Autoimmunity susceptibility genes

Barton A, Eyre S, Ke X, Hinks A, Bowes J, Flynn E et al (2009) Identification of AF4/ FMR2 family, member 3 (AFF3) as a novel rheumatoid arthritis susceptibility locus and confirmation of two further pan-autoimmune susceptibility genes. Hum Mol Genet 18 2518-2522... 

Wanstrat, A. and Wakeland, E., The genetics of complex autoimmune diseases Non-MHC susceptibility genes, Nature Immunol., 2, 802, 2001. 

Deficiencies of early components of the classical complement pathway (e.g. Clq, Clr/Cls, C2, C3, C4) are associated with the development of systemic lupus erythematosus. The prevalence of systemic lupus erythematosus in homozygous Clq, C4, or C2 deficiency is approximately 90%, 75%, and 10-30%, respectively. The strongest susceptibility genes for the development of systemic lupus erythematosus in humans are null mutants of Clq. Several findings are compatible with the hypothesis that complement deficiency causes systemic lupus erythematosus by the failure to clear immune complexes and apoptotic cells (Botto, 2001). In consequence, uncleared apoptotic bodies may provide the source of the autoantigens that drive the autoimmune response of systemic lupus erythematosus. 

In theory, all genes coding for products that are involved in the induction and maintenance of self-tolerance and in regulating immune effector functions as well as organ-specific functions may be involved in defining individual susceptibility. The most clearly established genetic association is with specific alleles within the MHC gene complex. However, with rare exceptions, a specific MHC haplotype is not sufficient for development of autoimmune disease. 

MHC genes also determine the susceptibility of individuals to autoimmune diseases. Among the diseases clearly related to MHC genes are insulin-dependent diabetes, multiple sclerosis, systemic lupus, erythematosus, myasthenia gravis, and rheumatoid arthritis. Alleles of MHC genes are also associated with non-immune system diseases, e.g., hemochromatosis, narcolepsy, and dyslexia. 

DM accounts for up to 10% of all cases of DM and is likely initiated by the exposure of a genetically susceptible individual to an environmental agent. Candidate genes and environmental factors are reportedly prevalent in the general population, but development of /3-cell autoimmunity occurs in less than 10% of the population and progresses to diabetes mellitus in less than 1% of the population. ... 

Compared with the autoimmune polyglandular and autoimmune lymphoproliferative syndromes described above, all other known autoimmune diseases and syndromes may not be inherited nonetheless, genes are responsible for differences in the susceptibility for disease development. Multiple genes, acting in concert with various environmental factors, seem to be involved in the autoimmune pathogenesis of most autoimmune diseases (see chapter 9). 

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