B Lymphocytes Are Crucial Antigen-Presenting Cells in the Pathogenic Autoimmune Response to GAD65 Antigen in Nonobese Diabetic Mice

Abstract

Recent reports have shown that B cells play a key role in the pathogenesis of T cell-mediated autoimmune diseases such as insulin-dependent diabetes mellitus (IDDM) in nonobese diabetic mice (NOD). We have investigated the role of B lymphocytes as APCs in the generation of autoreactive T cell responses by comparing spontaneous responses to self Ags in B cell-deficient and wild-type NOD mice. We determined that B cell-deficient mice had no spontaneous responses to 65-kDa glutamate decarboxylase (GAD65), its immunodominant peptides, and the 60-kDa heat shock protein. In contrast, these Ags are able to induce proliferative responses in the splenocyte cultures of B cell-positive NOD mice. However, T cells from B-deficient mice conserved the ability to respond to nonself Ags and mitogens. The Ag-presenting function of B cells was pivotal in the autoimmune response, since the proliferation of wild-type splenocytes to GAD65 was completely inhibited by blocking the surface Ig-mediated capture of the protein Ag by B cells. Responses to immunodominant GAD65 peptides were also absent in B cell-deficient NOD mice, suggesting that B cells are crucial with regard to the diversification of the autoimmune response to various self epitopes. We believe our results represent strong evidence that B cells are required as APCs to generate pathogenic autoimmune T cell responses and provide a direct correlation between the protection from autoimmune diabetes previously reported in B cell-deficient NOD mice and the lack of anti-GAD65 and anti-heat shock protein 60 T cell responses in these mice.

Antigen processing patterns determine GAD65-specific regulation vs. pathogenesis

“…In this case, the receptor would be a surface Ig specific for the p524-543 peptide. Not only is enhanced antigen uptake relevant, but also a putative unique protease activity in these APC could play a crucial role in generation of a high affinity BDC2.5 ligand (46)(47)(48). Finally, TCR-peptide-MHC interaction could be strengthened by modification of a crucial side chain of the peptide determinant (49,50).…”