Polyclonal Nature of Islet Cell Antibodies in Insulin-Dependent Diabetes

Abstract

Islet cell antibodies (ICA) are associated with insulin-dependent diabetes mellitus (IDD) and have been proposed as predictive markers for the disease. To determine whether ICA result from the activation of single autoreactive B-lymphocyte clones or are the result of polyclonal B-cell activation, we assayed ICA using polyvalent antisera specific to kappa or lambda light chains as well as monoclonal antibodies to IgG₁, IgG₂, IgG₃ and IgG₄ heavy chains by indirect immunofluorescence. Sera from 38 newly diagnosed IDD patients with IgG-ICA titers greater than 1:8 by end-point dilution were studied. ICA of both kappa and lambda light chains were present in all sera. The ICA were predominantly of the IgG₁ subclass (38/38), although ICA were also found to be IgG₂ in 53% (20/38), IgG₃ in 29% (11/38) and IgG₄ in 16% (6/38). The distribution of IgG heavy chains in ICA was compared to the ICA titer, age of onset of IDD and HLA-DR phenotype of the patient. No statistical correlation could be detected at a P value < 0.05. Our findings more likely exclude the occurrence of a single aberrant lymphocyte clone secreting ICA that may have arisen by somatic mutation in individual patients. Rather, these results are consistent with the hypothesis that ICA arise by polyclonal B-lymphocyte activation as a result of a defect of immune regulation. Since human antibodies to protein antigens are found predominantly in the IgG₁ subclass, our findings support the belief that the autoantigen involved in the stimulation of ICA formation is comprised, at least in part, of protein.

Key Words:

• Polyclonality
• islet cell antibodies
• insulin-dependent diabetes
• light and heavy chains