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To clarify the role of T cells in the kidneys of MRL/MpJ- lpr (MRL/ lpr) mice, cytokine mRNA expression was analyzed, and tissue localization of T cells was examined by immunohistochemistry. Cells infiltrating the glomeruli, glomerular circumference, and perivascular areas in ten female MRL/ lpr mice were captured by laser microdissection (LMD). Nested reverse transcription polymerase chain reaction (RT-PCR) of samples was performed with primers specific for β-actin, T-cell receptor β chain (TCR-Cβ), Thy-1, B220, CD4, CD8, interleukin (IL)-2, IL-4, IL-10, IL-13, IL-17, and interferon (IFN)-γ. Frozen sections of lesions were also stained immunohistochemically. B220, MAC-1, Thy-1, CD4, and CD8 staining was observed in glomeruli and perivascular areas, especially in glomerular circumference areas. T cells infiltrating the glomeruli, glomerular circumference areas, and perivascular areas produce INF-γ, IL-13, and IL-17 predominately. IL-10 positivity was identified in 60% of perivascular T cells but not in a substantial number of glomerular or periglomerular T cells. The results of our study suggest that the pathogenesis of renal lesions in MRL /lpr mice is complex and not due simply to the Th1 and Th2 balance. These findings also support the concept of different molecular mechanisms for glomerulonephritis and vasculitis in these mice. [ABSTRACT FROM AUTHOR]

Diffuse alveolar hemorrhage (DAH) is a rare and severe complication of IgA vasculitis (IgAV). Although glucocorticoids and immunosuppressive agents are used for its treatment, there is no consensus on the optimal form of treatment. We herein report the case of a 53-year-old, female patient with IgAV. She was initially resistant to glucocorticoid therapy and experienced acute respiratory failure due to DAH but responded well to rituximab (RTX) and plasma exchange (PLEX). While some previous case reports have suggested that RTX or PLEX can be effective for severe IgAV, there are no reports of a combination of RTX and PLEX being used successfully to treat IgAV-associated DAH. In the model of IgAV pathogenesis proposed herein, aberrant IgA1 and IgA-specific IgG autoantibodies play a pivotal role. PLEX may facilitate the prompt removal of these circulating, aberrant immunoglobulins while RTX inhibits their further production. Consequently, a combination of RTX and PLEX may represent an effective treatment approach for severe glucocorticoid-refractory cases of IgAV., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Objective Adult-onset Still's disease (AOSD) is a rare orphan disease, the diagnosis of which remains challenging. This study aimed to identify additional clues for establishing early diagnosis beyond the existing criteria. Methods A retrospective longitudinal cohort study was conducted at two community hospitals in Japan between March 2012 and December 2022. The clinical characteristics and medical histories of patients with AOSD were extracted from the clinical records. The primary outcome was to identify the key manifestations of AOSD for an early diagnosis beyond the existing criteria. Results Twenty-one patients (mean age, 58 years) were included in the study. Fever was the first symptom in 13 out of 21 patients (62%). Six out of 21 patients (29%) presented with a pruritic rash only, while two out of 21 (10%) initially presented with a sore throat. All patients visited more than one medical institution. The median time to reach a correct diagnosis was 41 days (IQR 19-138). Nineteen out of 20 patients (95%) exhibited a pruritic rash, identified as persistent pruritic linear streaks, with a median duration of 21 days (IQR 12-64) before the diagnosis of AOSD as a cutaneous manifestation. Conclusions Persistent pruritic linear streaks were a key feature in the context of an early diagnosis of AOSD, offering an option for reconsidering and revising the existing classification criteria., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committees of Tokyo Bay Urayasu Ichikawa Medical Center and Nerima Hikarigaoka Hospital issued approval 861 and 23110901, respectively. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Iwanami et al.)

Prognosis of rheumatoid arthritis (RA) patients has significantly improved with the recent use of biologics targeting TNFα, IL-6, and co-stimulatory molecule. In US and Europe, clear therapeutic benefit of anti-CD20 antibodies is also confirmed. As a disease specific marker, rheumatoid factor and anti-citrullinated protein antibody are crucial in RA, although the pathology of them is not defined. Here we focus on glycolytic enzyme such as glucose-6-phospate isomerase, that is confirmed as arthritogenic in two different mouse models, and discuss about pathogenic relevance to RA.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with a variable disease outcome, and is characterized with synovitis, erosive changes of the joints, pain and functional deficit. Etiology is unknown. In the pathogenesis of rheumatoid arthritis the key role have proinflammatory cytokines, particularly, tumour necrosis factor (TNFalpha). The prognosis of RA patients has improved significantly during recent years, after the introduction of TNFalpha-based therapy. Despite the wide use of these biologics, their precise mechanisms of action in RA remain unclear. In the K/BxN mice, glucose-6-phosphate isomerase (GPI) is an autoantigen recognized by T and B cells. Recombinant GPI immunization to DBA/1 mice also induced acute severe arthritis. This arthritis was clearly controlled by anti-TNFalpha Abs, suggesting similar etiology to RA. In this study, to understand the mechanisms of arthritis that was regulated by TNFalpha, we focused on TNFalpha-induced adipose-related protein (TIARP) in the generation of GPI-induced arthritis.

