We have found a novel polymorphic (Ala43Thr; ACC-->GCC) bcl-2 allele in a Japanese population. An in vitro expression study with a mouse IL-7-dependent 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 autoimmune disease in mice, we have investigated the possibility of whether a bcl-2 polymorphism has a different susceptibility to autoimmune disease. To evaluate the clinical impact of this polymorphism, the frequency of bcl-2 polymorphism was investigated in 221 children with insulin-dependent diabetes mellitus (IDDM), 237 adults with autoimmune disease (105 with rheumatoid arthritis, 57 with systemic lupus erythematosus, 55 with Sjögren's syndrome, and 20 others), and 290 healthy Japanese children and adults. The frequency 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<0.025) in adults with autoimmune disease. These results suggest that the 43Thr allele of bcl-2 confers resistance to autoimmune disease. The different anti-apoptotic function resulting from the different expression of bcl-2 protein in lymphocytes seems to be associated with the development of autoimmune disease, indicating that the bcl-2 gene affects human autoimmune disease.