Background: Humoral immunity against the protease inhibitor serpin B13 is associated with partial protection from type 1 diabetes. Results: Anti-serpin B13 antibodies up-regulate the cleavage of CD4 and CD19 molecules in lymphocytes residing in pancreatic islets and lymph nodes. Conclusion: Antibodies prevent serpin B13 from neutralizing proteases, thereby impairing leukocyte function. Significance: Enhancement of humoral immunity against serpin B13 should impede the progression of pathologic changes in type 1 diabetes.

Intracellular (clade B) ovalbumin (ov)-serpin protease inhibitors play an important role in tissue homeostasis by protecting cells from death in response to hypoosmotic stress, heat shock and other stimuli. Whether these serpins influence immunological tolerance and the risk for autoimmune diseases is not known. We found that a fraction of young autoimmune diabetes-prone non-obese diabetic (NOD) mice had elevated levels of autoantibodies against a member of clade B family known as serpinB13. High levels of anti-serpinB13 antibodies were accompanied by low levels of anti-insulin autoantibodies, reduced numbers of islet-associated T-cells and delayed onset of diabetes. Exposure to anti-serpinB13 monoclonal antibody (mAb) alone also decreased islet inflammation and co-administration of this reagent and a suboptimal dose of anti-CD3 mAb accelerated recovery from diabetes. In a fashion similar to that discovered in the NOD model, a deficiency in humoral activity against serpinB13 was associated with early onset of human type 1 diabetes. These findings suggest that in addition to limiting exposure to proteases within the cell, clade B serpins help to maintain homeostasis by inducing protective humoral immunity.

Type 1 diabetes mellitus (T1D) is characterized by a heightened antibody (Ab) response to pancreatic islet self-antigens, which is a biomarker of progressive islet pathology. We recently identified a novel antibody to clade B serpin that reduces isletassociated T cell accumulation and is linked to the delayed onset of T1D. As natural immunity to clade B arises early in life, we hypothesized that it may influence islet development during that time. To test this possibility healthy young Balb/c male mice were injected with serpin B13 mAb or IgG control and examined for the number and cellularity of pancreatic islets by immunofluorescence and FACS. Beta cell proliferation was assessed by measuring nucleotide analog 5-ethynyl-2-deoxyuridine (5-EdU) incorporation into the DNA and islet Reg gene expression was measured by real time PCR. Human studies involved measuring anti-serpin B13 autoantibodies by Luminex. We found that injecting anti-serpin B13 monoclonal Ab enhanced beta cell proliferation and Reg gene expression, induced the generation of ϳ80 pancreatic islets per animal, and ultimately led to increase in the beta cell mass. These findings are relevant to human T1D because our analysis of subjects just diagnosed with T1D revealed an association between baseline anti-serpin activity and slower residual beta cell function decline in the first year after the onset of diabetes. Our findings reveal a new role for the anti-serpin immunological response in promoting adaptive changes in the endocrine pancreas and suggests that enhancement of this response could potentially help impede the progression of T1D in humans. Type 1 diabetes mellitus (T1D)3 is an autoimmune condition that affects people of all ages. Although T1D was traditionally considered a pediatric disease, it has become clear that individuals over 20 years old can also develop detectable autoimmunity against pancreatic islets with concomitant sudden onset of insulin dependence (1). To date, the modifying factors that precipitate the clinical manifestation of autoimmune diabetes at different ages are largely unknown.We have focused on factors that regulate the timing of clinical onset of T1D. Recent observations from our laboratory have revealed a novel autoantibody directed against the serpin B13 protease inhibitor (2, 3) and demonstrated that it partially protects against early onset autoimmune diabetes (4). In T1D susceptible nonobese diabetic (NOD) mice, elevated secretion of anti-serpin B13 autoantibody is associated with protection from diabetes before 16 weeks of age, whereas decreased secretion of this antibody (Ab) in humans is associated with T1D onset before age 5 years (4). These observations suggest an inverse relationship between the serpin B13 autoantibody response and the appearance of the clinical features of T1D. We further linked the serpin Ab to reduced autoimmune inflammation in pancreatic islets, likely due to enhanced extracellular cleavage of key cell surface molecules expressed in T and B cells (5). Of note, serpins have been impl...

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When preparing figures for the above article, we inadvertently inserted an incorrect image into Fig. 4 (this data set belongs to Fig. 3A). The correct image for Fig. 4 is shown below. The content of Figs. 3A and 4 is very similar; therefore, this error did not affect our results or the conclusions of our paper.