Basic Immunology for ICU3

Immunology will be studied in greater depth later in your medical course, however you should be aware that the gut forms a major part of the immune system and there are auto-immune aspects to several important GI tract diseases. These include type 1 diabetes, coeliac disease, Crohn's disease (and IBD in general), pernicious anaemia, thyroid diseases and primary biliary cirrhosis (PBC), which is not the same as 'ordinary' alcoholic cirrhosis. You only need basic immunology for ICU3, but this section may tie up some of the loose ends which might otherwise be bothering you. One or more of the following books may be useful. There is an enormous overlap between them, and at this stage it would not be appropriate to memorise the immense detail in these comprehensive accounts:

• Burkitt et al Wheater's Functional Histology 4th edn. Churchill Livingstone; 2001 [chapter 11]
• Chapel et al Essentials of Clinical Immunology 4th edn. Blackwell; 1999 (website)
• Janeway et al Immunobiology 5th edn. Current Biology Publications; 2001 Highly recommended!
• Kumar & Clark Clinical Medicine 4th edn. Saunders; 1998 [see pages 153, 160 - 187]

• normal responses to trauma and infection

• the immune system protects the body against infection
• the immune system is tolerant to self, and many common antigens
• distinguish between cell-mediated immunity and humoral immunity
• distinguish between innate immunity and adaptive immunity
• cytokines & chemokines produce inflammation, fever and cachexia
• primary and secondary responses to infection



• basic anatomy and histology of the immune system

• main locations of lymphoid tissue in the body
• principal cell types in the immune system (outline only)
• immune cells circulate between tissues in their search for antigens
• immune cells enter and leave the vascular system using diapedesis and / or HEV



• killing invaders

• defensive techniques depend on the size of the invader
• for subcellular pathogens we swiftly kill the infected cells
• for foreign cells we use antibodies, phagocytosis and complement
• for multicellular parasites we use eosinophils and immunoglobulin E



• antigen presentation by host cells

• viable cells advertise their internal activities
• class I MHC display peptides from cytosolic proteins
• class II MHC display fragments from phagocytosed material
• most cells express class I, myeloid antigen presenting cells also have class II



• cell mediated immunity

• T lymphocytes normally mature in the thymus gland
• self-reactive T cell clones are eliminated by apoptosis
• Tc cells recognise "foreign" peptides bound to MHC I
• cytotoxic Tc cells kill virus-infected cells and tumour cells
• most Tc cells express the CD8 protein which assists MHC I binding
• non-B, non-T natural killer (NK) cells eliminate most cells lacking MHC



• cytokines & chemokines

• helper Th lymphocytes work by releasing cytokines
• Th cells recognise "foreign" peptides bound to MHC II
• most Th cells express the CD4 protein which assists MHC II binding
• Th1 cells activate macrophages and mediate an inflammatory response
• Th2 cells activate B lymphocytes and stimulate a humoral antibody response
• cytokines may induce fever, cachexia, cell killing and the acute phase response
• many other cell types secrete a huge variety of cytokines, with wide-ranging effects



• humoral immunity

• new B cells are produced continuously and mature in the bone marrow
• new B cells express a unique antibody variant bound to their plasmalemma
• new B cells cannot grow without Th2 cells that recognise the same antigen
• most B cells are failures and die after 48 hours as a result of apoptosis
• successful B cell lines found a clone of antibody-secreting plasma cells
• the antibody response improves with time as a result of somatic mutations
• recognise the basic structures of different antibody molecules as cartoons



• apoptosis

• unwanted cells are normally removed by apoptosis
• apoptosis is programmed cell death - contrast with necrosis
• there are multiple signalling methods that can trigger apoptosis
• perforins, granzymes, FAS-ligand and free radicals are effective triggers
• the apoptotic signalling cascade may involve cytochrome c release from mitochondria
• caspases are cysteine proteases cutting at aspartic acid residues that mediate apoptosis
• the final result is DNA fragmentation and the orderly dissolution of the unwanted cell



