, all the donor red cells would be 

haemolysed  by  the  anti-B  antibodies  in  the 

much   larger   volume   of   recipient’s   serum. Because the objective of transfusing whole blood 

is to make up for the loss of oxygen-carrying 

capacity in the recipient, this renders the trans-

fusion   ineffective.   Rectification   of   simple 

volume depletion does not require transfusion of 

whole blood unless there is also major loss of red 

cells.

  However, the ABO system is not the only one 

to be considered when matching blood for trans-

fusion. An individual’s Rhesus status and certain 

other antigens are also important. The Rhesus 

system,  first  discovered  in  Rhesus  monkeys, 

depends on three pairs of allelic genes, C and c, 

D and d, E and e, which are inherited as triplets, 

e.g. CDE or cDe, and code for the corresponding 

erythrocyte antigens. However, the ‘d’ antigen 

does not exist, i.e. d is a null gene, and the most 

important   consideration   is   whether   the   D 

antigen is present or absent, giving RhD÷ or 

RhD    groups.   Haemolytic   disease   of   the 

newborn (HDN) occurs when a Rhesus-negative 

(RhD ) mother has a child by a Rhesus-positive 

man. The child will always be Rhesus-positive 

because the D allele is unopposed (and domi-

nant). When the child’s RBCs come in contact 

with the mother’s circulation, as happens during 

birth, the mother will produce anti-RhD anti-

bodies. The child of the first pregnancy will 

usually be unaffected, but in subsequent preg-

nancies  the  mother’s  anti-RhD  Igs  cross  the 

placenta  to  cause  fetal  or  neonatal  red  cell 

destruction in the Rhesus-positive child. If no 

action is taken the fetus is aborted or the child 

stillborn. This may be prevented by the use of an 

antiserum   containing   anti-RhD   antibodies, 

which is administered prophylactically to the 

mother within 72 h of the first birth. This causes 

the  destruction  of  any  Rhesus-positive  fetal 

erythrocytes reaching the mother’s bloodstream 

so that they cannot stimulate the production of 

anti-RhD antibodies in the mother. A subsequent 

pregnancy will then occur normally, similar to a 

first  pregnancy,  but  anti-RhD serum  will  be 

needed after the birth of each child from an 

RhD ÷ father

  When  blood  transfusion  is  necessary,  the 

potential  recipient’s  ABO and  RhD  status  is 

determined. Normally, the patient’s plasma or 

serum is tested against the erythrocytes from two 

or more group O donors. If there is a positive reaction  (10%  of  patients), a  comprehensive 

panel of specific, typed erythrocytes is tested 

against the patient’s plama or serum, to deter-

mine the exact cause of the reaction. Full cross-

matching involves testing the recipient’s serum 

or plasma directly against the selected donor’s 

erythrocytes, looking for IgMs that cause agglu-

tination,  and  an  indirect  Coomb’s  test (see 

Chapter 11),  to  detect  IgGs  that  may  cause 

haemolysis of donor erythrocytes. Occasionally, 

erythrocyte   antigens   of   the   Kell   or   other 

uncommon groups give problems.

  In an emergency, group O RhD   blood can 

be used while the recipient’s blood group is 

determined.

  Organ transplants, of which blood transfu-

sion is a simple form, can also initiate a type II 

reaction.  Antibodies  directed  against  a  trans-

planted organ and pre-existing in the recipient’s 

blood, possibly due to prior blood transfusions, 

may contribute to a hyperacute graft rejection 

almost immediately after transplantation.

Type III: (immune complex) hypersensitivity

When an antigen combines with an antibody an 

immune complex is always formed, which is 

normally   cleared   by   the   reticuloendothelial 

system.    Complement    may    make    small 

complexes   soluble   within   the   bloodstream, 

whereas   the   larger   immune   complexes   are 

removed by phagocytes. Small complexes tend 

to be formed if the antigen is in excess, whereas 

antibody   excess   produces   larger   complexes. 

Under certain circumstances, relating to the size 

and number of these complexes, the clearance 

mechanisms are overwhelmed and circulating 

levels of immune complexes may increase. These 

become trapped in body tissues and often pene-

trate blood vessel walls and attach to the base-

ment membrane that separates the endothelial 

cells from the other tissues of the vessel wall.

Subsequent   complement   activation   causes recruitment and activation of neutrophils which release enzymes that cause collateral damage to the vessel wall and inflammation. In addition, platelets   adhere   to   the   inflamed   site   and initiate the clotting cascade, sometimes causing complete occlusion of smaller vessels A similar situation may occur in the skin if aneventually to a form of irreversible restrictive

antigen is injected intradermally. The resulting 

localized  inflammation,  known  as  an  Arthus 

reaction, reaches its peak after 4-10 h. Its inten-

sity is greatest when antigen and antibody are 

present in approximately equivalent amounts. 

The Arthus reaction is made use of in the skin 

test for tubercular antigens (Mantoux test; see 

below).

In the kidney, antigenic material from strepto-

coccal infections is responsible for some forms 

of  glomerulonephritis (see  Chapter 14),  in 

which  the  immune  complexes  lodge  in  the 

basement membranes of the glomeruli. Immune 

complex  tissue  deposition  is  also  involved  in 

some autoimmune diseases, e.g. systemic lupus 

erythematosus (SLE,  see  Chapter 12)  and 

rheumatoid  arthritis (RA,  see  Chapter 12), 

which explains the multisystem damage seen in 

these conditions.

In the early days of immunotherapy, large 

doses  of  antiserum (antitoxin)  produced  in 

immunized horses were used to treat infections 

such as diphtheria and tetanus. However, horse 

Igs are antigenic in humans and induce antibody 

formation. The resultant immune complex of 

horse antitoxin and human antibody led to the 

development  of  a  systemic  type  III  reaction 

known as serum sickness. Consequently, anti-

sera produced in horses are now used only rarely. 

Instead, human or humanized Igs are used, with 

a much lower risk of an anaphylactoid reaction. 

Human normal immunoglobulin (HNIG), which 

contains a range of Igs, is used to protect non-

immune contacts of patients with hepatitis A, 

measles and rubella. Other specific Igs are also 

used (see above). These carry a far lower risk of 

serum sickness but there is always the possibility 

of transmitting unsuspected viruses, although 

precautions are taken against this.

When antigenic material is inhaled, immune 

complexes may form in the lung alveoli. Thus in 

farmer’s lung and bird fancier’s lung (see Chapter

5) spores from mouldy hay, and feather and bird 

droppings and feather dust respectively, form 

immune complexes with IgGs in the alveoli, 

causing  extrinsic  allergic  alveolitis  with  a 

delayed (about 8 h) allergic type of response 

to antigen inhalation. Repeated episodes lead

airways disease (see Chapter 5).

Type IV: cell-mediated (delayed) hypersensitivity

Antibody production plays the major role in all of  the  three  types  of  hypersensitivity  so  far described. These reactions occur fairly rapidly, often within minutes to a few hours after contact with the antigen.

However, in some manifestations of hypersen-

sitivity, symptoms may not occur for days or 

even weeks after antigenic exposure. This is seen 

quite frequently in allergic contact dermatitis 

(see Chapter 13) where the allergen, such as a 

metal earring or a watch-strap, may have been in 

contact with the skin for some time before any 

inflammation is observed. This type of reaction 

also plays a role in pulmonary TB and leprosy, 

both   caused   by   Mycobacterium  species.   The 

process is similar to that discussed under CMI 

(Figure 2.8). The production of sensitized cyto-

toxic T cells plays a central role, but as they take 

more than 12 h to appear in the bloodstream the 

term delayed hypersensitivity is often used to 

describe this type of reaction. The lymphokines 

released  by  the  sensitized  T  cells  contribute 

directly to the overall tissue damage and recruit 

macrophages, which release lysosomal products 

and enzymes, causing further tissue damage. The 

result is chronic inflammation, often leading to 

the  formation  of  scar  tissue  to  repair  the 

damaged area (p. 56).

