B and T cell tolerance and autoimmunity in autoantibody transgenic mice.
One hallmark of systemic lupus erythematosus (SLE) is the presence of autoantibodies directed at a diverse group of proteins of the U1/Sm small nuclear ribonucleoprotein particles (snRNP). Patients with SLE and murine models of this disease generate high titers of affinity mature, isotype-switched autoantibodies characteristic of T cell-dependent immune responses. In this investigation, we made use of anti-snRNP Ig transgenic mice (2-12 Tg) to track regulation of autoreactive B cells in normal and autoimmune-prone mice. Autoantibody studies demonstrated that the regulation of anti-snRNP B cells is intact in non-autoimmune Tg mice, but not in MRL-lpr/lpr mice. We further utilize autoreactive Tg B cells as antigen-presenting cells (APC) and individual snRNP peptides to assess the presence of autoreactive T cells in the repertoire of non-autoimmune and MRL-lpr/lpr mice. We found that Tg B cells can direct specific T cell tolerance in a non-autoimmune-prone (C57Bl/6) background, whereas the same autoantibody transgene in MRL-lpr/lpr mice drives T cell autoimmunity. Moreover, Tg B cell APC could stimulate autoreactive T cells from wild-type (non-Tg) C57Bl/6 mice, indicating a lack of tolerance induction in the absence of the autoantigenic-presenting B cells. Thus, we have defined dual roles for autoantigen-presenting B lymphocytes in stimulating self-reactive T cells that inhabit the normal repertoire or, under some conditions, providing tolerance signals.
Yan
Jun
J
Section of Rheumatology, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520, USA.
Mamula
Mark J
MJ
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics; D001324:Autoantigens / Q000378:metabolism; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D004792:Enzyme Precursors / Q000378:metabolism; D005260:Female; D006801:Humans; D006825:Hybridomas / Q000276:immunology; D007108:Immune Tolerance; D047908:Intracellular Signaling Peptides and Proteins; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000276:immunology; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000276:immunology*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D001324:Autoantigens; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D017412:Ribonucleoprotein, U1 Small Nuclear; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse