Germinal center-independent, IgM-mediated autoimmunity in sanroque mice lacking Obf1.
Mice homozygous for a point mutation in the Rc3h1 gene encoding Roquin1, designated sanroque mice, develop a severe antibody-mediated autoimmune condition. The disease is T-cell intrinsic, exacerbated by macrophage-intrinsic defects and driven by excessive T follicular helper cell generation and spontaneous germinal centre (GC) formation. This culminates in abnormally high numbers of plasma cells secreting high-affinity autoreactive immunoglobulin G (IgG). Obf1 is a transcriptional co-activator required for normal T-cell-dependent antibody responses, and it is essential for GC formation under all circumstances so far tested. We crossed sanroque mice with Obf1-null mice to determine whether the hyperactivity of sanroque T cells could drive Obf1(-/-) B cells to differentiate to GC B cells, or conversely, if Obf1 loss would prevent sanroque-mediated autoimmune disease. Surprisingly, while sanroque/Obf1(-/-) mice did not form GC, they still developed autoimmune disease and succumbed even more rapidly than did sanroque mice. The disease was mediated by autoreactive IgM, which may have been derived from a pre-existing population of autoreactive B cells in the Obf1(-/-) mice responding to the over-exuberant activity of sanroque CD4 cells.
1] Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
Stephane
S
Chevrier
1] Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
Tobias
T
Kratina
1] Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
Dianne
D
Emslie
CSL Limited, Bio21 Institute, Parkville, Victoria, Australia.
Alexander
A
Karnowski
1] Molecular Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia [2] Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.
Lynn M
LM
Corcoran
D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D018858:Germinal Center / Q000276:immunology*; D005921:Glomerulonephritis / Q000276:immunology*; D007124:Immunoenzyme Techniques; D007074:Immunoglobulin G / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D015534:Trans-Activators / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
D001323:Autoantibodies; D007074:Immunoglobulin G; C490424:Pou2af1 protein, mouse; D015534:Trans-Activators; C501406:Rc3h1 protein, mouse; D044767:Ubiquitin-Protein Ligases