Objective Interferon regulatory factor 5 (IRF‐5) is a transcription factor that mediates intracellular signals activated by engagement of Toll‐like receptors (TLRs). IRF5 polymorphisms are associated with an increased or decreased risk of systemic lupus erythematosus (SLE) in various human populations, but the precise role of IRF5 in SLE development is not fully understood. This study was undertaken to examine the role of IRF5 in the development of murine lupus. Methods We crossed gene‐targeted IRF5‐deficient (IRF5^−/−) mice with MRL/MpJ‐lpr/lpr (MRL/lpr) mice and examined the progeny for survival, glomerulonephritis, autoantibody levels, immune system cell populations, and dendritic cell function. Results IRF5^−/−MRL/lpr mice survived longer than control IRF5^+/+MRL/lpr mice and displayed only very mild glomerulonephritis. Autoantibodies to SLE‐related nuclear antigens were lower in IRF5^−/−MRL/lpr mouse serum, and numbers of activated CD4+ T cells were reduced in the spleen. Splenic DCs from IRF5^−/−MRL/lpr mice produced lower levels of inflammatory cytokines when treated in vitro with TLR‐7 or TLR‐9 ligands or immune complexes. Interferon‐α production in response to CpG was also decreased. Conclusion Our results show that IRF5 is a crucial driver of lupus development in mice, and indicate that IRF5 may be an attractive new target for therapeutic intervention to control disease in SLE patients.

Objectives. To investigate the relationship between the production of Th1/Th2 cytokines and cell kinetics, cell division and proliferation in patients with Behçet's disease (BD). Methods. Peripheral venous blood was drawn from patients with BD (n = 24; 10 patients with active and 14 patients with inactive BD) and normal subjects (n = 22). Peripheral blood mononuclear cells were separated immediately and were cultured with concanavalin A (Con A) followed by phorbol 12-myristate 13-acetate and ionomycin (PMA+Ion). Intracellular cytokine production of interferon-γ (IFN-γ) (Th1) and IL-4 (Th2) in CD4⁺ T cells was determined by flow cytometry. Furthermore, CD4⁺ T cells labelled with CFSE [5 (and 6) carboxyfluorescein diacretate, succinimidyl ester] were stimulated and the cells were analysed for entry into the cytokine production effector pathway during cell division in active BD and normal subjects. Results. In active BD, enhanced entry into the Th1 response effector pathway of CD4⁺ T cells was observed after stimulation with Con A followed by PMA+Ion. Analysis of CD4⁺ T cells at an identical cell division number in response to Con A followed by PMA+Ion revealed that IFN-γ-producing cells were increased in active BD patients compared with normal subjects. These results suggest that the Th1 response of dividing CD4⁺ T cells is predominantly operating in active BD. Dividing CD4⁺ T cells stimulated with Con A followed by PMA+Ion showed a phenotype of activated effector memory T cells (CD45RA^low, CD45RO⁺, CD69^high). Conclusions. Cell kinetics play a crucial role in Th1 cell differentiation and pathophysiology in BD.

Objective: We previously reported that B cells lacking the RP105 molecule, which proved to be highly activated B cells, are increased in the peripheral blood of patients with systemic lupus erythematosus (SLE). In the present study, we attempted to determine whether RP105‐negative B cells obtained from SLE patients would be capable of producing autoantibodies as well as immunoglobulins.Methods: RP105‐positive and RP105‐negative B cells, sorted by cell sorter, were cultured for 5 days without stimulation, or were stimulated with Staphylococcus aureus Cowan 1 strain (SAC) or recombinant interleukin‐6 (IL‐6). For the assay of autoantibodies, RP105‐positive and RP105‐negative B cells were cultured separately for 10 days with anti‐CD3 antibody–stimulated T cells. The production of immunoglobulins and autoantibodies was determined by enzyme‐linked immunosorbent assay.Results: We demonstrated that RP105‐negative B cells, but not RP105‐positive B cells, obtained from SLE patients could spontaneously produce IgG and IgM in vitro until day 5. SAC and IL‐6 enhanced production of IgG and IgM by RP105‐negative B cells but failed to induce such production by RP105‐positive B cells. The latter cells, however, when cocultured with activated T cells in the presence of IL‐10, produced IgG, although the amount was very small compared with that produced by RP105‐negative B cells. Most important, under these conditions, anti–double‐stranded DNA antibodies were produced only by the RP105‐negative B cells obtained from SLE patients.Conclusion: These data indicate that RP105‐negative B cells, constituting a subset of B cells in SLE patients, are highly activated and may be responsible for the production of autoantibodies as well as polyclonal immunoglobulins.

Introduction: RP105 is a Toll-like receptor homolog expressed on B cells, dendritic cells (DCs), and macrophages. We investigated the role of RP105 in the development of collagen-induced arthritis (CIA). Methods: CIA was induced in RP105-deficient DBA/1 mice and the incidence and arthritis index were analyzed. The cytokine production by spleen cells was determined. The functions of the DCs and regulatory T cells (Tregs) from RP105-deficient or control mice were determined by adding these cells to the lymph node cell culture. Arthritis was also induced by incomplete Freund's adjuvant (IFA) plus collagen or by injecting anti-collagen antibody and lipopolysaccharide. Results: RP105-deficient mice showed accelerated onset of arthritis and increased severity. Interferon-gamma (IFN-γ) and tumor necrosis factor-alpha production by spleen cells from RP105-deficient mice was increased in comparison with that from wild-type mice. The DCs from RP105-deficient mice induced more IFN-γ production, whereas Tregs from those mice showed less inhibitory effect against IFN-γ production. RP105-deficient mice also showed more severe arthritis induced by collagen with IFA. Conclusions: These results indicate that RP105 regulates the antigen-presenting cell function and Treg development, which induced the attenuation of the cell-mediated immune responses and, as a result, suppressed the development of CIA.