• allergy and auto-immunity

• allergic and auto-immune diseases are common in the population
• there is often an inflammatory response against self-antigens
• disease many involve loss of tolerance for foods and gut comensals
• common allergic and auto-immune diseases include thyroiditis, type 1 diabetes, rheumatoid arthritis, coeliac disease, inflammatory bowel disease, primary biliary cirrhosis and many more

The function of the immune system is to protect the body from invasion. Immune cells recognise and remove foreign antigens (mainly proteins and carbohydrates) derived from other organisms, while tolerating very similar substances specified by the host genome. The distinction is normally precise: the body can often detect a single amino acid substitution, but the system is not perfect and mistakes can give rise to serious disease.

In addition to self-tolerance, the immune system commonly ignores harmless antigens present in the environment, such as foods and gut comensals, although it may react strongly if these substances are administered by a different route.

The immune response normally includes both cell-mediated immunity and humoral immunity. Cell-mediated immunity involves the direct killing and / or swallowing of infected host cells and pathogens by immune cells, whereas humoral immunity involves the production of soluble antibody proteins which circulate in the blood, and are secreted into other body fluids.

Some compounds (such as the repeating polysaccharide units in bacterial cell walls) are immediately recognised as foreign and attacked without delay. This innate immunity is particularly important after traumatic injuries. Cytokines & chemokines [see below] secreted by the first arrivals attract other immune cells to the site of the infection.

Cytokines & chemokines produced during an immune response give rise to inflammation, fever and cachexia. Inflammation involves vascular changes which allow immune cells better access to the infected tissue. This produces local pain, redness and swelling and a rise in overall body temperature which helps to combat infection. In addition, cytokines modify eating behaviour and metabolism, producing 'cachexia' which is the loss of appetite and tissue wasting often associated with trauma, cancer and other serious diseases.

The adaptive immune response takes several days to develop, and may depend on the route whereby antigen enters the body. The immune system can remember strong antigens for many years, and this is the basis for immunisation. Repeated exposure to the same antigen subsequently gives rise to a much more rapid and extensive response.

The white blood cells of the adult immune system are constantly replenished from haemopoietic stem cells in the bone marrow. Many of their nucleated daughter cells have relatively short lives, and eventually undergo apoptosis or programmed cell death. A few memory cells survive for long periods. Megakaryocytes (which give rise to platelets) and erythroid cells (generating red blood cells) also develop from the same precursors.

The stem cells give rise to two families of white blood cells: the myeloid cells (named after bone marrow) and the lymphoid cells, which take their name from the lymphatic system. Both families of leukocyte normally leave the bone marrow and enter other tissues through the high endothelial venules, or HEV. These specialised regions of the blood vessel wall have a distinctive 'cuboidal' endothelium that regulates leukocyte migration. See figure 11.15 in Wheater's Functional Histology, or sweep over the photograph with your mouse to see the endothelial cells and lymphocytes.

Myeloid cells include basophils, eosinophils, neutrophils, and monocytes (which give rise to macrophages). Neutrophils (also called polymorphs) are the most common. Click here for an extended account, or study chapter 3 in Wheater's Functional Histology. An important function of myeloid cells is to engulf and digest (phagocytose) a wide range of materials, including substances derived from the host. Some of these cells "present" significant fragments from the partially digested materials to selected lymphoid cells as part of an elaborate mechanism that distinguishes between self and non-self.

Lymphoid cells include the antibody-producing B cells which differentiate initially within the bone marrow, and T cells which complete their maturation in the thymus.

Other products of the pluripotent stem cell line include histamine-rich mast cells (click here for a picture, or see "Wheater" figure 4.14) which play an important role in the inflammatory response, and natural killer (NK) cells which recognise and kill some tumours and virus-infected cells.

The smallest viruses are less than 30nm in diameter (compare with ribosomes at 20nm) whereas nematode parasites could be over one million times larger. It would be amazing if one size of weapon fitted all. In fact we have evolved a variety of defensive measures, each one appropriate to the size of the invader.