TB exemplifies the link between this class of 

hypersensitivity and chronic inflammation. The 

actual tissue damage in the lung and formation 

of the tubercle (a granuloma) are not caused 

directly  by  the  bacteria  but  by  the  body’s 

attempts to deal with it via CMI. In the Mantoux 

test, a purified protein extract of tubercle bacilli 

(tuberculin) is injected intradermally. In individ-

uals previously sensitized to the mycobacterium 

by infection or immunization, a CMI hypersen-

sitivity  reaction  causes  inflammation  at  the 

injection site, the result being read 72 h after 

injection. The induration and red weal some-

times persist for up to a year. Because of this 

hypersensitivity a Mantoux test should always be performed before Bacillus Calmette-Guérin (BCG)  vaccination,  because  immunization  of tuberculin-positive subjects would result in an extensive, deforming, local inflammatory reac-

tion. However, no licensed tuberculin product is currently available in the UK.

Other stimuli eliciting this type of hypersensi-

tivity include insect bites, fungal infections and certain chemical haptens.

Type V: (stimulating/blocking) hypersensitivity

The  mechanism  of  this  is  completely  differ-

ent  from  those  of  the  previous  forms  of 

hyper-sensitivity.  In  the  best-known  example, 

Graves’  disease  (see  Chapter  9),  the  reaction 

is  autoimmune,  IgG  being  raised  against  the 

thyroid-stimulating  hormone (TSH)  receptors 

in  the  thyroid  gland.  The  IgG  has  a  similar 

effect to TSH, stimulating the thyroid cells to 

secreteexcessiveamounts    of    thyroid 

hormones,  resulting  in  hyperthyroidism  and 

causing  the  pathognomonic  sign  of ‘staring 

eyes’ (exophthalmos).  The  latter  is  the  result 

of  inflammation  of  the  oculomotor  muscles, 

caused   by   a   cross-reaction   between   the 

anti-receptor  IgG  and  a  component  in  the 

muscles.

Because  some  bacteria,  e.g.  Escherichia  coli, possess surface structures mimicking the TSH receptor, it is possible that the initiating event is infective.  E.  coli  is  ubiquitous  and  this  may explain why Graves’ disease is the commonest cause of thyrotoxicosis.

In other situations, uptake of Ig on receptors 

may  block  the  normal  response  to  receptor 

activity.

Autoimmune disease

In this most extreme form of maladaptation, the 

body turns its immunological defences against 

its own tissues. This can involve any of the types 

of hypersensitivity reaction described above and 

causes a wide variety of diseases. However, the 

immunopathological mechanisms for many of 

the autoimmune diseases are not well under-

stood, and may involve more than one type of

immune   response.   In   general,   autoimmune diseases may be associated with a number of 

different underlying abnormalities.

Sometimes, as in allergic contact dermatitis 

(see Chapter 13), normal proteins may be altered 

and   rendered   antigenic   by   reaction   with 

haptens.  The  attachment  of  drugs  such  as 

methyldopa to RBCs may induce the formation of 

autoantibodies   by   altering   red   cell   surface 

proteins. Similarly, virus infections may alter the 

expression of surface proteins of the cells they 

infect, leading to a failure of self-recognition, 

although their exact role in autoimmunity is still 

uncertain.    The    autoimmune    haemolytic 

anaemias (see Chapter 11) may be due to hyper-

sensitivity, but the condition often accompanies 

other autoimmune diseases.

If a protein is normally sequestered within a 

cell  or  tissue,  and  thus  not  exposed  to  the 

immune system, it follows that tolerance cannot 

develop and if such cells subsequently encounter 

the immune system, they will be recognized as 

‘non-self’. Spermatozoa are one example, and 

mumps  orchitis  (inflammation  of  the  testes 

caused by the mumps virus) may result in the 

abnormal contact between spermatozoa and the 

immune system, leading to testicular inflamma-

tion and infertility. Similarly, trauma to one eye 

that breaches the circulation sometimes results 

in sympathetic ophthalmitis and destruction 

of the other eye.

Antibodies produced against a pathogen may 

occasionally  cross-react  with  normal  healthy 

tissue.  The  organisms  most  often  associated 

with this type of problem are certain types of 

streptococci, especially in rheumatic fever (see 

Chapters 4 and 12). Although this disease is less 

common since the introduction of penicillin and 

with improved living conditions, the late compli-

cations are still sometimes encountered among 

the  older  population.  The  intense  pain  and 

inflammation of the joints experienced after an 

untreated streptococcal sore throat result from 

the formation of an antibody that is active against 

both  the  organism  and  synovial  membranes. 

Presumably the surface proteins of the strepto-

cocci bear some resemblance to those of certain 

human tissues. A more serious and long-term problem is the damage caused to cardiac tissues by these Igs. The effects on heart valves will even-similar agents are used in severe rheumatoid

tually lead to impairment of cardiac function that may become apparent only in later life.

By  far  the  largest  group  of  autoimmune 

diseases  is  caused  by  a  breakdown  in  self-

tolerance. In many diseases of uncertain aeti-

ology the immune system has failed to recognize 

certain tissues as ‘self’. We have seen that the 

immune  system  normally  distinguishes ‘self’ 

from ‘non-self’ by the nature of the cell surface, 

because surface proteins, principally MHC type I 

molecules (see below), determine a cell’s anti-

genic properties. There are two possible broad 

mechanisms for developing a lack of tolerance: 

the immune system may fail to recognize these 

surface proteins as being ‘self’ or, owing to an 

intrinsic property of the surface proteins, there is 

a tendency for them to become antigenic under 

certain   circumstances.   The   reasons   for   the 

development of autoimmunity in any particular 

disease   are   usually   unknown,   so   they   are 

described as idiopathic. An understanding of 

the  human  leucocyte  antigen (HLA)  system, 

described below, goes some way towards clari-

fying the problem. If failure of self-recognition is 

responsible, subsequent defects in T cell regula-

tion may give rise to an autoimmune reaction, 

e.g. in SLE (see Chapter 12), which is character-

ized by the development of autoantibodies to 

nucleoproteins.

There are other examples in which autoanti-

bodies, possibly resulting from defective T cell 

regulation,  play  a  major  role.  Hashimoto’s 

thyroiditis (see  Chapter 9)  is  a  well-known 

autoimmune  disease  in  which  the  antibodies 

produced   attack   both   thyroid   cells   and 

thyroglobulin,  causing  hypothyroidism(see 

Chapter 9). Similarly, almost all patients with 

pernicious  anaemia  (see  Chapter  11)  possess 

anti-parietal  cell  autoantibodies  and  50%  also 

have antibodies against intrinsic factor.

The role of Igs is less certain in other autoim-

mune diseases. RA is often associated with the 

production   of   IgMs,   known   collectively   as 

rheumatoid  factor. These do not attack the 

synovial membrane directly but combine with 

IgG  to  form  immune  complexes  that  subse-

quently  trigger  the  complement  cascade  and 

cause joint inflammation. The monoclonal anti-

body infliximab, a TNFa  inhibitor, and other

disease (see Chapter 12).

Although inflammatory bowel disease (see 

Chapter 3) and the seronegative arthropathies 

(see Chapter 12) have a possible autoimmune 

aetiology, no autoantibodies have been identi-

fied, although infliximab may also be valuable in 

these conditions, which possess strong associa-

tions   with   certain   HLA   types (see   below). 

Insulin-dependent(Type1)   diabetes(see 

Chapter 9), myasthenia gravis  and multiple 

sclerosis also have an autoimmune basis.

Increasing numbers of diseases are thought to 

involve autoimmunity, and our understanding 

of the mechanisms involved, although imper-

fect, is improving. With greater knowledge of the 

immune mechanisms and the various trigger fac-

tors involved, prophylactic measures and better 

treatments are gradually becoming available.

