Autoimmune Disease
Autoimmunity
represents the failure of self-tolerance. Before proceeding, the reader is
recommended to glance back at Fig. 22, which summarizes the mechanisms by which
the immune system normally safeguards its lymphocytes against self-reactivity.
This is essentially a problem for the adaptive immune system, since both B and
T cells generate their antigen-binding receptors by random gene rearrangement
(see Figs 12 and 13) and receptors recognizing self antigens are bound to be
generated in the process.
The main mechanisms by which these
are prevented from causing harm are shown in Fig. 22. The figure above
highlights some of the points at which they can break down or be induced to
fail. These are numerous, but two influences are particularly significant: genetics
and infection. Identical twins show concordance rates around 30% for
many autoimmune diseases (concordance is the frequency of disease in one twin
occurring in the other). The association of autoimmune diseases with individual
HLA genes, especially class II, implies a crucial role for CD4+ T cells,
although the association is fairly weak (relative risk 4–14; relative risk is the chance of developing the
disease compared with people
without the gene) except for ankylosing spondylitis, where the very strong link
(over 90) is with a class I gene, B 27. The role of infection in autoimmunity
is suggestive but seldom clear- cut: autoimmune disease frequently follows
infection, but no autoimmune disease has yet been convincingly shown to be due
to a specific pathogen. The killing of virus-infected cells by cytotoxic T
cells could be regarded as an exception, but here the autodestruction is a
beneficial part of recovery, although it may cause excessive damage, e.g.
hepatitis B and the myocarditis of coxsackie virus infection.
It is important to realize that autoimmunity
(centre of figure) does not necessarily mean autoimmune disease (right),
the latter term being restricted to conditions where there is reasonable
evidence that the symptoms are in fact due to autoantibodies and/or
autoreactive T cells (see opposite page). The finding of autoantibodies in the
absence of obvious disease, or even in healthy people, emphasizes the fact that
the precise aetiology of most
autoimmune diseases is still not fully understood.
Tolerance The mechanisms responsible for making sure that
lymphocytes do not generally react to self antigens (self-tolerance) are
explored in Fig. 22. However, in some cases tolerance is not complete. This can
result from incomplete clonal deletion, or a breakdown in peripheral tolerance.
Deficiency in the TREG subpopulation has been reported in several autoimmune
diseases, including diabetes, rheumatoid arthritis and SLE. Expression of class
II MHC antigens on thyroid epithelial cells, or pancreatic beta cells, perhaps
as a result of infection, may also contribute to breakdown of tolerance.
Sometimes, tissue injury or infection can allow antigens that are usually
screened from the immune system (e.g. in the eye) to become accessible.
Macrophages have a key role in many autoimmune diseases, by
releasing cytokines that cause local inflammation, enzymes and reactive
chemicals (free radicals) that damage the tissue. Antibodies against TNF-α, a
key macrophage-derived inflammatory cytokine, are very effective in treatment
of rheumatoid arthritis, psoriasis and Crohn’s disease. Macrophage activation
is dependent on autoreactive TH cells that release IFNγ and IL-17.
Cytotoxic T cells (TC) in killing virus-infected cells, may damage
normal tissues. Liver damage in hepatitis B is a classic example. In other
cases, however, autoreactive TC ‘break tolerance’ and target specific
autoantigens in organs such as the thyroid or the pancreas.
Drugs frequently bind to blood cells, either directly
(e.g. sedormid to platelets; penicillin to red cells) or as complexes with
antibody (e.g. quinidine). Alpha methyldopa can induce antibodies against
Rhesus blood group antigens, towards which B-cell tolerance is particularly
unstable.
Cross-reacting antigens shared between microbe and host may stimulate T
help for otherwise silent self-reactive B cells – the ‘T-cell bypass’. Cardiac
damage in streptococcal infections and Chagas’ disease appear to be examples of
this.
Polyclonal activation Many microbial products (e.g. endotoxins, DNA)
can stimulate B cells, including self-reactive ones. The EB virus infects B
cells themselves and can make them proliferate continuously.