Although it is possible to produce neutralising antibodies against viral infections, the most effective technique is simply to kill all the infected cells before the virus is able to replicate. It takes several hours to copy and re-package the viral nucleic acid inside mammalian cells, and during this period infected cells advertise their nefarious activities using MHC proteins [see below] on their plasmalemma. Specialised T-lymphocytes recognise this situation and swiftly kill the infected cells before the virus has had chance to spread.

Most antibodies have multiple binding sites for foreign molecules, and work at the most basic level by glueing the invaders together. It is more effective, however, to coat and mark the foreign cells with antibody ["opsonisation"] so that they become particularly attractive to macrophages. This antibody coating leads to phagocytosis and complement activation, which are the most effective killing techniques against unicellular invaders.

Macrophages and related phagocytic cells have surface receptors that can recognise foreign bodies, especially when these are already coated with antibody molecules. The phagocyte plasmalemma flows around the invader, until it is enclosed within a digestive vacuole. A characterstic burst of respiration is observed as the macrophage secretes an unwholesome cocktail of halogens, peroxides, superoxide and assorted free radicals into the vacuole. This lethal mixture bears a more than passing resemblance to domestic bleach.

The technique is simply to burn holes in the bacterial cell wall, rather than rely on precision engineering with digestive enzymes. It is easy to see a reason for this: prokaryotes and protozoa grow and evolve much more quickly than multicellular organisms, and would inevitably win a chemical arms race based on enzymes versus inhibitors. On the other hand our cells are usually bigger, with thicker armour and more powerful pumps. Most bacteria have no answer to bleach, and our ancestors have used it successfully for the last 2,000,000,000 years.

Our second major killing technique has also evolved to resist bacterial and protozoal counter measures. The complement system is an elaborate cascade of serum proteases and inhibitors whose objective is to assemble a functional "membrane attack complex" on the surface of the invading cell. Once activated, the system punches massive holes in the pathogen's cell wall, disrupting vital transmembrane gradients and killing the invader.

The complement system relies on a hair trigger where attacks are constantly initiated only to be aborted at the last moment. Our problem is to prevent these heavy weapons going off prematurely, or attacking the wrong kind of cells. Identification of the correct targets by the complement system relies partly on specific antigen-antibody complexes, and also on non-specific innate immunity provided by mannan binding protein, and other proteins that recognise fundamental features of the bacterial cell wall.

Yet another defensive system is employed against multicellular parasites, such as nematode worms and flukes. These parasites are recognised and tagged using the monovalent immunoglobulin E (IgE) which is mostly bound to host cell surfaces. The actual killing relies on toxic proteins secreted by eosinophils, which disrupt the outer membranes of the parasites. Unfortunately these same proteins are also toxic to our own cells, and play a major role in allergy and hypersensitivity.

All cells that are capable of protein turnover (this excludes red cells) degrade samples of their protein stock using cytosolic proteasomes and display peptide fragments of 8-12 amino acids bound to Class I MHC proteins on their cell surface. This external advertisement is used by the immune system to police intracellular processes throughout the body, and in particular to check for virus infection. MHC stands for major histocompatibility complex, a group of genes that were mapped by transplantation experiments using inbred strains of mice. In humans the homologous genes are known as the HLA (human leukocyte antigen) system.

Myeloid antigen-presenting cells (APCs) phagocytose bacteria and other debris, and partially digest this material in phago-lysosomes to generate peptides containing about 15 amino acids. They display some of these fragments on their cell surface, bound to Class II MHC proteins.

The essential difference between these two routes is that Class I MHCs are loaded with internally-derived peptides soon after synthesis in the endoplasmic reticulum, whereas Class II MHCs are loaded with externally-derived fragments within the phago-lysosomal compartment. Proteasomes are very large multi-enzyme complexes in the cytosol, which are responsible for the orderly degradation of surplus, damaged or mis-folded proteins. The resulting peptide fragments are actively transported into the lumen of the endoplasmic reticulum by the TAP transporter in an energy-requiring process.

The structure was reported by Reid et al in 1996. [Protein Data Bank code 1AGB.] Click HERE for a brief reminder of the main CHIME commands, or HERE for a full tutorial.

