Autoimmune Diseases

 Autoimmunity is not pathologic per se because natural autoantibodies, natural autoreactive T-cell clones, and the connected idiotypes and anti-idiotypes are part of the basic organization of the immune system. Autoimmune diseases (AIDS) are the consequence of a major failure in the regulation of the immune system, as the emergence of self-reactivity becomes aggressive and harmful to the organism. They represent a major cause of morbidity, and their incidence increases with aging.

 The primary causes of autoimmune diseases (AIDS) are still very poorly understood, and the precise target of the autoimmune reactions is not always known. In some cases, one organ, and eventually one target molecule, can be identified. Examples of these are myasthenia gravis, in which antibodies directed against the acetylcholine receptor have been identified, or autoimmune thyroiditis, where the presence of autoantibodies directed against receptors for thyroid stimulating hormone have been documented. Such antibodies may have very different impacts upon binding. Some may act as a mimic of the hormone and therefore activate thyrocytes, thereby inducing hyperthyroidism, which is characteristic of Graves' disease. Conversely, others will block receptor activation, leading to a hypothyroidism state, as seen in Hashimoto's disease. Another example of an organ-specific AID is insulin-dependent diabetes mellitus, in which the cellular target is the b islets of the endocrine pancreas. Some AIDs appear to be not organ-specific, such as systemic lupus erythematosous, when a number of autoantibodies are directed against a large variety of antigens, including DNA and nucleoproteins.

Several characteristics generally underline the occurrence of AIDs: (a) In most cases there is a genetic predisposition, with a frequent linkage to certain major histocompatibility complex (MHC) haplotypes; (b) they are chronic diseases that persist for years; and (c) although the molecular target of autoantibodies or autoreactive T-cell clones may be identified, this does not clarify the nature of the initial antigen, if any.

Linkage to an MHC haplotype is indicated by the increase of the relative risk for a given AID to occur. The most spectacular example is that of ankylosing spondylitis, a very severe arthritis that most frequently affects hips, for which 95% of patients are HLA-B27. This indicates a relative risk of about 70 (ie a B27⁺ individual has 70 times greater chance to have the disease than the average population). This AID is also particularly interesting because it has been observed that microorganisms such as Klebsiella share an identical sequence of six amino acid residues, Gln –Thr- Asp -Arg -Glu -Asp (QTDRED), with an epitope of the HLA27 molecule. It was postulated that this AID might be the consequence of an epitope mimicry, an infection with Klebsiella inducing an immune response that subsequently would cross-react with the HLA epitope of the host. A similar hypothesis was proposed for rheumatoid arthritis, a very common rheumatological disorder that may develop for years, because it was found to be associated with certain DR4 alleles expressing the Gln-

Lys –Arg- Ala- Ala (QKRAA) sequence. A similar sequence was found in Hsp 70, which might provide another example of epitope mimicry as the starter for the initial immunization.

The V_H and V_L regions of autoantibodies isolated from AID patients have been sequenced extensively, with the hope of detecting significant differences from natural, nonaggressive autoantibodies. Frequently, dominant expression of some V_H and/or V_L is observed, as in the case of anti-DNA autoantibodies isolated from lupus patients. In most occasions, but not always, these antibodies have mutated variable regions, as opposed to the germline sequences generally found in natural antibodies. The significance of this remains unclear, however, primarily because the autoantibodies developed by a rather large number of AID patients seem to be only passive witnesses of an autoimmune response, rather than being involved in pathogenesis, which is frequently attributed to cytotoxic T lymphocytes.

Numerous animal models have been defined and extensively studied. Many have stressed the importance of the genetic background, such as the obese strain of chickens that develop a hereditary spontaneous autoimmune thyroiditis that is quite similar to Hashimoto's disease. Another example is the nonobese diabetic (NOD) mice that develop an autoimmune diabetes, which spontaneously develops an insulitis that becomes full insulin-dependent diabetes mellitus at 7 months of age. New Zealand black (NZB) mice and other strains that spontaneously develop a systemic lupus erythematosous-like syndrome are another example. These models are interesting because they provide a possible key to understanding the genetic basis for the equivalent human diseases. Other approaches are centered more on attempts to isolate antigens that might induce an AID-like syndrome. An example of this is experimental autoimmune encephalomyelitis, which is a possible model for multiple sclerosis; it can be induced upon injection of myelin basic protein, from which encephalitogenic peptides and precise epitopes have been described. This disease can also be transferred with lymphocytes but not by serum, pointing to the role of cell-mediated immunity in this AID. Interestingly, T cells with a suppressive activity have also been identified, offering the possibility of modulating the immune system negatively by this approach. Such a treatment is eagerly awaited for most AIDs, particularly multiple sclerosis. Thus far, primarily nonspecific immunosuppressive agents are used, with the obvious problem of generating severe secondary effects.