The processes that lead to the production of islet cell autoantibodies in 
insulin-dependent (type 1) diabetes mellitus (IDDM) are largely unknown. Humoral 
autoimmunity may be the result of an antigen-independent polyclonal B cell 
activation, or a consequence of an antigen driven B cell activation and 
selection for the antigen. We have analysed the gene elements encoding the 
immunoglobulin variable regions of seven human monoclonal islet cell antibodies 
(MICA) 1-7 directed to the major islet autoantigen glutamate decarboxylase 
(GAD65). These autoantibodies were derived from two patients with newly 
diagnosed IDDM. The variable gene regions of the MICA revealed different 
sequences, and no relation between V gene usage and shared epitope recognition 
of the MICA was evident. An elevated usage of VH 1, VH 4 and Vlambda 2 gene 
segments was observed. The underrepresentation of VH 3 family members in the 
MICA discriminated them from most autoantibodies. The high relative avidities 
for GAD65 of MICA 1, 3, 4 and 6 and their high, nonrandom ratio of replacement 
versus silent mutations in the antigen binding regions indicated that the 
humoral response to GAD65 is driven by the antigen. MICA 2, 5 and 7 showed as 
well an excess of replacement mutations in the antigen binding regions, but 
revealed lower relative avidities for their antigen. Since these clones 
accumulated many somatic mutations in their variable gene regions, they may be 
characteristic for later stages of the autoimmune disease. The results suggest 
that, in humans, an antigen driven B cell activation and affinity maturation 
process may contribute to the production of GAD65-autoantibodies found in 
patients with IDDM.