Introduction: Tumor necrosis factor-alpha (TNFalpha) plays a pivotal role in rheumatoid arthritis (RA); however, the mechanism of action of TNFalpha antagonists in RA is poorly defined. Immunization of DBA/1 mice with glucose-6-phosphate isomerase (GPI) induces severe acute arthritis. This arthritis can be controlled by TNFalpha antagonists, suggesting similar etiology to RA. In this study, we explored TNFalpha-related mechanisms of arthritis., Methods: First, we performed GeneChip analysis using splenocytes of mice with GPI-induced arthritis. Expression of TNFalpha-induced adipose-related protein (TIARP) mRNA and protein in spleens, joints and lymph nodes was evaluated, and fluctuation of TIARP mRNA was analyzed after administration of anti-TNFalpha monoclonal antibody (mAb). Localization of TIARP in spleen and joints was also explored. Six-transmembrane epithelial antigen of the prostate (STEAP) families of proteins, the human ortholog of TIARP gene, were also evaluated in human peripheral blood mononucleocytes and synovium., Results: Among the arrayed TNFalpha-related genes, the expression of TIARP mRNA was the highest (more than 20 times the control). TIARP mRNA was detected specifically in joints and spleens of arthritic mice, and their levels in the synovia correlated with severity of joint swelling. Treatment with anti-TNF mAb significantly reduced TIARP mRNA expression in splenocytes. Among the splenocytes, CD11b+ cells were the main source of TIARP mRNA. Immunohistochemistry showed that TIARP protein was mainly localized in hyperplastic synovium. Among the STEAP family of proteins, STEAP4 was highly upregulated in joints of patients with RA and especially co-localized with CD68+ macrophages., Conclusions: The results shed light on the new mechanism of action of TNFalpha antagonists in autoimmune arthritis, suggesting that TIARP plays an important role in inflammatory arthritis, through the regulation of inflammatory cytokines.

Introduction: Immunization with glucose-6-phosphate isomerase (GPI) induces severe arthritis in DBA/1 mice. The present study was designed to identify the cytokines and co-stimulatory molecules involved in the development of GPI-induced arthritis., Methods: Arthritis was induced in DBA/1 mice with 300 microg human recombinant GPI. CD4+ T cells and antigen-presenting cells from splenocytes of arthritic mice were cultured in the presence of GPI. Tumor necrosis factor (TNF)-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12 levels were assessed using cytometric bead array. Monoclonal antibodies to TNF-alpha, IFN-gamma, IL-12, CD40L, inducible co-stimulator (ICOS), and cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig) were used to block TNF-alpha and IFN-gamma production, examine clinical index in mice with GPI-induced arthritis, and determine anti-GPI antibody production., Results: Large amounts of TNF-alpha and IFN-gamma and small amounts of IL-2 and IL-6 were produced by splenocytes from mice with GPI-induced arthritis. Anti-TNF-alpha mAbs and CTLA-4Ig suppressed TNF-alpha production, whereas anti-IFN-gamma mAbs, anti-IL-12 mAbs, and CTLA-4 Ig inhibited IFN-gamma production. A single injection of anti-TNF-alpha and anti-IL-6 mAbs and two injections of CTLA-4Ig reduced the severity of arthritis in mice, whereas injections of anti-IFN-gamma and anti-IL-12 mAbs tended to exacerbate arthritis. Therapeutic efficacy tended to correlate with reduction in anti-GPI antibodies., Conclusion: TNF-alpha and IL-6 play an important role in GPI-induced arthritis, whereas IFN-gamma appears to function as a regulator of arthritis. Because the therapeutic effects of the tested molecules used in this study are similar to those in patients with rheumatoid arthritis, GPI-induced arthritis appears to be a suitable tool with which to examine the effect of various therapies on rheumatoid arthritis.