Our laboratory has identified a novel autoantibody (AA) to serpinB13, a protease inhibitor of cathepsin L, and has found an association of this AA with protection from type 1 diabetes (T1D) in subjects enrolled in the Diabetes Prevention Trial for Type 1 Diabetes (DPT-1). Our additional studies with a monoclonal antibody (mAb) to serpinB13 confirmed these observations in mouse, and implicated this mAb in a protease-mediated cleavage of the Notch 1 receptor as the mechanism of development of pancreatic Ngn3+ endocrine progenitors and resistance to severe diabetes. Whether human AA to serpinB13 plays a similar active role in protection against T1D remains unclear. To examine the potential functionality of human serpinB13 AA, we dialyzed DPT-1 serum samples that were either positive or negative for serpinB13 AA and used them to stimulate mouse embryonic pancreas explants (E12.5) during a 48-hour in vitro culture. Using a quantitative IF microscopy approach, we found that pancreas explants exposed to serpinB13 AA positive serum samples had 50% more Ngn3+ cells compared with pancreas explants incubated with serpinB13 AA negative samples (p=0.0029). This effect was dependent on serpinB13AA rather than other serum factors as positive serum samples immunodepleted of this AA were no longer able to stimulate development of additional Ngn3+ cells (p=0.0016). These data demonstrate that serpinB13 AA is actively involved in regulating the pathways that control development of endocrine cell lineage in the pancreas. Consequently, to our knowledge, serpinB13 AA is the first example of an autoantibody that is not solely a biomarker, but also an active player responsible for improved outcomes in T1D. To examine the role of embryonic serpinB13 AA in human diabetes in future, we aim to measure serpinB13 AA in pregnant women with T1D, or at significant risk for this disease, and assess its impact on the development of diabetes in their offspring after birth.
Y. Kryvalap: None. J. Czyzyk: None.
American Diabetes Association (I-17-ICTS-083 to J.C.); National Institutes of Health (DK10873901A1)