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 spo...

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Bibliographic Details
Published in:Immunology and cell biology 2014-01, Vol.92 (1), p.12-19
Main Authors: Chevrier, Stephane, Kratina, Tobias, Emslie, Dianne, Karnowski, Alexander, Corcoran, Lynn M
Format: Article
Language:English
Subjects:
Animals
Autoantibodies - immunology
autoantibody
Autoimmune Diseases - immunology
Autoimmunity - immunology
B-Lymphocytes - immunology
CD4-Positive T-Lymphocytes - immunology
Cells, Cultured
Germinal Center - immunology
Glomerulonephritis - immunology
Immunoenzyme Techniques
Immunoglobulin G - immunology
Mice
Mice, Inbred C57BL
Mice, Knockout
Obf1
sanroque
T-Lymphocytes, Helper-Inducer - immunology
Trans-Activators - physiology
Ubiquitin-Protein Ligases - physiology
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Summary: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.
ISSN:0818-9641
1440-1711
DOI:10.1038/icb.2013.71