4 - MHC class II and non-MHC genes in the pathogenesis of systemic lupus erythematosus

Abstract

The actual cause of systemic lupus erythematosus (SLE) is unknown. This chapter reviews the genetic basis for SLE, the familial aggregation in SLE, the current status of genome-wide scans in families of SLE patients, organization of the MHC, the association of MHC genes and susceptibility to SLE, and the autoantibody subsets of SLE and their MHC class II associations. Family and twin studies clearly have established the importance of genetic factors in SLE, and studies of HLA class II and III genes have underscored their consistent associations with disease in nearly all ethnic groups, the contribution of non-MHC genes to SLE predisposition, clinical and autoantibody subsets, and course and prognosis are only being determined currently. Studies defining associations with non-MHC genes and linkage studies of multiplex families from several centers have raised as many new questions as they have answered. Inadequate power from small sample sizes and family collections, stemming undoubtedly from the clinical heterogeneity posed by SLE in no small part, has caused this. However, as the family collections continue, data are pooled and reanalyzed, and clinical subsets of SLE further considered, definitive candidate genes should emerge beyond perhaps the three that have withstood time and reconfirmation in different groups of patients: the MHC, the FCγ genes, and whatever disease-relevant gene found in the region on chromosome ´q41–42. This results in better insights into the immunologic perturbations that set the stage for SLE, which will in turn allow novel approaches to therapy.