The polymorphic 43Thr bcl-2 protein confers relative resistance to autoimmunity: an analytical evaluation

We have found a novel polymorphic (Ala43Thr; ACC-->GCC) bcl-2 allele in a J apanese population. An in vitro expression study with a mouse IL-7-dependen t pre-B cell line has revealed that inhibition of the programmed cell death function of 43Thr bcl-2 protein is suppressed compared with that of normal 43Ala bcl-2 protein. Since bcl-2 expression in B-lymphoid cells elicits au toimmune disease in mice, we have investigated the possibility of whether a bcl-2 polymorphism has a different susceptibility to autoimmune disease. T o evaluate the clinical impact of this polymorphism, the frequency of bcl-2 polymorphism was investigated in 221 children with insulin-dependent diabe tes mellitus (IDDM), 237 adults with autoimmune disease (105 with rheumatoi d arthritis, 57 with systemic lupus erythematosus, 55 with Sjogren's syndro me, and 20 others), and 290 healthy Japanese children and adults. The frequ ency of the 43Thr bcl-2 allele, either homozygous or heterozygous, was 14.5 % in normal controls, 6.8% (P<0.01) in children with IDDM, and 8.0% (P<0.02 5) in adults with autoimmune disease. These results suggest that the 43Thr allele of bcl-2 confers resistance to autoimmune disease. The different ant i-apoptotic function resulting from the different expression of bcl-2 prote in in lymphocytes seems to be associated with the development of autoimmune disease, indicating that the bcl-2 gene affects human autoimmune disease.