The Major Histocompatibility Complex and the HLA system

The limiting factor in organ transplantation is 

the phenomenon of rejection. The transplanted 

organ is recognized as ‘non-self’ and the immune 

system is activated to attack it. However, trans-

plantation between identical twins never causes 

rejection, although problems may still arise due 

to   adverse   technical   factors,   e.g.   infection, 

leakage of the donor ureter to recipient bladder 

anastomosis   in   renal   transplantation(see 

Chapter 14). The chances of success are reduced 

in inverse relation to the closeness of the rela-

tionship between donor and recipient. If the 

recipient is a sibling, the success rate may be as 

high as 80-90%, but this falls to 60% or less 

between  unrelated  individuals,  even  though 

strenuous efforts are made to find a suitable 

match. This is because there are surface antigens 

on  the  cells  of  transplanted  organs  that  are 

genetically determined and can be recognized by 

the immune system of the recipient (host) as 

foreign. There must be a finite, but large, variety 

of these groups of antigens because transplants 

between unrelated individuals do not always 

lead to rejection.

These surface antigens are described as histo-

compatibility antigens, determined by the major histocompatibility complex (MHC), a cluster of 

genes found on chromosome 6 in man. These 

specify surface antigen clusters that are unique 

to each individual and are present on all nucle-

ated cells of the body. They are termed human 

leucocyte antigens (HLAs) because they were 

originally discovered on the surfaces of human 

leucocytes,  and  the  antigens  themselves  are 

trans-plasma membrane glycoproteins with the 

physiological  role  of  enabling  the  immune 

system  to  recognize  them  as ‘self’,  thus  not 

mounting an immune reaction against them. All 

nucleated cells possess class I MHC molecules 

(see below); class II molecules are found only on 

B-lymphocytes and APCs.

Unfortunately,   the   terminology   is   rather 

confusing. The MHC complex is composed of 

gene clusters. MHC gene products are the HLA 

antigens. However, MHC molecules are not the 

genes, which would be logical, but are the same 

as HLA antigens. Further, some textbooks refer 

to  HLA  genes,  which  are  synonymous  with 

MHC genes. To avoid confusion with other texts 

the HLA surface antigens are described here as 

MHC  molecules,  which  has  the  widest  use. 

Apart from this usage, MHC refers to genes and 

HLA to antigens in this text.

There are six important MHC gene loci. Any 

individual  may  possess  two  of  a  number  of 

possible gene types (alleles) from each locus, 

each gene expressing a particular MHC mole-

cule. The A, B and C regions code for MHC class 

I molecules and the three D region genes (DP, 

DQ and DR) code for MHC class II molecules. A 

third   region   codes   for   certain   complement 

factors, sometimes referred to as class III mole-

cules. Each gene locus is therefore identified by a 

letter, and the individual alleles within each 

series are given a number, e.g. A1-A41, although 

these numbers are not necessarily consecutive. 

New   genes(and   therefore   antigens)   are 

constantly being discovered and are at first given 

the letter W, e.g. Dw3, to denote that their exis-

tence has yet to be officially recognized. It is also 

common for certain antigens to occur together, a 

phenomenon  known  as  linkage  disequilib-

rium. Thus DR3 and B8 will occur together more 

frequently than might be expected from chance 

alone. Also some types are more common in 

certain races, e.g. A1 is less common in black-

 skinned Africans, and Bw6 is only found in 

mongoloid races.

MHC class I molecules play an important part 

in  the  recognition  of  cells  that  have  been 

affected by viruses, as such cells express viral 

antigens on their surface. These are attacked by T 

cells only in the presence of an MHC molecule, 

possibly because T cell binding sites are not 

occupied by free viral antigens, maximizing the 

T cell potential for attacking infected cells. Class 

II molecules are important in the recognition by 

T cells of antigens taken up by APCs.

The HLA system therefore explains transplant 

rejection and some blood (leucocyte) groups. 

Only transplants between individuals with iden-

tical HLA antigens can be performed without 

recourse to immunosuppressive therapy. A high 

degree of HLA matching, short of identity but 

permitting a good chance of transplant success, 

is likely to occur only between close relatives. 

Most transplants are matched for A, B and DR 

antigens, but a single mismatch, i.e. MHC mole-

cules   not   possessed   by   the   recipient   but 

possessed by the donor, may have to be accepted 

(see Chapter 14).

The link between the HLA system and disease, 

in particular autoimmune disease, has a wider 

significance. Some known associations between 

the occurrence of certain HLA types and various 

diseases are listed in Table 2.6. However, with the 

exception of narcolepsy, this represents only an 

increased risk of developing the disease, e.g. there 

is a strong link between HLA-B27 and ankylosing 

spondylitis (see Chapter 12), and those individ-

uals who carry the B27 gene have a higher risk of 

developing this disease than those without it. 

Whether or not they do so depends on other 

factors,  such  as  contact  with  an  exogenous 

trigger, e.g. infection or a dietary toxin.

HLA antigens are also associated with some 

adverse drug reactions, e.g. HLA DR4 with SLE 

(see Chapter 12) due to hydralazine, a drug that is 

used occasionally for treating hypertension.

Some differences in drug handling are also 

specified  by  autosomal  genes,  i.e.  there  are 

two alternative genes (alleles), one from each 

parent,  coded  for  at  the  same  chromosomal 

locus. The gene for fast  acetylation is domi-

nant  to  that  for  slow  acetylation,  so  slow 

acetylators  are  homozygous  for  the  recessive single cohesive theory has yet to be established. 

It has been suggested that some HLA groups may 

bind antigens more avidly than others, resulting 

in a more intense reaction, or that possession of 

a particular HLA group may involve an increased 

immunological response to a particular antigen. 

It has also been proposed that in some cases 

there may be an inappropriate expression of 

MHC class II molecules on tissues where they are 

not normally found.

Inflammation

Definition

This important pathological process is defined as 

the ‘reaction of the living microcirculation and 

its contents to injury’. The term microcircula-

tion describes the system of small vessels (arteri-

oles,  venules  and  capillaries)  supplying  the 

tissues with blood, within which are the various 

classes of leucocytes important in the inflamma-

tory  process.  The  injury  can  be  any  sort  of 

damage to tissues, i.e. traumatic, heat, radiation, 

immunological or infectious (Figure 2.9).

   The function of an inflammatory reaction is 

to limit and eventually resolve any such injury. 

In  physical  injury,  direct  damage  to  vascular 

tissue  initiates  the  reaction.  Following  infec-

tion,  the  immune  system  is  responsible  for 

detecting the invader and initiating the inflam-matoryprocess, but the growth of microorganisms within  tissues  may  also  cause  some 

physical  damage,  e.g.  necrosis.  Sometimes, 

inappropriate   stimulation   of   the   immune 

system initiates the reaction, as in autoimmune 

disease,  or  hypersensitivity  reactions,  e.g.  to 

pollen  in  hayfever.  An  important  function  of 

the  vascular  responses  in  inflammation  is  to 

facilitate  the  access  of  blood-borne  defence 

mechanisms to the site of injury. In physical 

injury these defences may simply function to 

prevent  blood  loss  by  clotting,  followed  by 

healing  and  repair.  With  infection,  Igs  or  T-

lymphocytes in the blood must gain access to 

enable them to deal with the infection, before 

healing can take place.

Acute inflammation

The  stages  and  processes  involved  in  acute 

inflammation are readily seen if the forearm is 

scratched with some force. Almost immediately, 

a narrow red line will be seen on the skin along 

the line of the scratch. This is quickly followed 

by a more diffuse reddening around the line of 

injury and the red area will later become slightly 

raised. This sequence of events is the Lewis 

triple response, the three components of which 

are flush (central red area), flare (more diffuse 

red area) and weal (raised area). Furthermore, the 

inflamed area is somewhat warmer than the 

surrounding skin and, if the scratch was too 

vigorous, pain will also be experienced. This skin 

reaction displays the four so-called cardinal signs 

of inflammation, i.e. redness, heat, swelling and 

pain, described by Celsus in the first century AD. 