The peptides displayed by both types of MHC proteins are inspected by T cells, which have antigen receptors on their plasmalemma. T cell antigen receptors recognise the combined peptide + MHC complex and are therefore specific for either Class I or Class II MHC proteins. These T lymphocytes can be subdivided into "helper" Th cells and "cytotoxic" Tc cells.

Helper T lymphocytes normally bear a CD4 surface protein. They recognise peptides bound to Class II MHC molecules, usually on myeloid APCs, but they also recognise peptides displayed by B cells as explained below. Human immunodeficiency virus exploits the CD4 protein to infect and destroy these cells during the development of AIDS.

Cytotoxic T lymphocytes usually bear a CD8 surface protein. They kill any cells that display foreign peptides bound to Class I MHC molecules. This cell-mediated immunity eliminates some tumours and many virus-infected cells, before the virus can infect other cells. Herpes viruses evade detection by down-regulating MHC gene expression, making themselves invisible. Natural killer cells normally ignore cells bearing MHC proteins, so they recognise this unusual situation, and kill the virus-infected cells.

At least three separate killing methods are used by cytotoxic cells: (1) degranulation, (2) Fas ligand, (3) tumour necrosis factor [TNFa] and lymphotoxin [TNFb]. Degranulation involves the release of serine proteases called "granzymes" and perforin subunits from cytoplasmic granules in the cytotoxic cell. The target cells take up the proteases into temporary storage vesicles by receptor-mediated endocytosis. Perforin is a protein that is related to component C9 in the complement system. Like complement, perforin self-assembles when exposed to extracellular calcium concentrations and punches holes in the membranes of target cells. It is necessary for the release of vesicular granzymes into the target cell cytoplasm. Fas ligand is a protein exposed on the surface of activated CD4+ and CD8+ cells that binds to Fas receptors in the target cell plasmalemma. This triggers apoptosis of the target cell [see below]. TNFa is a soluble cytokine that kills some tumour cells and also plays a major role in some inflammatory complaints, such as Crohn’s disease and rheumatoid arthritis.

The HLA / MHC loci are highly polymorphic and hundreds of protein isoforms coexist within a breeding population. These differ in the type of peptide they most efficiently display. We inherit 3 major Class I HLA genes and 16 Class II genes from each parent. The parental copies probably differ and all are expressed. Diversity ensures that a species as a whole can resist the widest range of pathogens, although individuals might be susceptible to particular parasites which display badly on their APCs. Mice can apparently recognise individuals expressing particular MHC variants by smell, and prefer sexual partners that will maximise the immune diversity of their offspring. There is dispute as to whether humans have a similar ability.

Individual T cells recognise only a narrow range of antigen fragments displayed by APCs and most T cells have different [unique] receptors for the antigen / HLA complex. This variability is generated by error-prone somatic recombination involving the DNA within each T cell nucleus as these cells differentiate. The mechanism generating receptor diversity in T cells is a simpler version of the system used to generate antibody diversity in B cells [see below]. The recognition of an APC peptide - MHC complex by a T cell antigen receptor initiates an extremely complex transmembrane signalling system. This normally leads to the proliferation of those T cell clones which efficiently detect particular foreign antigens bound to MHC and the suppression of any T cell clones which recognise "self".

Cytokines are proteins made by cells that affect the behaviour of other cells. This definition is very broad (and should in theory include all the peptide hormones) so it is no surprise that there are already dozens of them, with more discovered every year. Chemokines are low molecular weight cytokines that are particularly involved in lymphocyte chemotaxis towards a focus of infection. The opportunities for confusion are enormous: each cytokine affects several different types of cell, most types of cell produce multiple cytokines, and several different kinds of cell may produce the same cytokine. It is neither practicable nor desirable for students to learn them all by rote, so we have tabulated a few of the most clinically important ones that we think you should know:

Note: Interleukin-1 comes in two flavours IL-1a and IL-1b which are apparently the products of different genes, but with very similar actions. There is also a natural inhibitor IL-1 RA which binds to IL-1 receptors but does not activate them.

