Satisfactory immunity depends on the interaction of such an enormous variety of cells and molecules that inevitably a corresponding variety of different defects can reduce its efficiency, all with much the same end result: increased susceptibility to infection (right). There is a tendency for somewhat different patterns of disease according to whether the defect predominantly affects T cells (top), antibody and/ or complement (centre) or myeloid cells (bottom).
Immunodeficiency may be secondary to other conditions (e.g. drugs, malnutrition or infection itself) or, less commonly, a result of primary genetic defects. It is remarkable how many of the latter are ‘X-linked’ (i.e. inherited by boys from their mothers; top left in figure), suggesting that the unpaired part of the X chromosome carries several immunologically important genes (see Fig. 47). In some cases it appears that cell differentiation is interrupted at a particular stage (black arrows), but much more often there is a variable mixture of partial and apparently disconnected defects. The remarkable advances in genetics, and especially the ability to sequence enormous amounts of DNA, have resulted in a rapid increase in the number of diseases for which the missing gene product has now been identified (e.g. individual complement components, polymorph or lymphocyte enzymes (black circles), or cytokine receptor and adhesion molecules). Treatments being developed focus on replacement therapy, using either genes (gene therapy) or proteins. Although generally rare, these diseases have taught immunologists an enormous amount about the human immune system, providing ‘experiments of nature’ which complement and expand the many experimental genetic models developed in animals, especially rodents (for further details see Fig. 47).
The incidence of primary immunodeficiency depends on the definition of normality. Some scientists would argue that any manifestation of disease caused by infection reflects some level of immunodeficiency. Certainly both the frequency with which ‘normal’ people succumb to colds, sore throats and food poisoning etc. and the severity of the ensuing illnesses varies enormously between individuals. However, serious deficiency is found only in about one person per 1000.
Ret. dys. Reticular dysgenesis, a complete failure of stem cells, not compatible with survival for more than a few days after birth.
SCID Severe combined immunodeficiency, in which both T and B cells are defective. Some cases appear to be caused by deficiency of an enzyme, adenosine deaminase (ADA), which can be replaced by blood or marrow transfusion. Others result from a mutation in a cytokine receptor (the shared γ chain of the IL-2, IL-4 and IL-7 receptor). Recent gene therapy trials have used recombinant retroviruses to introduce the missing gene into bone marrow stem cells and have resulted in reconstitution of fully functional immune system. In a small number of children, however, tumours apparently caused by retroviral insertion have been reported. In some cases, HLA class I or II mole- cules are absent from lymphocytes (‘bare lymphocyte syndrome’).
Atax. tel. Ataxia telangiectasia, a combination of defects in brain, skin, T cells and immunoglobulin (especially IgA), apparently resulting from a deficiency of DNA repair.
Wisk. Ald Wiskott-Aldrich syndrome, a combination of eczema, platelet deficiency, and absent antibody response to polysaccharides. The genetic defect for this disease lies in a protein regulating cytoskeleton formation, but how this results in the pathology remains unclear.
Defects predominantly affecting T cells DiGeorge syndrome: absence of thymus and parathyroids, with mal- development of other third and fourth pharyngeal pouch derivatives. Serious but very rare; it may respond to thymus grafting.
Nezelof syndrome: somewhat similar to DiGeorge syndrome but with normal parathyroids and sometimes B-cell defects.
PNP Purine nucleoside phosphorylase, a purine salvage enzyme found in T cells. Deficiency causes nucleosides, particularly deoxy- guanosine, to accumulate and damage the T cell.
Cytokine defects, or defects in their receptors, appear to be rare, but IL-2 and IFNγ deficiency have been reported, as have individuals with deficiencies in the IL-12 receptor, and hence an inability to mount TH1 responses. Deficiencies in TH17 cells may lead to increased susceptibility to common and normally harmless fungal infections. There are also rare defects in several of the leucocyte adhesion molecules.