If the injury has been excessive a fifth sign, loss 

of function, may occur. Two important points 

should be noted: the same sequence of events 

occurs no matter what the cause of the injury, 

and the reaction is similar whatever the precise 

nature  of  the  damage  and  which  tissue  is 

involved. However, the nature of any functional 

impairment would clearly depend on the organ 

involved

  The triple response resolves completely in a 

few hours and is therefore a simple example of 

acute  inflammation, the  major  pathological 

features  of  which  are  hyperaemia,  exudation 

and leucocyte migration. If the inflammation is 

inappropriate,  particularly  when  the  cause  is immunological, or the reaction is out of propor-

tion to the damage caused by the stimulus or persists  when  the  stimulus  is  removed,  it 

becomes maladaptive and pathological. Because 

tissue damage plays a large part in many disease 

processes it is not surprising that many diseases 

have  an  underlying  inflammatory  pathology. 

Such  conditions  or  diseases  are  normally 

suffixed with ‘itis’, e.g. dermatitis is inflamma-

tion of the skin, arthritis is inflammation of the 

joints

Hyperaemia

An  essential  function  of  inflammation  is  to 

provide an increased blood flow to the damaged 

area, facilitating the transport of agents involved 

in defence or repair. After a brief reflex vasocon-

striction, and possibly also clotting to minimize 

local bleeding, the local arterioles dilate, flushing 

the capillary network with blood Substance  P  may  be  the  neuropeptide  trans-

mitter released from nerve endings to initiate 

this part of the response. This involvement of 

the  nervous  system  may  partly  explain  the 

emotional link often observed with exacerba-

tions of certain inflammatory conditions, e.g. 

eczema and ulcerative colitis. A more diffuse and 

prolonged  vasodilatation  is  achieved  by  the 

release of chemical mediators. Table 2.2 lists 

some common cytokines and it is clear that their 

effects explain the redness and heat associated 

with inflammation: the rise in local temperature 

is partly the result of an increase in local blood flow and partly of a higher metabolic rate in the inflamed area.

  Exudation

The swelling observed is caused by leakage of 

blood plasma through the vessel wall into the 

tissue  interstitial  space,  causing  oedema . In normal capillaries the 

hydrostatic pressure of the blood forces fluid 

into the interstitial space. This pressure is partly 

offset by the oncotic pressure exerted by plasma 

proteins, which are too large to pass through 

normal capillary walls and so are retained in 

the bloodstream. In inflammation this balance 

is  upset.  Arterial  vasodilatation  results  in  an 

increased   capillary   hydrostatic   pressure   and 

hence an increased volume of interstitial fluid . In addition, the endothelial junctions of the capillary walls become leaky and allow some 

plasma proteins to enter the tissue space, thus 

increasing tissue oncotic pressure and further 

facilitating  the  movement  of  fluid  from  the 

blood to the interstitial space. A more diffuse 

vascular leakage from venules distant from the 

site of injury, adding to the exudate volume, is 

caused by chemical mediators. The exudation, 

which results in tissue swelling, is offset by an 

increase in lymphatic drainage, which returns 

the exudates to the blood via the lymph nodes 

and the lymphatic ducts. However, if micro-

organisms  are  the  inflammatory  trigger,  the 

infection can spread into the lymphatic system 

resulting  in  lymphangitis (inflamed  lymph 

vessels)    and    lymphadenopathy(swollen, 

possibly tender, lymph nodes). A more general account of oedema is given in Chapter 4 and 

Figure 4.9

  Some of the pain experienced in local inflam-

mation  may  also  be  due  to  swelling,  which 

stretches capillary walls and associated nerves

  The increased blood flow to the region and the 

exudation bring antibodies to the site of infec-

tion and dilutes any bacterial or other toxins. 

Exudation may also carry fibrinogen into the 

tissues that, on conversion to insoluble fibrin by 

the action of thrombin, stabilizes any blood clots

  Although blood clotting is essential if physical 

trauma  has  resulted  in  haemorrhage,  fibrin 

deposition in other circumstances may cause 

more  problems  than  it  resolves.  The  initial 

exudate is a clear, cell-free fluid but eventually 

WBCs will appear in the exudate, attracted to the 

site by chemokines, particularly in the presence 

of infection

  Various forms of exudation can occur that may 

have   important   consequences   should   the 

inflammation fail to resolve quickly. The clear 

exudate seen under a blister is known as serous 

exudate, whereas the thick, protein-rich exudate 

from mucous membranes, e.g. a runny nose, is 

termed mucinous. If WBCs enter the exudate, as 

described  below,  it  is  described  as  purulent. 

Often a mixed picture is seen, with microorgan-

isms, leucocytes and damaged tissue fragments 

producing a mucopurulent exudate (pus).

Leucocyte migration

Humoral and cell-mediated immunity are not 

the   only   mechanisms   of   defence   against microorganisms; WBCs of all classes are also 

involved.   The   neutrophils(polymorpho-

nuclear    leucocytes)    are    responsible    for engulfing and digesting microorganisms. These migrate from the bloodstream to the site of 

inflammation ) and are the first to appear in an acutely inflamed area.

  Loss of fluid from the bloodstream as a result 

of exudation increases blood viscosity locally 

and reduces its flow rate. The leucocytes, which 

are normally distributed evenly throughout the 

blood, then tend to collect along the endothe-

lium outside the central axial stream (margina-

tion), where they adhere and, by mechanisms not fully understood, squeeze through the junc-

tions between endothelial cells and enter the 

tissue space. This movement of leucocytes is 

known as diapedesis.

  Leucocytes are attracted to the site of inflam-

mation  by  chemotaxins,  some  of  which  are 

components of the complement system (C3a, 

C5a). Certain bacteria, e.g. staphylococci and 

Klebsiella, also seem to exert a highly chemo-

tactic effect, attracting very large numbers of 

neutrophils to the site of infection. Neutrophils 

then  engulf  and  digest  the  microorganisms, 

particles  of  tissue  debris,  etc.  During  phago-

cytosis,  proteolytic  enzymes  may  be  released 

from the lysosomes within WBCs, causing further 

local damage. After a day or so the number of 

neutrophils falls, to be replaced by macrophages

Systemic inflammation

The preceding discussion has considered exam-

ples of local inflammation. The acute inflamma-

tory response does not normally involve general 

activation of the immune system and is restricted 

to a specific organ or tissue. In systemic inflam-

mation  the  reaction  is  more  widespread  and 

involves stimulation of the immune system. This 

is  seen  especially  if  an  infection  reaches  the 

general circulation, i.e. septicaemia. RA is a good 

example of systemic inflammatory disease: the 

main problem for the patient may be with the 

joints, but there is a general inflammatory process 

involving many other parts of the body remote 

from the affected joints

  The  clinical  features  usually  accompanying systemic inflammation include:

•  a   raised   neutrophil   count(neutrophil leucocytosis)

•  raised body temperature (pyrexia, fever)

•  lethargy and tiredness

•  anaemia, seen especially in the more chronic systemic inflammatory conditions such as RA,SLE and polmyalgia rheumatica

The acute phase response involves the hepatic production of increased   amounts   of   large 

proteins, e.g. fibrinogen, alpha1-antitrypsin , C-reactive protein and serum amyloid-associated protein (SAA) . There is also synthesis of Igs, the shift from normal hepatic protein synthesis of albumin to Igs being mediated by IL-6, activated by IL-1.

  This change in blood proteins causes changes in the physicochemical properties of the RBCs and the plasma, raising the erythrocyte sedimentation rate (ESR). If anticoagulated blood is placed in a glass tube, RBCs tend to clump 

and sediment to the bottom. The greater the clumping  the  faster  the  sedimentation;the length  of  the  column  of  clear  supernatant plasma remaining after 1 h (in mm) gives the ESR, normally 20 mm/h. is therefore a non-specific   sign   of   systemic   inflammation and/or immune stimulation, which can be determined at the bedside if necessary. However, the rate of sedimentation is also affected by the haemoglobin (Hb) concentration, age and sex, being higher in females. An alternative is to measure the plasma viscosity, which is a more direct measure of the concentration of acute phase proteins and can be determined within 15 min of taking the sample..

