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Peptidylarginine deiminase inhibition prevents diabetes development in NOD mice

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posted on 17.11.2020, 23:12 by Ada Admin, Fernanda M. C. Sodré, Samal Bissenova, Ylke Bruggeman, Ronak Tilvawala, Dana P. Cook, Claire Berthault, Santanu Mondal, Aïsha Callebaut, Sylvaine You, Raphael Scharfmann, Roberto Mallone, Paul R. Thompson, Chantal Mathieu, Mijke Buitinga, Lut Overbergh
Protein citrullination plays a role in several autoimmune diseases. Its involvement in murine and human type 1 diabetes has recently been recognized through the discovery of antibodies and T-cell reactivity against citrullinated peptides. In the current study, we demonstrate that systemic inhibition of peptidylarginine deiminases (PADs), the enzymes mediating citrullination, through BB-Cl-amidine treatment, prevents diabetes development in NOD mice. This prevention was associated with reduced levels of citrullination in the pancreas, decreased circulating autoantibody titers against citrullinated GRP78 and reduced spontaneous NETosis of bone marrow-derived neutrophils. Moreover, BB-Cl-amidine treatment induced a shift from Th1 to Th2 cytokines in the serum and an increase in the frequency of regulatory T cells in the blood and spleen. In the pancreas, BB-Cl-amidine treatment preserved insulin production and was associated with a less destructive immune infiltrate, characterized by reduced frequencies of effector memory CD4+ T cells and a modest reduction in the frequency of IFNγ-producing CD4+ and CD8+ T cells. Our results point to a role of citrullination in the pathogenesis of autoimmune diabetes, with PAD inhibition leading to disease prevention through modulation of immune pathways. These findings provide insight in the potential of PAD inhibition for treating autoimmune diseases like type 1 diabetes.

Funding

This work was supported by IMI2-JU under grant agreement No 115797 (INNODIA) and No 945268 (INNODIA HARVEST). This Joint Undertaking receives support from the Union’s Horizon 2020 research and innovation program and “EFPIA”, ‘JDRF” and “The Leona M. and Harry B. Helmsley Charitable Trust”. Further support came from the KU Leuven (C16/18/006), the Flemish Research Foundation (a predoctoral fellowship for SB (11A0220N), DPC (11Y6716N) and AC (1189518N) and a post-doctoral fellowship for MB (12R0719N)), and the NIH (R35GM118112 to PRT).

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