In discussing factors or conditions that can modify the severity and course of autoimmune disease a clear distinction between etiology and pathogenesis becomes often difficult. This is due to the fact that autoimmune diseases have a multifactorial etiology requiring both genetic features and environmental conditions to occur. The question as to whether a given genetic or epi genetic factor is permissive to an autoimmune disease or only modifying the pathogenesis is open in most cases.
The first evidence for an involvement of certain genes in the development of autoimmune diseases came from clinical experiences in humans revealing familial incidence of certain autoimmune diseases. This was confirmed by the observations that certain strains of experimental animals spontaneously exhibit enhanced frequencies of certain autoimmune disorders, and that selective breeding for the autoimmune phenotype resulted in further enhanced incidence and severity. The best-established animal models for spontaneous autoimmune diseases are strains of mice with manifestations of systemic lupus erythematosus, and the obese strain chickens afflicted with an organ-specific disease, i.e. autoimmune thyroiditis. Also the susceptibility to the induction of experimentally induced autoimmune disease has been shown to be genetically determined.
Various loci have been found to be involved in the development of autoimmune diseases, some of them are associated with the major histocompatibility complex (MHC). The best example for the association of an autoimmune disease with a certain MHC allele is HLA-B27, which confers an 85-90-fold relative risk of ankylosing spondylitis. Further examples include rheumatoid arthritis associated with HLA-DR4 and insulin-dependent diabetes mellitus (IDDM), with HLA-DR4 and DR3. In the latter it was shown that a certain allele, i.e. HLA-DR2, confers protection with a relative risk of 0.2. Mechanisms that are discussed to explain MHC associations of autoimmune diseases include 1) insufficient thymic presentation of autoantigens, 2) abnormal presentation of autoantigens to peripheral T helper cells, 3) association with alleles of non-MHC loci, such as the genes for TNFa/p, that map to the MHC and are linked with certain MHC alleles, and 4) antigenic mimicry between microbial antigens and autologous MHC molecules.
Another set of genes - not associated with the MHC - is involved in different mechanisms of im-munoregulation, and, finally, the susceptibility of the respective target organ in organ-specific autoimmune diseases appears also to be under genetic control. The latter two types of genes have been defined by classical genetic analysis of experimental and spontaneous autoimmune diseases in animal models.
Immune responses in general are not only regulated by mechanisms intrinsic to the immune system, but also by endocrine and neuroendocrine signals. It has long been recognized that many autoimmune diseases preferentially occur in females, whereas males appear protected probably due to immunosuppressive properties of androgens. Similar observations were made when obese strain chickens were first developed. However, with continuous selective breeding this sex difference disappeared, which suggests that sex hormones only have a modifying role in this disease.
Hormones involved in stress responses, such as glucocorticoids, catecholamines, endogenous opiates and most of the anterior pituitary hormones, have strong effects on specific and natural immune functions. It is well known that acute or chronic stress can exacerbate certain autoimmune diseases in humans. Chemical sympathectomy (by means of 6-OH-dopamine) has been shown to influence the course of experimental autoimmune disease in animals. Obese strain chickens were found to have enhanced plasma levels of corticoid-binding globulin leading to a diminished availability of free glucocorticoids. Early in vivo supplementation with free corticosterone prevented the onset of thyroiditis. Further to this, obese strain chickens were shown to have a central defect in the responsiveness of the hypothalamo-pituitary-adrenal axis to signals of the activated immune system, resulting in the lack of the peripheral glucocorticoid response after immunization as it is observed in healthy controls, and it was concluded that the defect in this negative feedback may predispose to autoimmunity. Findings in two experimentally induced models, i.e. experimentally induced encephalomyelitis and experimentally induced arthritis in rats, strongly supported this concept, and there is now good evidence that human patients suffering from rheumatoid arthritis show endocrine abnormalities indicating altered pituitary functions, which may contribute to etiology and/or pathogenesis of the disease.
Aging is known to be associated with increased autoimmune phenomena. However, these increased 'forbidden' responses as manifested in mildly elevated levels of autoantibodies are not necessarily pathogenic. Some authors have assigned this age-associated autoimmunity even a physiological role as a possible scavenger mechanism for cell and tissue constituents that accumulate due to enhanced tissue damage at higher age. Most of the acute severe autoimmune diseases usually start at young to middle ages, only certain chronic processes, e.g. chronic polyarthritis, tend to severe at higher ages.
Little is known about environmental influences on autoimmune disease. In general, any exogenous agent or condition that affects the immunogenic properties of autoantigens and/or the regulation of the immune response can be expected to modify autoimmune diseases. Modification of autoantigens and/or immune reactivity can occur by several bacterial and viral infections, and the outbreak of several autoimmune diseases indeed appears to be associated with certain infectious diseases, such as IDDM or multiple sclerosis following certain viral infections. Another way by which bacterial or viral infections may induce autoimmune disease is the abovementioned antigenic cross-reaction with autoantigens.
Autoimmune diseases as side-effects of drugs comprise type II reactions against drug-modified autologous white or red blood cells, but also lupus-like phenomena in patients taking ^-adrenergic blockers or drugs like hydralazine and procainamide. While the mechanism(s) of action of 3-blockers in this respect is not clear, in vitro investigations have shown that hydralazine and procainamide induces self-reactivity in cloned, heteroantigen-specific T cell lines by DNA methylation. This suggests that DNA methylation as a mechanism of gene expression plays a role in the specificity of immune responses, and that drugs or substances that interfere with the regulation of gene expression in general may have the potential to induce forbidden immune responses leading to autoimmune disease.
See also: Aging and the immune system; Autoantigens; Autoimmune disease, induced experimental models; Autoimmune diseases; Autoimmunity; Glucocorticoids; Goodpasture's syndrome; Hypersensitivity reactions; Immune complexes; Insulin-dependent diabetes mellitus, human; MHC disease associations; Neuromuscular junction autoimmunity; Neuroendocrine regulation of immunity; Sex hormones and immunity; Systemic lupus erythematosus, experimental models; Systemic lupus erythematosus (SLE), human; Thyroid autoimmunity, experimental models; Thyroid autoimmunity, human; Tissue typing.
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