Enhanced Anti-Serpin Antibody Activity Inhibits Autoimmune Inflammation in Type 1 Diabetes

Czyzyk, Jan; Henegariu, Octavian; Preston-Hurlburt, Paula; Baldzizhar, Raman; Fedorchuk, Christine; Esplugues, Enric; Bottomly, Kim; Gorus, Frans; Herold, Kevan C.; Flavell, Richard A.

doi:10.4049/jimmunol.1200467

Cited by 9 publications

(22 citation statements)

References 44 publications

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“…Luminex Assay-Luminex-based technology was used to measure the serum-binding activity of serpin B13 exactly as described previously (15).…”

Section: Methodsmentioning

confidence: 99%

“…1D). This early expression pattern may be responsible, in part, for the generation of a humoral response to serpin B13 in young NOD mice (15).…”

Section: Serpin B13 Is Expressed In the Pancreas-previous Analysismentioning

confidence: 99%

“…To identify this compartment, we stained frozen sections of NOD pancreatic tissue using a mAb that was produced in our laboratory (15). We found that a small amount of serpin B13 was expressed in the pancreatic islets (Fig.…”

Section: Serpin B13 Is Expressed In the Pancreas-previous Analysismentioning

confidence: 99%

“…revealed that serpin B13 is expressed in the pancreas, although the exact tissue compartment in which it is likely to be found remained unclear (15). To identify this compartment, we stained frozen sections of NOD pancreatic tissue using a mAb that was produced in our laboratory (15).…”

Section: Serpin B13 Is Expressed In the Pancreas-previous Analysismentioning

confidence: 99%

“…Recently, we found that young diabetes-prone nonobese (NOD) 2 mice (10, 11) secrete autoantibodies against a member of the clade B family called serpin B13 (12)(13)(14) and that this response is associated with protection from early-onset autoimmune diabetes (15). Because autoantibodies that interfere with enzyme cascade activities have been described in several pathologic conditions (16 -19), we aimed to address whether anti-serpin B13 autoantibodies actively protect from autoimmune diabetes by regulating the balance between this serpin and its protease targets.…”

mentioning

confidence: 99%

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Anti-serpin Antibody-mediated Regulation of Proteases in Autoimmune Diabetes

Baldzizhar

Fedorchuk

Jha

et al. 2013

Journal of Biological Chemistry

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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.

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“…Luminex Assay-Luminex-based technology was used to measure the serum-binding activity of serpin B13 exactly as described previously (15).…”

Section: Methodsmentioning

confidence: 99%

“…1D). This early expression pattern may be responsible, in part, for the generation of a humoral response to serpin B13 in young NOD mice (15).…”

Section: Serpin B13 Is Expressed In the Pancreas-previous Analysismentioning

confidence: 99%

Section: Serpin B13 Is Expressed In the Pancreas-previous Analysismentioning

confidence: 99%

Section: Serpin B13 Is Expressed In the Pancreas-previous Analysismentioning

confidence: 99%

mentioning

confidence: 99%

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Anti-serpin Antibody-mediated Regulation of Proteases in Autoimmune Diabetes

Baldzizhar

Fedorchuk

Jha

et al. 2013

Journal of Biological Chemistry

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Cellular proliferation in mouse and human pancreatic islets is regulated by serpin B13 inhibition and downstream targeting of E-cadherin by cathepsin L

Lo¹,

Kryvalap²,

Sheu³

et al. 2019

Diabetologia

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Aims/hypothesis We previously reported that exposure to antibodies neutralising serpin B13, a protease inhibitor expressed in exocrine pancreatic ducts, promotes beta cell proliferation, underscoring the importance of a functional relationship between exocrine and endocrine pancreas. The aim of the present study was to identify the molecular events that link inhibition of serpin B13 to islet cell proliferation. Methods We used an in vitro culture system consisting of isolated pancreatic islets, an extract of pancreatic ductal epithelium and a monoclonal antibody (mAb) to serpin B13 or IgG isotype control. In vivo studies involved treatment of mice with these mAbs. Results The catalytic activity of cathepsin L (CatL), a cysteine protease target of serpin B13, was augmented in the pancreas of mice injected with serpin B13 mAb. Furthermore, the addition of serpin B13 mAb to the islets, together with the pancreatic ductal epithelium lysate, caused CatL-dependent cleavage of E-cadherin and concomitant upregulation of REG genes, ultimately leading to beta cell proliferation. Direct blockade of E-cadherin with mAb also markedly enhanced REG gene induction, while chemical inhibition of β-catenin, a binding target of E-cadherin, prevented the serpin B13 mAb-induced upregulation of REG genes. Conclusions/interpretation Our work implicates the CatL-E-cadherin-REG pathway in the regulation of islet cell proliferation in response to signals generated in exocrine pancreatic tissue and demonstrates that protease activity may promote adaptive changes in the islets. Data availability Microarray data that support the findings of this study have been deposited in Gene Expression Omnibus (GEO) with the accession no. GSE125151.

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Serpins, Immunity and Autoimmunity: Old Molecules, New Functions

Gatto

Iaccarino

Ghirardello

et al. 2013

Clinic Rev Allerg Immunol

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Serine protease inhibitors (serpins) are evolutionary old, structurally conserved molecules which encompass nearly all branches of life. More than 1,000 serpins were characterized to date which are subdivided into 16 subgroups (A-P) according to their common ancestry; among them, 37 are found in humans. Serpins were termed after their capability to inhibit serine proteases, but mounting evidence suggests that they may achieve a greater deal of functions, ranging from embryological growth to synaptic plasticity, development of both myeloid and lymphoid immune cells, and modulation of apoptosis. Serpins are mainly extracellular molecules, although some of them (namely, ov-serpins or clade B serpins) mostly act inside the cells, being either ubiquitously or tissue-specifically expressed. Among newly characterized serpin functions, regulation of cellular proliferation through apoptosis modulation and proteasome disturbance seems to play a major role. Accordingly, several serpins were found to be hyperexpressed in tumor cells. Indeed, apoptosis dysregulation is likely to be a cornerstone in both tumorigenesis and autoimmunity, since uncontrolled cellular viability results in tumor proliferation, while inefficient disposal of apoptotic debris may favor the rescue of autoreactive immune cells. Such a process was widely documented in systemic lupus erythematosus (SLE). Interestingly, alterations in the expression of some serpins, e.g., the ov-serpin SERPINB3, are being unraveled in patients affected with SLE and other autoimmune disorders, suggesting that a failure in serpin function might affect immune homeostasis and self-tolerance, thereby contributing to autoimmunity. Here, we provide an overview of serpin origin, function, and dysfunction, focusing on human serpins and ov-serpins, with a hub on SERPINB3.

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Enhanced Anti-Serpin Antibody Activity Inhibits Autoimmune Inflammation in Type 1 Diabetes

Cited by 9 publications

References 44 publications

Anti-serpin Antibody-mediated Regulation of Proteases in Autoimmune Diabetes

Anti-serpin Antibody-mediated Regulation of Proteases in Autoimmune Diabetes

Cellular proliferation in mouse and human pancreatic islets is regulated by serpin B13 inhibition and downstream targeting of E-cadherin by cathepsin L

Serpins, Immunity and Autoimmunity: Old Molecules, New Functions

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