IL-1 released by macrophages acts on the hypothalamus to raise the setting of the body thermostat, producing the fever associated with infectious disease. It also promotes the synthesis of corticotropin releasing hormone (CRH) and hence indirectly ACTH and corticosteroids. This forms part of a negative feedback loop autoregulating immune system activity, because corticosteroids ultimately have an immunosuppressant effect.

IL-6 acts on the liver and initiates the acute phase response. This is an early stereotyped reaction to major trauma and infection which puts the body on a "war footing" before the nature of the threat has been properly identified. The liver synthesises increased amounts of acute phase proteins (C-reactive protein, mannan binding lectin and others) which are reasonably effective against a broad range of microorganisms although they lack individual specificity.

There is considerable overlap between the actions of the individual cytokines, so that many of the above effects are shared between TNFa, IL-1 and IL-6. In addition these pro-inflammatory cytokines activate the immune system, mobilising neutrophils from bone marrow, causing dendritic cells to migrate to lymph nodes, and also initiating changes in adipocyte and muscle metabolism to facilitate the febrile response.

Chemokines are low molecular weight cytokines that are particularly involved in attracting lymphocytes and phagocytic cells towards a focus of infection. They are important mediators of the inflammatory response.

All antibodies are derived from "Y" shaped glycoprotein molecules, with two identical antigen binding sites that contain two heavy polypeptide chains and two light chains linked by disulphide bridges. Most of the amino acid sequence is the same in all human antibody molecules, but the light chains and the heavy chains both contain variable regions where the sequence differs extensively in different antibodies and confers the antigen binding specificity. These protein components are arranged in different ways in the different classes of antibody molecule IgM, IgG, IgE and IgA [see below].

As each B cell differentiates, a carefully regulated sequence of somatic recombination events in the nuclear DNA eventually results in the expression of a randomly selected heavy chain variant associated with a randomly selected light chain variant. Multiple copies of this newly designed protein molecule are displayed on the outer surface of the B cell. The number of possible antibody variants is vastly greater than the total number of B cells produced during the lifetime of the animal, so every emerging B cell initially bears a novel antibody attached to its plasmalemma by the constant Fc region of the antibody molecule.

In the vast majority of cases these newly expressed antibodies serve no useful purpose. After about 48 hours struttin' their stuff around the lymphatic system, worthless B cells undergo apoptosis, to be replaced by other hopefuls from the same precursor line.

A tiny minority of new B cells bear useful antibodies that bind to foreign antigens within the body. Matching B cells respond to strong polymeric antigens (such as bacterial cell walls) without assistance, but they need help from T cells to respond to proteins. Bound antigens are internalised by B cells and degraded within the phagolysosomal compartment. Some peptide fragments are displayed on the B cell surface, using Class II MHC proteins. If a helper T cell (bearing a unique antigen receptor variant) recognises this processed antigen, a productive exchange of information occurs between the two cell types.

This message-passing usually results in B cell activation. Auto-immune B cells cannot find a helper T cell and normally die. Activated B cells undergo further differentiation and cell division in germinal centres within the lymph nodes to found a clone of antibody-secreting cells. The first antibody produced is immunoglobulin-M (IgM), which is a pentameric molecule with a central connecting piece and ten antigen binding sites. Further development leads to the formation of plasma cells that secrete large amounts of IgG into the bloodstream. The electron micrograph below shows the extensive rough endoplasmic reticulum in these cells. Most plasma cells undergo apoptosis when their task is done, but a small proportion persist as memory cells, that will accelerate the immune response should the same antigen be encountered in the future.

IgG closely resembles the original divalent antibody molecule exposed on the surface of the naive B cell, minus its membrane attachment site. The antibody secreted into the lungs and GI tract is mostly IgA with four antigen binding sites. IgM has ten antigen binding sites. This is convenient because the individual binding sites on this early immature product often have a lower antigen affinity than the later versions.