  An  alternative  to  the  ESR is to measure C- reactive protein (CRP), the level of which is increased by the action of IL-1 on the liver. This is measured by an automated immunoassay and is less affected by variables than the ESR. It rises rapidly,  within  less  than 6h of the onset of fever, inflammation and in trauma, but is less useful  than  the  ESR  for  monitoring  chronic inflammatory conditions.

Inflammatory mediators

The list of chemical mediators believed to be involved in the various stages of inflammation increases inexorably. The following is a brief review.

  Mediators   can   be  classified   according  to whether they are derived from tissue or plasma. The principal tissue-derived mediators are the prostaglandins  (PGs)  and vasoactive amines. Histamine is widely distributed in the body, particularly in specialized white cells resident in tissue called mast cells. Release of preformed histamine from cyto-plasmic. granules in mast cells is important in I hypersensitivity reactions. Platelet activation by platelet activating factor (PAF) causes the release of serotonin, ADP and thromboxane A2 (Tx A2). ADP release causes a conformational in  the  platelet  fibrinogen  receptor, the glycoprotein GPIIb-IIIa complex, enabling platelets to bind to fibrinogen, leading eventually to the formation of a stable fibrin plug. This effect is complemented by the action of TX A2, a potent vasoconstrictor, causing reduced blood flow and reduced blood loss.

  There  are  many  types  of  PGs,  which  are derived  from  the  action  of  cyclo-oxygenase enzyms on arachidonic acid formed from membrane phospholipids.the most important PGs involved in inflammation are PGE2  and PGI2. Together with the throm- boxanes, also derived from arachidonic acid, these constitute the class of mediators known as the acidic lipids.

  A further group of mediators, derived from arachidonic acid via the 5-lipoxygenase pathway, are the leukotrienes (LTs): the previously termed   Slow   Reacting   Substance   of Anaphylaxis (SRSA) is a mixture of LT mediators. Two leukotriene receptor antagonists (LTRAs), montelukast and zafirlukast, have been developed the treatment of asthma.

  The other two major classes of mediators, the vasoactive   polypeptides(e.g.   bradykinins) ) and complement, are both derived from plasma. The complement system ) is most commonly activated by infection. The C3a and C5a fragments seem to be the most active in the inflammatory process, and the C5a. fragment  also  appears  to  initiate  histamine release. The actions of both kinins and histamine are potentiated by PGs.

  There is thus a highly sophisticated system of interactions that enable the body to initiate and maintain   the   inflammatory   reaction   long enough to deal adequately with the origin injury  and  also  to  switch  it  off  when  the response is no longer required. Histamine and serotonin are responsible for the initial reaction, but their effect is short-lived, about 2 h. The reaction is then maintained by the kinins. PGs may extend the reaction still further, although their main role is probably to control the extent and intensity of the process, because certain classes of PGs have been shown to be anti-inflammatory. Lysosomal enzymes released from neutrophils may further help to maintain the reaction. The close links between the inflamma-tory and immunological processes ensure that invading  microorganisms  and  environmental antigens are usually dealt with effectively. The blood clotting/fibrinolytic system also aids in the healing process.

  The relative importance of particular mediators may vary between tissues. Thus, rhinitis and hayfever seem largely, but not entirely, mediated by histamine, but this plays only a minor role in asthma.

  The therapeutic agents employed to modify the inflammatory process usually interfere with the action of the chemical mediators. The anti- histamines have a limited, and in many cases short-lived, activity. Two widely used classes of anti-inflammatory agents act by inhibition of PG production.   These   are   the   corticosteroids, which inhibit the conversion of phospholipids to   arachidonic   acid,   and   the   NSAIDs, which  inhibit  cyclo-oxygenase activity. The corticosteroids are the most potent anti-inflammatory drugs available and are effec- tive in controlling most types of inflammation, although they have a delayed onset of action. The NSAIDs have been used extensively to treat rheumatoid diseases and as analgesics, but are reported to increase the risk of myocardial infarction. At the time of writing the precise role of NSAIDs, one of  the most widely used group of drugs over many years, awaits clarification.

Sequels to inflammation

Acute inflammatory reactions are usually benefi- cial and do not always lead to major medical problems. There may be serious problems when organ function is severely compromised, e.g. in meningitis, hepatitis and asthma, but these reac- tions  also  usually  subside  quickly  and  the inflammation is unlikely to cause permanent damage if the cause is treated promptly. It is the sequels to inflammation, i.e. the resolution and healing processes, which may sometimes cause permanent damage.

Resolution

The most favourable outcome to inflammation would be the complete removal of the causative agent without any residual deleterious effects. However, complete resolution is possible only if there has been very little tissue damage and 

minimal cell death (necrosis). In the examples of a simple triple response or minor skin damage, these criteria are obviously fulfilled.

  If the cause of inflammation is an infection, the offending organism needs to be dealt with 

quickly. Prompt treatment of an infection of a vital organ using antibiotics will prevent inap- propriate resolution (see below) and the poten- tial loss of function of that organ. For example, in kidney infection (pyelonephritis), prompt treatment prevents fibrosis of kidney tubules, renal papillary necrosis and eventual renal failure.

 In addition to elimination of the initial trigger, exudate and dead cells must also be removed promptly, because delay may result in fibrosis. To do this efficiently the inflamed area needs to be well supplied with capillary and lymphatic vessels. In pneumonia (infection and inflamma- tion of the lung alveoli), there  may  be  no  lasting  damage  once  the causative   organism   has   been   dealt   with, providing the initial infection is not too severe. The alveoli themselves have a very good blood supply and any fibrin that has been laid down and  subsequently  dissolved  by  plasmin  can be  readily  removed  via  the  circulation.  The remaining debris is cleared by lung macrophages and the tissue then usually reverts to its normal state. In more serious bacterial infections, or if effective antibiotic treatment is not available, there may be pus formation, necrosis and perma- nent tissue damage, e.g. bronchiectasis, though this is rare nowadays.

  Organization, healing and fibrosis

If there is an excessive amount of exudate that cannot be removed easily, or if a large amount of  necrotic  tissue  is  present,  organization  or ‘healing’ of the damaged tissue may take place. The result may be the formation of scar tissue.

  Exudation carries fibrinogen into the inflamed area where it will eventually be converted into insoluble fibrin. Capillary buds then begin to grow into the area of dead tissue (angiogenesis) and inflammatory debris as part of the healing process, and these further facili- tate the migration of macrophages and fibroblasts into  the  area.  The  fibroblasts  then  lay  down connective fibrous tissue (collagen), which gra- ually replaces the fibrin. This immature fibro- vascular tissue is granulation tissue, and the process  by  which  it  is  formed  is  known  as organization.   The   formation   of   excessive amounts of abnormal connective tissue, leading to the production of scar tissue and impaired tissue or organ function, is the process of fibrosis.

  A good example of this is that when exudate forms in the pleural cavity, e.g. following pneu- monia, it tends to clear slowly, because the blood supply to this area is poor. Consequently, granu- lation tissue may form an adhesion between the two pleural surfaces. The lungs then become less compliant,  making breathing painful  and  difficult,  a  condition  known  as pleurisy. Progressive fibrosis may then lead to severe restrictive lung disease. Adhesions may complicate the healing process in many tissues, e.g.  they  may  cause  considerable  pain  and discomfort if they form following abdominal surgery, because the gut is continually mobile.