Defects predominantly affecting B cells Agammaglobulinaemia or hypogammaglobulinaemia may reflect the absence of B cells (Bruton type), their failure to differentiate into plasma cells (variable types) or selective inability to make one class of immunoglobulin–most commonly IgA, but sometimes IgG or IgM. In X-linked hyper-IgM syndrome, there is a genetic defect in the CD40 ligand molecule on T-helper cells, which results in an inability to switch from making IgM to IgG.
Autoimmunity, allergies and polyarthritis are remarkably common in patients with antibody deficiencies, while both T- and B-cell defects appear to increase the risk of some tumours, especially those of the haemopoietic system.
Virtually all the complement components may be genetically deficient; sometimes there is complete absence, sometimes a reduced level, suggesting a regulatory rather than a structural gene defect. In addition, deficiency of inactivators may cause trouble, e.g. C1 inhibitor (hereditary angiooedema), C3b inhibitor (very low C3 levels). In general, defects of C1, C4 and C2 predispose to immune complex disease, particularly SLE, and of C5–9 to neisserial infection (meningococcal, gonococcal). C3 deficiency, as expected (see Fig. 6), is the most serious of all, and seldom compatible with survival. Low levels of mannose-binding protein (MBP) predispose to severe infections in children.
Defects affecting myeloid cells
CGD Chronic granulomatous disease, an X-linked defect of the oxygen breakdown pathway (see Fig. 9) usually involving a cyto- chrome, leads to chronic infection with bacteria that do not themselves produce peroxide (catalase positive) and with fungi such as Aspergil- lus spp. Gene therapy trials are in progress to try and replace the missing enzyme subunit. In a minority of cases there is another, non- X-linked, defect.
Myeloperoxidase, G6PD (glucose-6-phosphate dehydrogenase), PK (pyruvate kinase) and other polymorph enzymes may be genetically deficient, causing recurrent bacterial and fungal infection.
Ched. Higashi In the Chédiak–Higashi syndrome, the polymorphs contain large granules but do not form proper phagolysosomes. In other cases the response to chemotaxis is impaired (‘lazy leucocyte’).
Receptors of innate immunity
Genetic defects in several of these receptors (see Fig. 5) have now been reported, and more will undoubtedly be discovered. Some examples are Toll-like receptor 5 deficiency associated with susceptibility to Legionnaires’ disease, NOD-2 deficiency associated with Crohn’s disease, and variations in the mannose receptor associated with susceptibility to leprosy and tuberculosis. Mutations in the interferon signalling pathway are associated with increased severity of common viral infections.
Age Immunity tends to be weaker in infancy and old age, the former being partly compensated by passively transferred maternal antibody. In the industrialized world, infection has become an important cause of illness and death in the elderly.
Malnutrition is associated with defects in antibody and, in severe cases, T cells; this may explain the more serious course of diseases (e.g. measles) in tropical countries. Both calorie and protein intake are important, as well as vitamins and minerals e.g. iron, copper and zinc.
Drugs can cause immunodeficiency, either intentionally (see Fig. 40) or unintentionally.
Infections Immunosuppression is found in a great variety of infections, being one of the major parasite ‘escape’ mechanisms (see Figs 27–32). HIV infection, by progressively destroying CD4 T cells, weakens the whole immune system (for more about AIDS see Fig. 28). Other viruses, such as measles, can temporarily depress T-cell function. Although this transitory effect may be of little consequence in the industrialized world, the increased susceptibility to common environmental pathogens, especially in food and water, is a major danger and cause of death to many children living in conditions of poor sanitation and hygiene in many other parts of the world. In all cases of T-cell deficiency, cell-mediated responses are of course reduced, but there are often secondary effects on antibody as well.
Tumours are often associated with immunodeficiency, notably Hodgkin’s disease, myeloma and leukaemias; it is sometimes hard to be sure which is cause and which effect.