GENETIC SUSCEPTIBILITY TO SYSTEMIC LUPUS-ERYTHEMATOSUS

Considerable evidence suggests that the development of systemic lupus erythematosus (SLE) has a strong genetic basis. Recent studies have em phasized that this disease, like other autoimmune diseases, is a compl ex genetic trait with contributions from major histocompatibility comp lex (MHC) genes and multiple non-MHC genes. Etiologic genes in these d isorders determine susceptibility, and no particular gene is necessary or sufficient for disease expression. Studies of murine models of lup us have provided important insight into the immunopathogenesis of IgG autoantibody production and lupus nephritis, and genetic analyses of t hese mice overcome certain obstacles encountered when studying patient s. Genome-wide linkage studies of different crosses have mapped the po sition of at least 12 non-MHC disease-susceptibility loci in the New Z ealand hybrid model of lupus. Although the identity of the actual gene s is currently unknown, recent studies have begun to characterize how these genetic contributions may function in the autoimmune process, es pecially in terms of their role in autoantibody production. Studies of MHC gene contributions in New Zealand mice have shown that heterozygo sity for particular haplotypes greatly increases pathogenic autoantibo dy production and the incidence of severe nephritis. The mechanism for this effect appears to be genetically complex. Studies in human SLE h ave mostly focused on the association of disease with alleles of immun ologically relevant genes, especially in the MHC. Associations with va rious complement component deficiencies and an allele of a particular Fc gamma receptor gene (FCGR2A) also have been described. In a diversi on from previous association studies, a recent directed linkage analys is of sibpairs with SLE was based on mapping studies in murine lupus a nd may be an important step toward identifying a new disease-susceptib ility gene in patients. Since the genes that predispose to autoimmunit y are probably related to key events in pathogenesis, their identifica tion in patients and murine models will almost certainly provide impor tant insight into the breakdown of immunological self-tolerance and th e cause of autoimmune disease.