  Fibrosis and scarring are important patholog- ical processes in a wide variety of disease states. For example, if scarring occurs in the pyloric sphincter (between the stomach and duodenum) as a result of the chronic inflamma- tion   associated   with   peptic   ulceration, the sphincter may become incompe- tent, allowing large amounts of acid to be lost from the stomach. A further possible complica- tion of fibrosis following peptic ulceration is shrinkage of the scarred area, or cicatrization, causing pyloric stenosis. This can grossly affect the transit of food through the stomach and duodenum.  A  similar  process  may  cause  an oesophageal stricture, leading to problems with swallowing.

  oesophageal stricture, leading to problems with swallowing.Following myocardial infarction, part of the ischaemic area dies and is replaced by scar tissue. 

The  normal  elasticity  and  contractility  of  the myocardium  is  lost,  possibly  leading  to  heart 

failure. Arrhythmias will ensue if the damage is in the conducting tissue of the heart.

  Therefore in a vital organ, such as the heart, brain, kidney or liver, the development of scar tissue may be serious, even fatal in some circum-stances, whereas in others, e.g. a joint, the result will be loss of function

Wound healing

The degree of scarring following organization depends on the extent of previous damage and 

inflammation. This is particularly true of wound healing, which is a special case of organization. 

Although a wound can be inflicted on any tissue, wound healing commonly refers to repair of the 

skin

  Following injury or laceration of the skin, blood vessels are damaged and a clot forms, 

consisting of coagulated blood and other debris, including  microorganisms. The  healing  that 

follows a clean cut, or when the edges have been brought together promptly by suturing or after a 

ragged wound, is similar in all cases. The final difference between these situations is merely 

that a ragged wound produces a larger scar, but the following sequence of events takes place in all of these:

•  Initially, macrophages enter the wound area, to ingest and digest the debris

•  New blood vessels start to grow inwards from the  edges  of  the  wound,  initially  as  solid

cords of cells but soon becoming canalized, allowing blood to flow through them.

•  The ingrowing blood vessels eventually join within   the   wound   forming‘loops   and 

arcades’.

•  The young vessels are leaky, allowing both blood cells and plasma to seep out. This is the 

serous exudate often seen in healing wounds.

•  The   new   capillaries   differentiate   into arterioles and venules.

•  Fibroblasts appear in the serous fluid, and lay 

down connective tissue.

•  This mixture of newly formed blood vessels, connective tissue and serous fluid forms gran-

ulation tissue, usually heralding good wound healing

•  After the laying down of granulation tissue and removal of any remaining debris, the

epithelium   begins   to   regenerate.   This   is achieved by mitosis of the epithelial cells 

surrounding  the  wound,  which  gradually migrate to cover the wound surface.

 If the wound is small, the underlying scar tissue is eventually replaced, merging with surrounding tissues,  but  in  larger  wounds  scarring  may become permanent. Wound healing is indistin-

guishable from the other forms of fibrosis and organization discussed earlier, except that it is visible when it occurs in the skin.

  It has become apparent recently that wound healing is partly under the control of oestrogens. This is not as surprising as it may appear, because there  has  to  be  a  mechanism  of  preventing excessive blood loss and promoting tissue repair following ovulation and menstruation. There is a delicate  balance  in  wound  healing  between an  inflammatory  response,  which  removes tissue debris and minimizes infection, and the deposition of the collagen/proteoglycan matrix that  closes  the  wound  and  underlies  tissue  repair. If inflammation predominates, the pro- inflammatory   cells (neutrophils   and   maco- phages)  that  accumulate  at  the  site  release matrix-dissolving enzymes. It appears that the reaction  of  oestrogen  and  its  ER-beta-receptor (ERb)  inhibits  expression  of  the  cytokine macrophage migration inhibitory factor, so the attraction  of  pro-inflammatory  cells  into  the wound is reduced and matrix production and repair  are  maximized.  If  oestrogen  levels  are low, or the interaction with ERb is impaired, the reverse situation holds. Thus males heal more slowly than females. Giving oestrogen to young , and combined HRT in postmenopausal females, promotes rapid wound healing.however, elderly males are likely to require anti- androgen   treatment.   These   findings   have important implications for the management of  chronic venous ulcers in the elderly.

Suppuration

The bacterium Staphylococcus aureus, implicated in many types of infection in man, is pyogenic(pus-producing). The presence of pus can alsolead to fibrosis and the formation of scar tissue. The most common example of suppuration is seen in boil formation, usually caused by Staph. aureus and related bacteria. Although leucocytes are  attracted  into  the  area  to  deal  with  the organism in the usual way, in this case they are initially largely unsuccessful and die at the site of infection. The creamy pus so formed is a mixture of dead leucocytes, bacteria, lipid, exudate and necrotic tissue. Staph. aureus  also produces a coagulase  that  leads  to  the  formation  of  a ‘capsule’ composed of partially organized coagu- lated plasma which surrounds the area of suppu- ration. This prevents the bacteria from spreading throughout the body, but incidentally prevents the access of antibiotics to the site. Thus anti- biotics, whether systemic or topical, are usually ineffective in treating large boils or abscesses, unless they are first drained surgically. When the infection has eventually cleared, this connective tissue remains and, depending on the size of the boil, scar tissue may be visible and permanent.

Chronic inflammation

The  persistence  of  an  inflammatory  reaction for months or even years implies that its cause has not been removed or that there is a contin- uing  pro-inflammatory  stimulus (see  above). Chronic  inflammation  may  or  may  not  be  preceded  by  an  acute  phase.  By  convention, inflammation  lasting  more  than 6 months  is described as chronic, but this does not imply anything  about  its  severity.  Commonly  acute inflammation  is  the  precursor  of  the  chronic condition, but this progression does not always occur (see below).

Apart  from  its  duration,  two  main  features distinguish chronic from acute inflammation: the leucocytes involved and the occurrence of  fibrosis.

  The   most   important   class   of   leucocyte involved   in   chronic   inflammation   is   the macrophage,    which    soon    replaces    the neutrophils recruited in the early stages of acute inflammation. Macrophages are not only longer- lived than neutrophils, but are also extremely robust. Even if bacteria that have been engulfed by  macrophages  are  not  killed  outright,  the macrophage  itself  may  remain  unharmed or even allow the organism to multiply within the cell, as in TB. In this way a microorganism can persist for years at the site of infection. Further- more, macrophages have the ability to change in character: they can become epithelioid cells, or they can combine to form multinucleate giant cells, both of which are present in granulomas.

  If the reaction is prolonged, healing and repair will often accompany the inflammation, rather than follow it. Thus fibroblasts have an impor- tant role in chronic inflammation, and fibrosis is the main cause of residual damage, as in orga- nization and repair. The laying down of connec- tive tissue may be a lengthy process, with years elapsing before any loss of organ function is noted, as in hepatic cirrhosis. There may also be alternating cycles of inflammation and repair, e.g. in peptic ulcer, and again damage may not be apparent until many cycles have occurred.

Chronic inflammation following acute inflammation

There  is  considerable  overlap  in  the  various sequels  to  inflammation.  If  suppuration  and abscess formation predominate this is sometimes termed  chronic   suppurative   inflammation, whereas the organization and repair (resulting in fibrosis)  described  earlier  is  termed  chronic fibrous inflammation. A further example of chronic suppurative inflammation is encoun- tered following staphylococcal bone infection  (osteomyelitis), in which some bone may be destroyed by the bacteria during the initial acute phase. This necrotic tissue is poorly penetrated by blood, and so protects the surviving bacteria from the body’s defence mechanisms. Thus the infection becomes chronic and large numbers of macrophages and fibroblasts continue to migrate into   the   area,   which   becomes   chronically inflamed.

  Certain other types of tissue seem prone to chronic  inflammatory  changes  following  an acute phase, the classic example being peptic ulceration. Small acute erosions in the duodenum or stomach may be visible after slight trauma, e.g. ingestion of alcohol. It is only if the mucosal protection mechanisms are defi- cient, or if the trauma is prolonged or repeated frequently,  that  a  chronic  sequel  occurs.  The connective tissue subsequently formed results in a weakening of the stomach wall, with the danger of gastric bleeds or even perforation during a subsequent  acute  episode.  Other  parts  of  the gastrointestinal tract can be similarly affected.

