ANTIENDOTHELIAL CELL AUTOANTIBODIES IN BB RATS WITH SPONTANEOUS AND INDUCED IDDM

Anti-endothelial cell (anti-EC) antibodies occur in several autoimmune diseases, including human IDDM, but the time course of their developm ent and their importance in disease pathogenesis are unknown. To study such antibodies further, we investigated the BB rat model of autoimmu nity. Diabetes-prone (DP) BB rats spontaneously develop autoimmune dia betes, whereas coisogenic diabetes-resistant (DR) BB rats are disease free but can be induced to become diabetic by the depletion of T-cells expressing the RT6 alloantigen. Anti-EC autoantibodies were readily d etectable in both untreated DP-BB rats and RTB-depleted DR-BB rats bef ore the onset of diabetes. Their concentration increased with time. Th e anti-EC antibodies in DP-BB rats were almost exclusively of the IgG2 b subclass, whereas those in RT6-depleted DR-BB rats included both the IgG1/2a and the IgG2b subclasses, We also found that intravenous inje ctions of purified immunoglobulins from RT6-depleted DR-BB rats induce d abnormal pancreatic vascular leakage in mice. The preabsorption of i mmunoglobulins against cultured ECs abolished this activity. The pretr eatment of mice with silica also abolished the ability of immunoglobul ins of RT6-depleted DR-BB rats to induce pancreatic leakage, suggestin g that monocytes are involved in the mechanism of anti-EC autoantibody -induced vascular leakage. We conclude that anti-EC autoantibodies are present in rat strains that are genetically predisposed to develop au toimmune diabetes. Their presence early in the disease process and the ir ability to induce pancreatic vascular leakage suggest that they may participate in diabetes pathogenesis.