The J chain is an additional cysteine-rich polypeptide, which is recognised by mucosal epithelial cells and facilitates the secretion of IgA into the gut lumen, saliva, lungs, sweat, milk and genito-urinary tract.

The B cell activation process is hedged around with safeguards, to eliminate (so far as possible) any auto-antibodies that cross-react with "self". There is always a risk that this might happen, because proliferating B cell clones undergo further genetic re-arrangements that improve their performance if their first antibodies show promise. Less effective clones are removed by apoptosis. Some cells within the immune system retain a memory for every self-antigen that was present before birth, and normally there are mechanisms that eliminate or neutralise any B cell which shows signs of auto-immunity. Should these safeguards fail serious diseases will almost certainly result.

The exact route of antigen entry affects the immune response. Subcutaneous injections are most likely to result in the production of soluble antibodies, whereas feeding or intravenous injections are more likely to result in immune tolerance.

The enormous range of antigens present within the gut are processed via Peyer’s patches in the lamina propria and the mucosa-associated lymphoid tissue, or MALT, which contains about 70% of the body's lymphoid cells. On the whole, this system is remarkably effective at responding selectively to invading pathogens, while tolerating a much larger number of harmless food antigens, and commensal organisms. It isn’t perfect, as illustrated by the frequency of gut infection, food allergy and autoimmune disease affecting the GI tract.

Peyer’s patches are devoid of villi, and migratory M cells concentrated within the surface epithelium allow the selective uptake of food antigens and micro-organisms. These are processed and presented to the gut lymphocytes, which proliferate in germinal centres within the patch. Lymphocytes circulate between the MALT and the bloodstream, leaving the circulation via the high endothelial venules and draining from the tissue via the lymph ducts and the abdominal lymph nodes to re-enter the circulation via the thoracic duct and the left subclavian vein. The circulation rate is 1-2% per hour. This maximises the opportunities for contact between a novel antigen and those very rare nascent B and T lymphocytes that are able to bind and ultimately neutralise the new invader.

Apoptosis or programmed cell death is used throughout the body remove damaged, unwanted or virus-infected cells. It is employed extensively within the immune system to select the most useful clones. It also plays a major role in embryology, pathology and in cancer chemotherapy. (These references are included for general interest, to illustrate the current direction of research activity. You don't need all this detail for ICU3!) In otherwise healthy cells apoptosis is commonly provoked by the binding of Fas ligand or TNFa to cell surface receptors, but other triggers include granule release by cytotoxic cells, free-radical damage to cell components, or irreparable damage to the DNA.

Intracellular apoptotic signalling exploits amplifying cascades of cysteine proteases called caspases that activate their protein substrates by cleaving them after aspartate residues. A major event in some of these signalling pathways is the mitochondrial permeability transition, which creates holes in the mitochondrial membranes, preventing ATP synthesis and releasing cytochrome c into the cytosol, where it activates the later stages of the process. The ultimate result is fragmentation of the DNA and the orderly dissolution of the cell.

PARP stands for poly(ADP-ribose) polymerase, an enzyme which ADP-ribosylates a wide variety of nuclear proteins, using NAD as the ADP-ribosyl donor. (You will encounter this curious process in other parts of the cell when you study the actions of cholera and diphtheria toxins on mammalian cells.) Nuclear ADP-ribosylation is strongly induced by the presence of DNA strand breaks. It plays a role in DNA repair and the recovery of cells from moderate DNA damage. Inactivation of PARP implies that the cell has "given up" on DNA repair, and the cellular machinery now regards death as inevitable.

The life or death decision depends on a continuously shifting balance between pro- and anti-apoptotic factors. Radiation and cytotoxic drugs are effective against susceptible tumours because these cells are already teetering on the brink of self-destruction, and the slightest push will tilt the balance. The proto-oncogene Bcl-2 is an anti-apoptotic gene whose protein product inhibits the mitochondrial permeability transition. It is named after B cell lymphomas, which are tumours of the MALT tissue in the small intestine where redundant B cells fail to die at the appropriate time.

