Aberrant V(H) gene utilization in patients with established insulin dependent diabetes mellitus

We have compared the B-lymphocyte repertoire in seven IDDM patients with 12 healthy controls by examining the variable heavy (V(H)) gene expression. The V(H) gene representation in the pool of pokeweed mitogen (PWM) stimulated, immunocompetent B cells and in the pool of naturally activated plasma cells (actual repertoire) was analysed by RNA-RNA in situ hybridization. Differences between IDDM patients and normal controls in the relative expression of several V(H) gene families were observed. In IDDM patients, the V(H)3 was significantly underrepresented in the PWM stimulated repertoire. In the actual B cell repertoire the V(H)5 clones were underrepresented among diabetic patients. Moreover, the altered distribution of V(H) gene usage between the PWM stimulated repertoire and the actual repertoire observed in normal controls was found to be less pronounced in the IDDM patients. This observation suggests a defect in the V-gene directed cellular selection occurring between resting, immunocompetent B cells and naturally activated plasma cells. The possible implication of the observed aberrations in the B cell selection process for the pathogenesis of autoimmunity is discussed.