Background Despite growing insights in the breach of immune tolerance, it remains currently unknown which molecules drive or control pathogenic B cells in human rheumatoid arthritis (RA).
Objectives To identify cellular and molecular pathways implicated in RA-specific humoral autoimmunity.
Methods Synovial tissue samples were obtained by arthroscopy from untreated individuals with RA and inflammation matched SpA controls. Gene expression profiling was performed on tissue samples using 44K Whole Genome Human microarrays. Top differentially expressed genes were validated on three independent cohorts by RT-qPCR and immunohistochemistry. Collagen-induced arthritis (CIA) experiments were conducted using Bob1-knockout mice and their littermate controls.
Results Microarray screening for genes differentially expressed in the inflamed synovium revealed a prominent and disease-specific B cell signature with the B cell-specific transcriptional co-activator Bob1 among the most upregulated genes. Immunohistochemistry and real-time qPCR analyses conformed microarray data and demonstrated elevated expression of Bob1 not only in established RA, but also at the early phase of the disease. Next we determined whether lack of functional Bob1 modifies disease onset/or severity in CIA. The results showed that Bob1−/− mice were fully resistant to CIA compared to their wild-type (WT) littermates and failed to produce pathogenic anti-collagen autoantibodies. To determine whether this remarkable resistance to CIA is related to failure of germinal centre (GC) formation or to intrinsic B cell defects in the absence of functional Bob1 we transferred WT B-cells to Bob1-deficient animals followed by CIA induction. After adoptive transfer Bob1-deficient mice were still resistant to CIA, suggesting that resistance to CIA is related to GC formation rather to intrinsic B cells defects in the absence of Bob1. In order to prove that functional Bob1 exclusively in B cells is required for susceptibility to CIA, we adoptively transferred various combinations of WT and Bob1-deficient B and T cells to RAG-1- null mice followed by CIA induction. The results showed that only animals that received WT B-cells displayed signs of arthritis and contained anti-collagen antibodies.
Conclusions The specific increase in Bob1 expressing cells in RA synovitis and the resistance of Bob1-defecient mice to development of CIA indicate that Bob1 may contribute to humoral autoimmunity in RA. These data strongly suggest that expression of Bob1 in B cells is indispensable for GC formation and required for the development of CIA and the formation of anti-collagen antibodies. The mechanisms behind an aberrant Bob1 expression and the break of peripheral tolerance in RA is currently under investigation.
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