SH3 domain-binding protein 2 (SH3BP2) is an adaptor protein that is predominantly expressed in immune cells, and it regulates intracellular signaling. We had previously reported that a gain-of-function mutation in SH3BP2 exacerbates inflammation and bone loss in murine arthritis models. Here, we explored the involvement of SH3BP2 in a lupus model. Sh3bp2 gain-of-function (P416R knock-in; Sh3bp2KI/+) mice and lupus-prone B6.MRL-Faslpr mice were crossed to yield double-mutant (Sh3bp2KI/+Faslpr/lpr) mice. We monitored survival rates and proteinuria up to 48 weeks of age and assessed renal damage and serum anti-double-stranded DNA antibody levels. Additionally, we analyzed B and T cell subsets in lymphoid tissues by flow cytometry and determined the expression of apoptosis-related molecules in lymph nodes. Sh3bp2 gain-of-function mutation alleviated the poor survival rate, proteinuria, and glomerulosclerosis and significantly reduced serum anti-dsDNA antibody levels in Sh3bp2KI/+Faslpr/lpr mice. Additionally, B220+CD4−CD8− T cell population in lymph nodes was decreased in Sh3bp2KI/+Faslpr/lpr mice, which is possibly associated with the observed increase in cleaved caspase-3 and tumor necrosis factor levels. Sh3bp2 gain-of-function mutation ameliorated clinical and immunological phenotypes in lupus-prone mice. Our findings offer better insight into the unique immunopathological roles of SH3BP2 in autoimmune diseases.

Angiotensin II (Ang II) is the main effector peptide of the renin-angiotensin system (RAS), which regulates the cardiovascular system. The RAS is reportedly also involved in bone metabolism. The upregulation of RAS components has been shown in arthritic synovial tissues, suggesting the potential involvement of Ang II in arthritis. Accordingly, in the present study, we investigated the role of Ang II in bone erosion and systemic bone loss in arthritis. Ang II was infused by osmotic pumps in tumor necrosis factor-transgenic (TNFtg) mice. Ang II infusion did not significantly affect the severity of clinical and histological inflammation, whereas bone erosion in the inflamed joints was significantly augmented. Ang II administration did not affect the bone mass of the tibia or vertebra. To suppress endogenous Ang II, Ang II type 1 receptor (AT1R)-deficient mice were crossed with TNFtg mice. Genetic deletion of AT1R did not significantly affect inflammation, bone erosion, or systemic bone loss. These results suggest that excessive systemic activation of the RAS can be a risk factor for progressive joint destruction. Our findings indicate an important implication for the pathogenesis of inflammatory bone destruction and for the clinical use of RAS inhibitors in patients with rheumatoid arthritis.

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

DesCripTionA 29-year-old man presented with a 10-year history of pain in his right ankle. The ankle was tender and swollen, and there was Achilles tendinitis. He had no complaints of buttock pain, abdominal pain, dysuria or a feeling of incomplete voiding. Skin examination was normal. Laboratory investigations revealed a leucocyte count of 6.0×109 /L and a serum C reactive protein level of 5.21 mg/dL. Liver and renal function tests were normal. Rheumatoid factor, anticyclic citrullinated peptide antibody and antinuclear antibody were negative. Urinalysis was positive for occult blood, but there was no leucocyturia. Locus B human leukocyte antigen (HLA) typing was positive for B27. Plain radiography of the right ankle joint showed narrowing of the subtalar joint space and heel spurs on the plantar aspect of the calcaneus (figure 1). Contrast-enhanced CT scans demonstrated enhanced lesions in the peripheral zone of the prostate (figure 2). Culture of urine taken after prostate massage revealed Neisseria meningitidis. The diagnosis was reactive arthritis associated with prostatitis caused by N. meningitidis. He was successfully treated with antibiotics and low-dose prednisolone followed by methotrexate.Reactive arthritis is a form of HLA-B27-associated peripheral spondyloarthropathy that arises following infection, but the pathogens cannot be cultured from the affected joints.1 In most cases, a preceding enteric or genitourinary infection triggers the reactive arthritis. In our case, we could not confirm that the urinary infection preceded the onset of arthritis. However, the patient had several features of reactive arthritis, including positive HLA-B27 serology, asymmetric chronic arthritis in the lower extremities, enthesitis and persistent urinary tract infection. Therefore, it is reasonable to consider that the arthritis was associated with chronic asymptomatic prostatitis in this patient.Organisms that induce reactive arthritis classically include Chlamydia, Yersinia, Salmonella, Shigella, Campylobacter and Clostridium spp.1 Our case is unique in that the patient developed chronic reactive arthritis associated with prostatitis attributable to N. meningitidis, which has not been previously described as a causative organism. Interestingly, in one report, PCR and sequencing analysis identified N. meningitidis DNA in synovial fluid samples from 1 of 15 patients with reactive arthritis, although the pathogenic role was unclear.

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