T-Lymphocyte Changes Linked to Autoantibodies: Association of Insulin Autoantibodies With CD4⁺CD45R⁺ Lymphocyte Subpopulation in Prediabetic Subjects

The onset of insulin-dependent (type I) diabetes is predictable before hyperglycemia by the presence of islet cell autoantibodies (ICAs) and competitive insulin autoantibodies (CIAAs). CIAA⁺ICA⁺ first-degree relatives of individuals with type I diabetes have increased numbers of CD4 cells bearing the CD45R antigen and reciprocal depressions of the CD4 cells bearing the CD29 determinant. In addition, depressed CD4/CD8 ratios are present. In this study, we investigated the correlation between autoantibody levels and T-lymphocyte changes in the prediabetic state. The data demonstrate a clear linear relationship between rising CIAA levels, a marker of disease rate, and rising elevations in the CD4⁺CD45R⁺/CD4⁺CD29⁺ ratio in 37 CIAA⁺ICA⁺ and CIAA⁺ICA⁻ relatives (r = 0.93). In marked contrast, the degree of CD4/CD8 depression found in individuals with prediabetes or long-term diabetes failed to correlate with either CIAA (r = 0.32) or ICA (r = 0.29) levels. The investigation of T-lymphocyte changes in siblings of individuals with type I diabetes with different stable autoantibody patterns (CIAAs and/or ICAs), and thus varying risks for diabetes, revealed differences in the prediabetic groups. Fifteen CIAA⁺ICA⁻ relatives with high CIAA levels (>80 nU/ml) had high CD4⁺CD45R⁺/CD4⁺CD29⁺ ratios (P = 0.03) and depressed CD4/CD8 ratios (P = 0.008). In contrast, CIAA⁺ICA⁻ relatives with low CIAA levels (39–80 nU/ml), and thus low risk of diabetes, had no alteration in their CD4/CD8 ratio (P = 0.75) or CD4⁺CD45R⁺/CD4⁺CD29⁺ ratio (P = 0.33). Nineteen CIAA⁻ICA⁺ siblings with a predicted intermediate risk for diabetes showed heterogeneity in the presence of T-lymphocyte abnormalities. No statistically significant trend was observed in the peripheral T-lymphocyte composition with all CIAA⁻ICA⁺ relatives combined. This study links the magnitude of the well-described CIAA production to the magnitude of altered numbers of T lymphocytes bearing the CD45R⁺ and CD29⁺ antigens in the prediabetic stage. We conclude that prediabetic relatives prone to frank hyperglycemia represent a heterogeneous population now definable by autoantibody production and the newly described T-lymphocyte changes. This study represents an initial delineation of a link between abnormal alterations in the humoral and cellular immune response.