No major role for the CTLA-4 gene in the association of autoimmune thyroid disease with IDDM.

IDDM is a T-cell-mediated autoimmune disease depending on both genetic and environmental susceptibility factors. The HLA class II region (IDDM1) and the insulin promoter region (IDDM2) account for -50 and 10%, respectively, of IDDM genetic risk. At least 15 other IDDM susceptibility markers have been identified by genomewide scanning studies (1). One must consider that IDDM is a heterogeneous disorder that can vary in terms of age at clinical onset, duration of hyperglycemia before strict insulin dependency, existence of familial aggregation, occurrence of complications, and presence of extrapancreatic autoimmune diseases, so that different genes might influence the course or the presentation of the disease. The CTLA-4 gene, which has been mapped to the IDDM12 locus (2q33), is a good candidate gene in IDDM (2). Apart from recognition of major histocompatibility complex (MHC)/peptide complex by the T-cell receptor (TCR), T-cell activation requires a co-stimulatory signal mediated by CD28/B7 interaction. The CTLA-4 gene encodes a T-cell surface molecule whose binding to the B7 molecule on antigen-presenting cell delivers a negative signal to the T-cell and can mediate its apoptosis (3). Thus, CTLA-4 expression on T-cells might well influence the course of an ongoing immune process. CTLA4-deficient mice develop a severe lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, including the pancreas (4,5). In the same respect, the blockade of the CD28/B7 co-stimulatory signal prevents the occurrence of diabetes but not of insulitis in the NOD mouse model, suggesting that it either promotes a shift of the immune response or makes an additional signal unavailable for the final destructive stage (6). Recently, linkage to IDDM of a point mutation in exon 1 of CTLA-4 (position 49 A/G) leading to a Thr/Ala substitution in the leader peptide has been