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Interleukin-10+ Regulatory B Cells Arise Within Antigen-Experienced CD40+ B Cells to Maintain Tolerance to Islet Autoantigens.
- Source :
- Diabetes; Jan2015, Vol. 64 Issue 1, p158-171, 14p, 1 Chart, 7 Graphs
- Publication Year :
- 2015
-
Abstract
- Impaired regulatory B cell (Breg) responses are associated with several autoimmune diseases in humans; however, the role of Bregs in type 1 diabetes (T1D) remains unclear. We hypothesized that naturally occurring, interleukin-10 (IL-10)-producing Bregs maintain tolerance to islet autoantigens, and that hyperglycemic nonobese diabetic (NOD) mice and T1D patients lack these potent negative regulators. IgV<subscript>H</subscript> transcriptome analysis revealed that islet-infiltrating B cells in long-term normoglycemic (Lnglc) NOD, which are naturally protected from diabetes, are more antigen-experienced and possess more diverse B-cell receptor repertoires compared to those of hyperglycemic (Hglc) mice. Importantly, increased levels of Breg-promoting CD40<superscript>+</superscript> B cells and IL-10-producing B cells were found within islets of Lnglc compared to Hglc NOD. Likewise, healthy individuals showed increased frequencies of both CD40<superscript>+</superscript> and IL-10<superscript>+</superscript> B cells compared to T1D patients. Rituximab-mediated B-cell depletion followed by adoptive transfer of B cells from Hglc mice induced hyperglycemia in Lnglc human CD20 transgenic NOD mouse models. Importantly, both murine and human IL-10<superscript>+</superscript> B cells significantly abrogated T-cell-mediated responses to self- or islet-specific peptides ex vivo. Together, our data suggest that antigen-matured Bregs may maintain tolerance to islet autoantigens by selectively suppressing autoreactive T-cell responses, and that Hglc mice and individuals with T1D lack this population of Bregs. [ABSTRACT FROM AUTHOR]
- Subjects :
- B cells
AUTOIMMUNE diseases
LABORATORY mice
OBESE-hyperglycemic syndrome
T cells
Subjects
Details
- Language :
- English
- ISSN :
- 00121797
- Volume :
- 64
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Diabetes
- Publication Type :
- Academic Journal
- Accession number :
- 100109314
- Full Text :
- https://doi.org/10.2337/db13-1639