In:
Arthritis & Rheumatology, Wiley, Vol. 69, No. 4 ( 2017-04), p. 750-762
Abstract:
The molecular mechanisms steering abnormal B cell responses in autoimmune diseases remain poorly understood. We undertook this study to identify molecular switches controlling pathologic B cell responses in rheumatoid arthritis (RA). Methods Candidate molecules were identified by gene expression profiling of RA synovitis and validated by quantitative polymerase chain reaction and immunohistochemistry. B cell–specific expression was confirmed by immunofluorescence, immunoblotting, and flow cytometry. The role of Bob1 in pathologic B cell responses was assessed in collagen‐induced arthritis (CIA). Results Transcriptional profiling of RA synovitis revealed a prominent B cell signature, with the transcriptional coactivator Bob1 and its putative target BCMA being among the most up‐regulated genes. Further analysis confirmed the microarray data and demonstrated elevated levels of Bob1 in B cells in RA synovium. A functional study showed that Bob1‐deficient mice failed to produce pathogenic anti–type II collagen (anti‐CII) antibodies and were resistant to CIA. Adoptive transfer of cells from Bob1‐deficient and Bob1‐sufficient mice to recombination‐activating gene 1–null mice demonstrated that Bob1 deficiency exclusively in B cells abrogated germinal center (GC) B cell formation, anti‐CII antibody production, and CIA development. Consistent with data from animal studies, immunophenotyping of human B cell subsets revealed increased expression of Bob1, predominantly in centrocytes and centroblasts. Correspondingly, Bob1 expression in RA synovitis was strongly correlated with CD21L , a molecular marker of GCs. In addition, similar Bob1 overexpression and correlation with CD21L expression was evidenced in parotid salivary gland tissue from patients with primary Sjögren's syndrome. Conclusion These expression and functional data identify the transcriptional coactivator Bob1 as a candidate molecular switch of pathogenic B cell responses in autoimmune diseases in humans.
Type of Medium:
Online Resource
ISSN:
2326-5191
,
2326-5205
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2754614-7
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