  Cholangitis (inflammation of the bile ducts) may result from the presence of bile stones, often precipitated by infection or aggravated by it. If the stones are not removed, repeated episodes of infection  and  possibly  acute  cholestasis may  eventually  lead  to  chronic inflammation and atrophy of the bile ducts.

Chronic inflammation without previous acute inflammation

In both biliary tract disease and peptic ulceration  there is a discernible phase of acute inflamma- tion, and prolongation of the acute phase may eventually lead to chronic changes. However, there is frequently no evidence of an initial acute reaction and inflammation is chronic from the outset. Even in conditions such as RA, where an ‘attack’ exhibits all the signs of acute inflamma- tion, the underlying process is chronic in char- acter, although of variable severity. Sometimes no acute phase is seen but a dense mass of tissue known as a granuloma is often formed, which should be distinguished from the  granulation tissue in wound healing described earlier. A granuloma may be produced by an infection  or  aseptic  foreign  bodies  such  as asbestos, or may be of unknown origin, as in sarcoidosis.

 The   classical   example   of   granulomatous chronic inflammation is tuberculosis . The bacillus is able to survive within macrophages, thus providing a focus for granuloma formation, known in this case as a tubercle.  At  the  centre  of  the  tubercle  is  an area of caseated (‘cheese-like’) necrotic tissue. Surrounding this are epithelioid and giant cells derived  from  macrophages.  The  structure  is enclosed in a layer of T-lymphocytes. Granu- lomas  are  also  seen  in  Crohn’s  disease, sarcoidosis and RA (as rheumatoid nodules).

  Cell-mediated immunity (CMI) is often associ- ated with chronic granulomatous inflammation because of the sensitizing or stimulatory effect that T cells have on macrophages. Because TB invokes a CMI response, it is not surprising that chronic inflammation plays such a large part in its pathology.

Ischaemia

Causes

Ischaemia is a deficiency of blood supply to tissues. If the deficiency is sufficiently severe and prolonged, the tissue eventually dies (necrosis). The most common general cause is a failure of blood flow resulting from obstruction or cardio- vascular insufficiency. Tables 2.8 and 2.9 classify the general causes of ischaemia, with examples of resulting clinical conditions. These various conditions  are  discussed  in  the  appropriate chapters.

  When   arteries   are   chronically   inflamed (arteritis), the artery wall may be permanently damaged  by  the  neutrophil  infiltration  and necrosis. If this involves small arteries, the entire arterial wall is affected and complete occlusion of  the lumen may occur. If a larger artery is affected, only part of the wall may be damaged and blood is still able to pass. Healing subsequently occurs 

with the formation of scar tissue, which may weaken the artery wall and produce an aneurysm 

(bulge) that may eventually rupture .

  A common cause of vascular obstruction is atherosclerosis, which affects 

the intimal lining of the artery wall, particularly in   medium   to   large   arteries.   Atheromatous 

plaques are laid down that partially occlude the lumen and become sites for thrombus formation.  In  contrast,  arteriosclerosis  affects  the 

media of the arterial wall, which becomes hard 

and inelastic. Once again, small arterioles may 

become occluded. The distinction between these 

two conditions is discussed in Chapter 4.

  A thrombus (blood clot) may be formed over 

the site of an atheromatous plaque in an artery. 

Thrombi may also form in large veins, usually in 

the region of valves, owing to stasis of blood. If a 

venous thrombus in the leg (deep-vein throm-

bosis), or a fragment of it, breaks away from its 

site  of  formation,  it  will  travel  downstream 

through veins of increasing diameter, through the heart and into the pulmonary tree, until it 

lodges in a small artery. This obstruction to the 

circulation is known as an embolus, i.e. a clot or 

clot fragment derived from a blood clot formed 

at one site, which lodges in another. Because it is 

often  impossible  to  distinguish  between  an 

embolus and a thrombus, and because it does 

not  affect  treatment,  it  is  usual  to  speak  of 

thromboembolic disease. The site of formation 

of the original clot determines the organ eventu-

ally affected, which may be predicted on the 

basis of the anatomy of the vascular tree. We 

have  just  seen  one  example  of  this,  with 

pulmonary embolism (see Chapter 5), which may result in rapidly fatal respiratory failure if it is sufficiently large. Emboli can also be due to air introduced into the bloodstream inadvertently during IV therapy (air embolus) or may be the result of deep diving, causing nitrogen emboli if the diver rises to the surface too rapidly, causing the divers’ syndrome known as the bends. Fat droplets released from the site of a fracture (fat embolus) do not cause an infarction as such, but can  result  in  a  severe  interruption  of  gas 

exchange if deposited in the lung.

Thrombosis in a coronary artery may itself 

cause a myocardial infarction (see Chapter 4) 

or may throw off an embolus that travels further into  the  coronary  arterial  tree  to  obstruct  a 

smaller vessel and so affect a smaller area of heart muscle. Emboli formed on damaged heart 

valves  can  reach  the  retina,  affecting  sight, 

whereas those resulting from atrial fibrillation 

tend to cause strokes by occluding a cerebral 

artery.

   Small   thromboemboli   are   quite   quickly 

dissolved  by  natural  clot-dissolving  factors 

derived from blood plasminogen (plasmin), red 

cells  and  vessel  walls,  e.g.  tissue-type  plas-

minogen  activator (t-PA;  see  Chapter 11). 

Temporary   interruptions   of   CNS   function, 

known as transient ischaemic attacks (TIAs), 

are common and usually last less than 15 min, 

but  may  persist  for  up  to 24 h.  Circulatory 

brain   obstructions   of  longer   duration   are 

classed  as  strokes.  Acute  MI  is  treated  in  the 

early  stage  with  fibrinolytic (thrombolytic) 

drugs, e.g. alteplase (rt-PA), reteplase, tenectoplase 

and streptokinase, and the latter is also used in 

several other thromboembolic situations. All of 

these  are  unsuitable  for  use  in  early  stroke 

unless it is certain that the stroke has not been 

caused  by  a  cerebral  haemorrhage,  which 

would be exacerbated by clot dissolution.

   Constriction of the vascular smooth muscle 

(vasospasm) may occur in coronary arteries, as 

in  variant  angina (see  Chapter 4),  and  in 

peripheral arteries, causing Raynaud’s disease 

(see Chapter 12).

Poor perfusion of tissue may also arise from 

circulatory insufficiency. If cardiac output is low, 

e.g. because of heart failure or arrhythmia (see 

Chapter 4), the blood supply to many tissues will 

be reduced. This may also occur if the blood 

volume is low, perhaps following severe blood 

loss, causing shock.

Shock

Shock is a syndrome of severely compromised 

peripheral  blood  flow  with  very  low  cardiac 

output and blood pressure. Severe blood loss 

causes a fall in blood pressure and haemor-

rhagic (hypovolaemic) shock. Other forms of 

shock include a sudden fall in cardiac output due 

to  cardiac  damage (cardiogenic  shock;  see 

Chapter 4) and the production of certain bacte-rial endotoxins that cause profound vasodilata-

tion (septic shock).

In  severe  sepsis  causing  shock,  widespread 

clotting results in disseminated intravascular 

coagulation  and  large  amounts  of  clotting 

factors and platelets are consumed. The resultant 

failure of blood clotting may result in haemor-

rhage, an apparently paradoxical situation in 

which widespread clotting gives rise to bleeding, 

which exacerbates the hypotension and shock.

However it is caused, a precipitate fall in blood 

pressure  invokes  homeostatic  mechanisms  to 

conserve blood flow to vital organs such as the 

heart, lungs, kidney and brain, which would be 

irreversibly damaged by even short periods of 

ischaemia. This central conservation may be at 

the expense of other organs or tissues, when 

vasoconstriction, mediated by sympathetic stim-

ulation, diverts blood away from the periphery. 