There is cross-talk between the different pathways, so (for example) granzymes and caspase 8 can both activate the mitochondrial route, and are consequently subject to modulation by Bcl-2. Once triggered, apoptosis is auto-catalytic because activated caspase 3 can itself activate caspase 8, which can in turn initiate the mitochondrial permeability transition and the release of cytochrome c. The cross-talk and positive feedback normally ensures a clear decision on whether each cell will live or die.

There is an excellent brief review of apoptosis by Bleackley & Heibein (2001) Natural Product Reports 18(4): 431-440. This article is available electronically, but only through the University campus network. Click here for the HTML version or here for the PDF. Masochistic students may prefer the somewhat longer article by Strasser et al (2000) Annual Review of Biochemistry 69, 217-245 which is also available as a PDF.

The function of the immune system is to protect the body against invading pathogens, but patients sometimes mount an inappropriate immune response against harmless antigens from their environment, or even against their own tissues, by mistake. Such errors may give rise to serious disease: to allergy and hypersensitivity in the first case, and to auto-immune disorders in the second.

Students will encounter the following nine diseases elsewhere in ICU3, when we study the relevant parts of the gut and the endocrine system. They are gathered together here to emphasise their common features, which arise from the involvement of the immune system, and their association with particular HLA genotypes. Women are much more commonly affected than men, and it is hypothesised that this may be due to immunisation with foetal cells during pregnancy and childbirth.

More information may be added here later, plus links to the other sections of the course:

• Addison's disease: (Kumar & Clarke p. 943-945, review article: Peterson et al (2000) Trends in Endocrinology & Metabolism 11(7), 285-290) Adrenal insufficiency (Addison's disease) may arise either from secondary tuberculosis or from autoimmune destruction of the adrenal cortex. The major autoantigens are the various steroid hydroxylases associated with cytochrome P450. It is relatively rare, with an prevalence between 4 and 12 cases per 100,000 population. This is a potentially serious, life-threatening condition, which often leads to major disturances in salt and water balance, and requires prompt treatment with steroid hormones.

• coeliac disease: (Janeway et al p. 482, Kumar & Clarke p. 254-256, review article: Kumar et al (2001) Clinical and Diagnostic Laboratory Immunology 8(4) 678-685) Coeliac disease is a common condition induced by gluten, which is a protein found in wheat and closely-related cereals, but not in oats or maize. In susceptible individuals this leads to an autoimmune reaction against endomysium [smooth muscle] and the production of autoantibodies against reticulin and transglutaminse. Symptoms are variable but include tiredness and diarrhoea. The prevalence may approach 1% of the general population, based on the most sensitive tests. It is associated with a particular HLA genotype which carries an increased risk of type 1 diabetes and autoimmune thyroid disease. It is treated by excluding gluten from the diet.

• type 1 diabetes: (see also Janeway et al p. 493 & 508, Kumar & Clarke p. 962-964, review article: Atkinson & Eisenbarth (2001) Lancet 358, 221-229) Type 1 diabetes results from autoimmune destruction of the pancreatic b cells, and a consequent total failure of insulin production. It is a relatively common condition, predominantly affecting younger patients, and the incidence is increasing world-wide, although it varies markedly in different racial groups. Do not confuse with type 2 diabetes, which is a very common condition, predominantly affecting older obese patients, that is due to insulin resistance in the target tissues.

• hepatitis: (Kumar & Clarke p. 313, review article: Manns & Strassburg (2001) Gastroenterology 120(6), 1502-1517) Most cases of hepatitis are acute, self-limiting viral infections where the patient makes a full recovery, but around 20% of chronic hepatitis cases have an autoimmune origin. Without treatment, autoimmune hepatitis has a poor prognosis. It is a relatively rare condition with a prevalence of about 1 case per 100,000 population. A variety of autoantigens have been identified, including cytochrome P450, and the condition may be associated with other autoimmune diseases such as diabetes, thyroiditis and rheumatoid arthritis. Treatment involves immunosuppressive drugs.

