Study of two diseases with autoimmune characteristics (IDDM and SLE) has demonstrated that alleles carried in the MHC can confer disease susceptibility. The MHC alleles most strongly associated with the development of IDDM are encoded within the class II region (HLA-DR or -DQ). Recent studies indicating that the class III gene products TNF alpha and beta may play a critical role in the initiation of the autoimmune attack on the pancreatic beta-cells have suggested the possibility that the class III region may also contribute to genetic susceptibility in IDDM. In SLE, although there is some evidence suggesting that certain alleles of class II genes may confer disease risk, a more striking association has been detected in the class III region. Deficiency of the class III encoded C4A molecule (either homozygously or heterozygously) shows a high correlation with disease risk. This finding is attractive because C4A plays a central role in the metabolism of immune complexes, the aberrant deposition of which leads to the most prominent alterations in SLE.