Immunodeficiency
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.
Secondary immunodeficiency
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.
