IMMUNOGLOBULIN VARIABLE GENE ANALYSIS OF HUMAN AUTOANTIBODIES REVEALSANTIGEN-DRIVEN IMMUNE-RESPONSE TO GLUTAMATE-DECARBOXYLASE IN TYPE-1 DIABETES-MELLITUS

Insulin-dependent (type 1) diabetes mellitus is an organ-specific auto immune disease frequently associated with an islet-specific humoral au toimmune response. The role of islet cell autoantibodies in the diseas e process is unclear; in particular, it is not known whether they are a non-specific side effect of islet cell destruction or play a role in the autoimmune network leading to type 1 diabetes. Here we report the immunoglobulin gene usage and somatic mutation rates of a panel of se ven human monoclonal islet cell autoantibodies (MICA 1-7) directed tow ards the major islet cell autoantigen glutamate decarboxylase (GAD). T hese autoantibodies were produced from cells from two patients with ne wly diagnosed type 1 diabetes. VH1, VH4 and V lambda 2 gene segments w ere frequently used in the MICA, but no correlation between V gene usa ge and epitope recognition was found. The nonrandom ratio of replaceme nt versus silent mutations in the variable gene region, an accumulatio n of replacement mutations in the complementarity determining regions, which confer antigen binding, and the high relative avidity for GAD o bserved for MICA 1, 3, 4, and 6, suggested that the immune response to GAD is driven by the antigen. In contrast, MICA 2, 5, and 7, revealin g a lower affinity for antigen, have accumulated a large number of sil ent mutations. These latter antibodies may, therefore, be characterist ic for later stages of the chronic autoimmune disease. Our results arg ue in favor of an antigen-driven autoantibody response to islets in hu man type 1 diabetes. They suggest that GAD is an important target of a utoimmunity associated with type 1 diabetes.