This restricts blood flow to skeletal muscle, liver, 

skin and intestines, etc. Renal ischaemia may 

cause serious long-term problems.

The clinical features of shock include severe 

hypotension, increased heart rate, cold extremi-

ties and a pale appearance, fever or hypothermia. 

The patient may also feel disorientated and/or 

lose  consciousness.  Respiratory  distress  syn-

drome,  with  breathlessness,  hyperventilation 

and tachypnoea, from stimulation of the respira-

tory centre caused by a metabolic acidosis and 

hypoxaemia,  possibly  central  cyanosis,  may 

further  add  to  the  patient’s  overall  state  of 

distress. The exact combination of signs and 

symptoms will depend on the severity and cause 

of the shock, the degree to which the compen-

satory   mechanisms   have   been   an   effective 

response and the organs most affected.

In severe shock, the patient may present as 

cardiac arrest or collapse. The heart, lungs and brain may eventually succumb to the effects of ischaemia. When coronary perfusion is compro-

mised, cardiac output is further reduced, adding to the vicious cycle of shock.

Other  serious  problems  may  occur  in  the 

lungs, resulting in a dramatic reduction in lung 

function (sometimes called shock lung). This is 

probably caused by changes in the capillaries 

and alveoli resulting from a combination of poor 

perfusion and the consequent release of PGs or 

other mediators. The result is a form of alveolitis

(see Chapter 5), with exudate flooding the airAn inhibitor of TNFa, i.e. adalimumab, etaner-

sacs, causing pulmonary oedema and conges-

tion,  impairing  gas  exchange  and  increasing 

hypoxaemia, which aggravates ischaemia, and 

an increased risk of infection, i.e. pneumonia.

Treatment of shock

The most important initial requirement is imme-

diate resuscitation, i.e. maintain a patent airway 

and restoration of breathing and blood flow. 

Oxygen  and  artificial  respiratory  support  are 

usual.

Blood  and  samples  from  any  identifiable, 

accessible source of infection are required for 

urgent laboratory investigation, and empirical 

antimicrobial   treatment (see   Chapter 8)   is 

commenced until the laboratory results are avail-

able. Careful patient monitoring for early detec-

tion and treatment of abnormalities of acid-base 

balance, cardiac function, blood gases, respira-

tory rate, body temperature, kidney function, 

mental state, etc. and any infection.

Infusion of colloid solutions, e.g. polygelatin, 

hydroxyethyl starch or dextran, is required to 

restore cardiac preload and so effective heart 

action (see Chapter 4). This also corrects fluid 

loss  in  haemorrhage.  Some  clinicians  prefer 

simple crystalloid infusions. Volume replenish-

ment is often followed by the use of inotropes 

and vasopressors, e.g. dopamine  infusion, plus 

adrenaline  if   hypotension   persists,   to   give 

bridging support until the patient is stabilized.

The associated loss of RBCs is best managed 

with oxygen and respiratory support, but if the 

Hb level is very low, whole blood transfusion is 

indicated.

Transfusion of whole blood is expensive and 

the correct blood group may not be available in 

an emergency. Further, stored blood is deficient 

in   platelets,   calcium   and   oxygen-carrying 

capacity,   and   is   hyperkalaemic.   In   normo-

volaemic patients, whole blood transfusion will 

lead to fluid overload, increased blood viscosity 

and hypertension, especially in the elderly. The 

best strategy seems to be the careful use of a 

colloid solution for any fluid replacement and of 

packed red cells to give a slightly lower than 

normal packed cell volume. Platelets are required 

in haemorrhagic states.

cept  or infliximab  (see Chapter  12), has been 

shown to give some benefit and inhibition of 

other pro-inflammatory agents may also help. 

Activated protein C, which is involved in the 

clotting cascade (see Chapter 11), significantly 

improves survival.

Shock, especially due to sepsis, high blood loss and myocardial damage has a high mortality.

Effects of ischaemia on body tissues

It will now be clear that the significance of local 

ischaemia  will  depend  on  the  physiological 

importance of the organ affected and the extent 

of the damage caused. Provided that blood flow 

is not completely obstructed, the tissue may 

survive, although its function may be compro-

mised. When the blood supply is so reduced that 

necrosis occurs, permanent damage or failure of 

the organ results. An area of necrosis of an organ 

resulting from ischaemia is termed an infarct, 

which may occur in almost any organ or tissue. 

The extent of ischaemic damage depends on a 

number of factors. Highly vascular tissues and 

those that can draw blood from other sites may 

have, or can develop, a collateral blood supply, 

which bypasses the obstruction, and so survive 

periods of ischaemia more readily than poorly 

vascularized ones. Extensive damage results if a 

major vessel is obstructed or if the obstruction is 

of long duration.

Furthermore, some tissues are more sensitive 

to the effects of hypoxia, e.g. the brain and 

kidney, and  others have  a limited ability to 

regenerate  after  infarction.  Highly  integrated 

organs, e.g. the heart and brain, may lose their 

ability to function properly, even if only partially 

damaged. An infarcted area, e.g. in the feet, has 

a poor blood supply and the resultant inability 

to mount a local immunological or phagocytic 

response may result in the tissue necrosis known 

as gangrene, which may or may not be exacer-

bated by infection, especially anaerobes. How 

these factors apply to various organs and the 

clinical consequences of hypoxia and infarction 

are shown in Tables 2.8 and 2.9.

Ischaemia in any muscle results in anaerobic 

metabolism  to  maintain  energy  supply.  The lactic and other hydroxyacids so formed lead to 

the symptoms of cramp, and angina pectoris 

can be considered to be a form of myocardial 

cramp. For the reasons listed in Table 2.9, periods 

of hypoxia in skeletal muscle are unlikely to 

result in any serious permanent damage. The 

opposite is true of the myocardium where, if the 

patient survives the initial event, formation of 

scar tissue can result in arrhythmias and conges-

tive heart failure (see Chapter 4). However, the 

general clinical effects of a poor peripheral circu-

lation are reduced wound healing and the persis-

tence of infections. In extreme circumstances 

this can lead to gangrene and loss of digits or 

even limbs, as in diabetes mellitus, in which 

abnormal lipid metabolism ultimately affects the 

circulation severely.

Obstruction of pulmonary arteries will not 

necessarily   lead   to   infarction,   but   a   large embolus may occasionally obstruct blood flow to a large area of lung tissue and greatly compro-

mise lung function.

The brain is particularly sensitive to a reduc-

tion in blood flow and hypoxia because it has 

no  reserves  of  either  oxygen  or  glucose. 

Fainting (syncope),  resulting  from  temporary 

cerebral hypoxia, is often remedied by simply 

placing  the  head  between  the  knees  or  lying 

down  with  the  legs  raised  to  increase  blood 

flow  to  the  head.  Unfortunately,  the  conse-

quences of a cerebral infarct cannot be as easily 

resolved  because  nerve  cells  have  very  little 

capacity  for  regeneration.  Thus  necrosis  can 

occur  after  only 5 min  of  hypoxia  and  even 

small  infarcts  (strokes)  can  cause  paralysis  or 

permanent cognitive impairment.

We have noted that the kidney is also very 

sensitive  to  ischaemia  and  both  acute  and 

chronic  renal  ischaemia  can  lead  to  renal

failure.  Furthermore,  any  reduction  in  blood 

flow  to  the  kidney  will  tend  to  activate  the 

renin/  angiotensin  system,  resulting  in  renal 

vasoconstriction  and  further  ischaemia (see 

Chapter 14).

The treatment of thromboembolic disease, e.g. 

myocardial infarction, is dealt with in Chapters

4 and 11 and that of pulmonary embolism in 

Chapter 5. Anti-inflammatory drugs are covered in Chapters 5 (asthma, etc.), 12 (arthritis, etc.) and 13 (eczema, psoriasis, etc.).