Autoantibodies are found in every individual but rarely cause
disease. In some diseases, raised autoantibody levels are clearly effect rather
than cause (e.g. cardiolipin antibodies in syphilis). But in some dis- eases
they are the first, major or only detectable abnormality and can cause damage
in a variety of ways. They can attach to tissues and activate the complement
system (see Fig. 6) leading to inflammation. They can react with specific
receptors blocking important hormone or neurotransmitter signals. Or they can
react with target autoantigens in blood, forming large complexes (see Figs 20
and 36), which accumulate in skin, lung
or kidneys causing inflammation and organ damage.
The precise mechanisms that give
rise to autoimmune diseases remain incompletely understood. Much of our current
knowledge comes from the study of animal models, such as experimental allergic
encephalitis and collagen-induced arthritis, in which autoimmunity is induced
by direct immunization with self-proteins. These models have taught us much
about how tolerance may be broken, but important differences remain between the
corresponding animal and human diseases.
Genetics of autoimmunity Most autoimmune diseases have a genetic
component and much effort is being devoted to identifying the genetic ‘risk
factors’ associated with particular autoimmune diseases. The strongest
associations are those with specific alleles of the MHC class
II genes (see opposite page),
confirming that CD4+ T cells have an
important role in the aetiology of these
diseases. However, there are at least 20 other loci that contribute to an
individual’s propensity to develop a particular autoimmune disease. Some of
these appear to control the level of cytokines, others affect signalling pathways
in immune cells while yet others affect non-immunological steps in tissue
damage.
Haemolytic anaemia and thrombocytopenia, although they can
be caused by drugs, are more often idiopathic. The correlation between
autoantibody levels and red cell destruction is not always very close,
suggesting another pathological process at work.
Thyroiditis is one of the best candidates for ‘primary’
autoimmunity. There may be stimulation (thyrotoxicosis) by antibody against the
receptor for pituitary TSH, or inhibition (myxoedema) by cell destruc- tion,
probably mediated by cytotoxic T cells and autoantibody.
Pernicious anaemia results from a deficiency of gastric intrinsic
factor, the normal carrier for vitamin B12. This can be caused both by
autoimmune destruction of the parietal cells (atrophic gastritis) and by
autoantibodies to intrinsic factor itself.
Diabetes, Addison’s disease (adrenal hypofunction) and other endocrine
diseases are often found together in patients or families, suggesting an
underlying genetic predisposition. The actual damage is probably mainly T-cell
mediated, against pancreatic β cells and the adrenal cortex, respectively.
Myasthenia gravis, in which neuromuscular transmission is
intermittently defective, is associated with autoantibodies to, and destruction
of, the postsynaptic acetylcholine receptors. There are often thymic
abnormalities and thymectomy may be curative, although it is not really clear
why.
Rheumatoid arthritis is characterized by autoantibody against IgG
(rheumatoid factor) although not in every case. Joint damage may be partly
mediated via immune complexes, and injections of antibodies against CD20, which
result in depletion of B cells, is an effective treatment in a proportion of
patients. T-cell-dependent activation of macrophages (type IV hypersensitivity)
may also contribute. In either case the cytokines TNF-α and IL-1 cause the main
pathology, by activating degradation of cartilage.
SLE In systemic lupus erythematosus the
autoantibodies are against nuclear antigens, including DNA, RNA and nucleic
acid binding proteins. The resulting immune complex deposition is widespread
throughout the vascular system, giving rise to a ‘non-organ-specific’ pattern
of disease. A localizing role for the antigen itself may explain why different
complexes damage different organs. Patients with SLE also have very high levels
of type I interferons, perhaps resulting from innate responses to circulating
nucleic acids (see Fig. 5), which con- tribute to a generalized inflammation.
Treatment of autoimmunity
No cures exist for most autoimmune
diseases, and treatment is symptomatic; examples are anti-inflammatory drugs
for rheumatoid arthritis, insulin for type I diabetes, anti-thyroid drugs for
thyrotoxicosis. Where autoantibodies are to blame (e.g. in myasthenia)
plasmapheresis to remove them can provide short-term benefit. Remarkable
improvement in patients with rheumatoid arthritis and Crohn’s disease has been
achieved by treatment with a high-affinity antibody against TNF-α, which
presumably blocks the inflammatory cascade within the affected tissue: this
remains the best example of successful therapy using an anticytokine antibody.
More antigen-specific approaches to immunomodulation, such as vaccination
against particular families of T-cell receptors, or the simulation of specific
TREG cells, are still at an experimental stage.
