Regulation of Cathepsin G Reduces the Activation of Proinsulin-Reactive T Cells from Type 1 Diabetes PatientsReportar como inadecuado




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Autoantigenic peptides resulting from self-proteins such as proinsulin are important players in the development of type 1 diabetes mellitus T1D. Self-proteins can be processed by cathepsins Cats within endocytic compartments and loaded to major histocompatibility complex MHC class II molecules for CD4+ T cell inspection. However, the processing and presentation of proinsulin by antigen-presenting cells APC in humans is only partially understood. Here we demonstrate that the processing of proinsulin by B cell or myeloid dendritic cell mDC1-derived lysosomal cathepsins resulted in several proinsulin-derived intermediates. These intermediates were similar to those obtained using purified CatG and, to a lesser extent, CatD, S, and V in vitro. Some of these intermediates polarized T cell activation in peripheral blood mononuclear cells PBMC from T1D patients indicative for naturally processed T cell epitopes. Furthermore, CatG activity was found to be elevated in PBMC from T1D patients and abrogation of CatG activity resulted in functional inhibition of proinsulin-reactive T cells. Our data suggested the notion that CatG plays a critical role in proinsulin processing and is important in the activation process of diabetogenic T cells.



Autor: Fang Zou, Nadja Schäfer, David Palesch, Ruth Brücken, Alexander Beck, Marcin Sienczyk, Hubert Kalbacher, ZiLin Sun, Bernhard O.

Fuente: http://plos.srce.hr/



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