Abstract
B7-H3, a newly identified B7 family member, has functional duality as a co-stimulator and co-inhibitor that fine-tunes T cell-mediated immune responses. Given that B7-H3 expression on human monocytes and dendritic cells is enhanced by inflammatory cytokines, its potential inmmunoregulatory role at sites of inflammation has been suggested. Further, monocytes play crucial roles in the pathophysiology of various inflammatory disorders including autoimmune diseases; however, the immunological role of B7-H3 in rheumatoid arthritis (RA) has not been defined. Thus, we aimed to investigate the possible roles of monocyte B7-H3 in the pathogenesis of RA. Synovial monocytes, but not peripheral monocytes, in RA patients predominantly express surface B7-H3. The 4Ig isoform of B7-H3 is exclusively induced on the cell surface, whereas the 2Ig B7-H3 isoform is constitutively expressed in the intracytoplasmic region of both peripheral and synovial monocytes. B7-H3 knockdown experiments reveal that surface B7-H3 has an inhibitory effect on IFN-γ production in CD4 memory cells. Moreover, surface B7-H3 expression on synovial monocytes inversely correlates with RA clinical parameters. Our findings demonstrate that activation-induced B7-H3 expression on synovial monocytes has the potential to inhibit Th1-mediated immune responses and immunomodulatory roles affecting RA pathogenesis.
Highlights
Marily attack synovial membranes [1, 2]
There was a significant inverse correlation of B7-H3 expression on synovial monocytes with rheumatoid arthritis (RA) disease severity as measured by disease activity score in 28 joints (DAS28) (Fig. 7; R2 ϭ 0.246, p ϭ 0.031), suggesting that B7-H3 may participate in the regulation of inflammatory responses in RA
Our studies demonstrate that the expression of B7-H3, a recently identified B7 family member, is distinctively up-regulated on the cell surface of synovial monocytes from RA patients compared with both their peripheral monocytes and healthy controls
Summary
The synovial environment in RA is comprised of a complex mix of cell types including T cells, B cells, neutrophils, monocytes/macrophages, and fibroblast-like synoviocytes [3]. A growing body of evidence has revealed that the interactions between T cells and a variety of infiltrating immune cells and structural cells in the synovial environment play central roles in the pathogenesis of RA [4]. In this context, it has recently been shown that in vivo activated monocytes derived from the synovial fluid of active RA patients promote Th17 responses, largely in a cell contact-dependent manner. Aberrant expression of co-signaling molecules has been implicated in the pathogenesis of many immune disorders [9, 10]
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