Background B7-H3 (B7-H3), newly identified B7 family member, has functional duality as a T-cell costimulator or coinhibitor for fine-tuning T-cell mediated immune responses. Given that B7-H3 expression is enhanced in human monocyte and dendritic cells by inflammatory cytokines, it has been suggested their potential inmmunoregulatory function at sites of inflammation. Monocytes play a crucial role 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.
Objectives We aimed to investigate the possible roles of B7-H3 on monocyte in pathogenesis of RA.
Methods Synovial fluid and peripheral blood from 33 RA patients and peripheral blood from 19 healthy controls (HCs) were obtained. The expression of B7-H3 on monocytes in RA patients and HCs were analyzed using flow cytometic analysis and quantitative RT-PCR. Purified synovial and peripheral monocytes were used for immunoblotting and intracellular flow cytometic analysis to investigate the distinct expression and localization of two isoforms of B7-H3. B7-H3-expressing THP-1 cells were transfected with B7-H3-specific siRNA and subjected to coculture assay with CD4 T cells. Proliferation and cytokine production of the cocultured T cells were assessed by CFSE dilution and ELISA, respectively. Clinical relevance of enhanced B7-H3 expression in RA was tested by comparison with clinical parameters and disease severity in the patients and with synovial cytokine levels measured by multiplex cytokine assay.
Results Synovial monocytes but not peripheral monocytes in RA patients predominantly induce surface B7-H3 expression. The induced B7-H3 is exclusively 4Ig isoform, whereas 2Ig B7-H3 isoform constitutively express the intracytoplasmic region both peripheral and synovial monocytes. The B7-H3 knockdown experiments provided the evidence that 4Ig B7-H3 isoform has an inhibitory effect on interferon-gamma (IFN-γ) production of CD4 memory cells. Moreover, the expression level of 4Ig B7-H3 on synovial monocytes was inversely correlated with clinical parameters such as C-reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), and Disease Activity Score in 28 joints (DAS28).
Conclusions Our findings demonstrate that activation-induced B7-H3 expression on synovial monocytes has the potential to inhibit Th1-mediated immune response and immunomodulatory role affecting pathogenesis of RA.
Disclosure of Interest None declared