B lymphocytes are crucial antigen-presenting cells in the pathogenic autoimmune response to GAD65 antigen in nonobese diabetic mice.
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.
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
M
M
Falcone
J
J
Lee
G
G
Patstone
B
B
Yeung
N
N
Sarvetnick
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000201:enzymology / Q000276:immunology*; D001324:Autoantigens / Q000008:administration & dosage / Q000276:immunology*; D001402:B-Lymphocytes / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000209:etiology / Q000276:immunology*; D000939:Epitopes; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007111:Immunity, Cellular; D007515:Islets of Langerhans / Q000276:immunology; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D011947:Receptors, Antigen, B-Cell / Q000276:immunology / Q000502:physiology; D016176:T-Lymphocyte Subsets / Q000276:immunology
D019138:Antibodies, Blocking; D001324:Autoantigens; D000939:Epitopes; D010446:Peptide Fragments; D011947:Receptors, Antigen, B-Cell; D005968:Glutamate Decarboxylase