• inflammatory bowel disease: (Kumar & Clarke p. 261-268, review articles: Davidson & Diamond (2001) NEJM 345(5), 340-350; Beutler (2001) Immunity 15(1), 5-14 [counter collection - no electronic copies] ) It may be difficult to distinguish between the recognised forms of IBD. These are Crohn's disease (full thickness lesions affecting any part of the GI tract, but especially the terminal ileum and anus) and ulcerative colitis affecting only the colonic mucosa. Symptoms include tiredness and bloody diarrhoea, and it may be associated with other problems (such as arthritis) outside the GI tract. The total prevalence of IBD is about 150 cases per 100,000 population. It is treated with aminosalicylates and immunosuppressive drugs.

• pancreatitis: (Kumar & Clarke p. 346-349, review article: Etemad & Whitcomb (2001) Gastroenterology 120(3), 682-707) Pancreatitis is an extremely painful, potentially life-threatening condition. It occurs in both acute and chronic forms, and has numerous diverse causes including alcoholism, bile duct obstruction, dyslipidaemia, genetic predisposition and autoimmunity.

• pernicious anaemia: (Kumar & Clarke p. 366-367, review article: Okuda (1999) J. Gastroenterology & Hepatology 14(4), 301-308) Autoantibodies to the a subunit of the potassium/proton ATPase in parietal cells slowly produce an atrophic gastritis and a total failure of both gastric acid and intrinsic factor production. As a result vitamin B12 can no longer be absorbed using intrinsic factor in the terminal ileum, leading to defective DNA synthesis and megaloblastic anaemia. This is a common condition, predominantly affecting elderly patients, which may be associated with other forms of autoimmune disease.

• primary biliary cirrhosis: (Janeway et al p. 502, Kumar & Clarke p. 324-325, review article: Medina et al (2001) Europ. J. Clin. Invest. 31(1), 64-71) Primary biliary cirrhosis (PBC) is a chronic cholestatic liver disease associated with anti-mitochondrial antibodies directed against the E2 subunits of either the pyruvate dehydrogenase or the branched chain a oxo acid dehydrogenase complexes. It leads to the progressive obliteration of the bile ducts, and eventually to jaundice and cirrhosis. Most patients are middle-aged women, and the prevalance is about 7.5 cases per 100,000 population. It is difficult to treat effectively and it has become an indication for liver transplantation.

• thyroid diseases: (Janeway et al p. 497-498, Kumar & Clarke p. 930-941, review articles: [No need to read them both!] Lin (2001) BMJ 322, 1525-1527; Andrikoula & Tsatsoulis (2001) Europ. J. Endoc. 144(6), 561-568) Autoimmune thyroid diseases are common in the general population, and women are affected much more frequently than men. Anti-thyroid antibodies may be either stimulatory, resulting in Graves' disease, or inhibitory leading to autoimmune atrophic thyroiditis and to Hashimoto's disease. Thyroid conditions often co-exist with other manifestations of autoimmune disease.

For a general discussion of allergy and auto-immunity see chapters 12 & 13 in Janeway et al although the information on specific diseases is better in Kumar & Clark. Try to avoid getting bogged down in this voluminous material. Students have to start somewhere, but it can be overwhelming in a first-year course.

Recapitulation

This account relates mainly to protein antigens. Carbohydrates and nucleic acids are also antigenic, but for these molecules antigen processing is not involved. B cells recognise native antigens, and T cells recognise processed antigens. Both components must be brought together and matched in order to trigger an immune response. B cells and T cells may, however, recognise different parts of the same antigen. New lymphocytes are constantly produced, but the great majority fail to bind any antigen and undergo apoptosis. More effective antibodies are produced with continued exposure to antigen and the main type of antibody produced changes from IgM to IgG as the immune response develops. The whole process is regulated by cytokines, and direct cell-to-cell contacts. Phagocytes recognise the constant Fc part of soluble antibodies attached to pathogenic organisms. This increases the likelihood that the invaders will be taken up, digested and processed, further stimulating the immune response. On the whole, myeloid cells are more closely involved with phagocytosis, T cells with cell-mediated immunity, and B cells are associated with humoral immunity, but components from all three cell lines are required for each type of response.

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