Search

Autoreactive CD4 T cells are thought to play pivotal roles in the pathogenesis of rheumatoid arthritis (RA). Recently, a subset of CD4 T cells that express high levels of programmed death-1 (PD-1) but are distinct from follicular helper T cells have been identified in the joints of RA patients and named peripheral helper T (Tph) cells. Because PD-1 is expressed on T cells chronically stimulated with the Ags, we tested a hypothesis that Tph cells are the pathogenic autoreactive CD4 T cells in RA. We found that human Tph cells in RA joints produce proinflammatory effector cytokines, including IFN-γ, TNF-α, and GM-CSF, in addition to B cell-helping cytokines, such as IL-21 and CXCL13. Flow cytometric analysis showed different bias of TCR Vβ usage between PD-1high Tph cells and PD-1low/neg CD4 T cells, including Th1 cells, in the joint or memory CD4 T cells in the peripheral blood, whereas there was little difference between the latter two subsets. In line with this, deep sequencing of TCR demonstrated an overlap of expanded clones between peripheral blood memory CD4 T cells and PD-1low/neg CD4 T cells but not Tph cells in the joint. Interestingly, Tph cells preferentially exhibited autologous MLR in vitro, which required recognition of self-MHC class II and was pronounced by blocking PD-1 signaling. Taken together, these results suggest that Tph cells are the pathogenic autoreactive CD4 T cells in RA, which expand locally in the joints and are regulated by PD-1 signaling. [ABSTRACT FROM AUTHOR]

Objectives: To assess long-term outcomes for seven biological disease-modifying antirheumatic drugs (bDMARDs) and one Janus kinase (JAK)-inhibitor in rheumatoid arthritis. Methods: We retrospectively analyzed data from 801 rheumatoid arthritis patients visiting our rheumatology clinic between 2003 and 2017. We determined drug survival rates, drug discontinuation, and switching rates in these patients. Results: Among the drugs administered to naïve subjects, the drug-survival rate was highest for tocilizumab, at 77.8% after 6 years, whereas the rates for golimumab, etanercept, abatacept, infliximab, and adalimumab, were 61.5%, 48.9%, 41.6%, 34.5%, and 34.4%, respectively. Switching drugs led to decreased survival rates. The discontinuation rates for all drugs due to adverse events and poor efficacy increased rapidly in the first 2 years and the first 6 months, respectively. Conclusions: This report is a long-term analysis of a large cohort of rheumatoid arthritis patients from a single rheumatology clinic in Japan. We conclude that to maximize the survival rate of antirheumatic drugs, it is important to maintain their effectiveness over long periods of time by appropriate drug choices and optimizing dosage before switching drugs. [ABSTRACT FROM AUTHOR]

Generation of neoantigens by citrullination is implicated in the production of anti-citrullinated protein Abs in rheumatoid arthritis, but citrullination is also a physiological process. To verify whether citrullin-specific B cells are immunologically ignorant or tolerant in normal conditions, transgenic (Tg) mice expressing IgM with the V region of an anti-cyclic citrullinated peptide (CCP) mAb cloned from a rheumatoid arthritis patient were generated. CCP-specific B cells developed in the anti-CCP IgM Tg mice with an alteration of bone marrow B cell fractions, and the number of mature B cells decreased compared with wild-type or the control anti-influenza nucleoprotein-specific IgM Tg mice. In addition, B cells in anti-CCP IgM Tg mice are functionally anergic. Thus, tolerance is induced in CCP-specific B cells in vivo, suggesting that the immune systems are naturally exposed to citrullinated Ags, and anti-CCP Ab production requires additional steps beyond the generation of neoantigens by citrullination. [ABSTRACT FROM AUTHOR]

γδ T cells develop at the double-negative (DN) 2 and DN3 stages and acquire functions to produce IL-17 and IFN-γ in fetal thymus. However, the relationship between differentiation stages and their functions was unclear. In this study, we found that, although IFN-γ-producing and IL-17-producing γδ T cells developed from DN2 cells, only IFN-γ-producing γδ T cells developed from DN3 cells, indicating the direct generation of IL-17-producing γδ T cells from the DN2 stage, not through the DN3 stage. Single-cell analysis revealed that DN2 cells contained heterogeneous γδ T cell precursors with or without an ability to develop IL-17 producers. Inactivation of B cell leukemia/lymphoma 11b, a zinc finger transcription factor responsible for transition from early to late stages of DN2 cells, completely abrogated the development of IL-17-producing γδ T cells, although a unique subset of IFN-γ-producing γδ T cells expressing a high level of promyelocytic leukemia zinc finger was able to develop. Thus, our results reveal that γδ T cells are functionally differentiated to IFN-γ and IL-17 producers at different developmental stages in fetal thymus. [ABSTRACT FROM AUTHOR]

Objectives: The treatments for rheumatoid arthritis (RA) have been greatly improved, and the tight control of disease activity yields superior clinical outcomes. This study aimed to elucidate the accompanying changes in hip destruction following the implementation of a treat-to-target strategy for patients with RA. Methods: We extracted 190 hips over two periods, i.e. the early period (1998–2003) and the late period (2013–19), with 103 and 87 hips, respectively. The observed rheumatic changes, such as inward migration, upward migration, and femoral head collapse, were quantitatively evaluated, while osteoarthritic changes, such as the formation of a capital drop, were investigated from radiographs before primary total hip arthroplasty. Results: A comparison of the two periods' data showed that the degree of inward migration (−3.44 vs. −7.45 mm; P < .001) and upward migration (+4.3 vs. +0.95 mm; P < .001) significantly decreased in the late-period group. The collapse of the femoral head was not significantly different. The incidence of capital drops was significantly higher in the late-period group (7.8% vs. 27.5%; P < .001). Conclusions: The degree of inward and upward migration representative of rheumatic changes reduced, whereas the frequency of capital drops as osteoarthritic changes increased during the late period. [ABSTRACT FROM AUTHOR]

T cell development and homeostasis requires IL-7R α-chain (IL-7Rα) signaling. Tyrosine Y449 of the IL-7Rα is essential to activate STAT5 and PI3K, whereas PI3K recruitment requires IL-7Rα methionine M452. How IL-7R activates and regulates both signaling pathways differentially remains unclear. To characterize differential signaling, we established two lines of IL-7Rα mutant mice: IL-7R-Y449F mice and IL-7R-M452L mice. IL-7R-Y449F mice showed decreased PI3K and STAT5 signals, whereas IL-7R-M452L mice showed decreased PI3K but significantly increased STAT5 signaling, owing to a competition between PI3K and STAT5 signaling through Y449 of IL-7Rα. The number of T, B, and mature innate lymphoid cells were markedly reduced in IL-7R-Y449F mice, whereas IL-7R-M452L mice showed impaired early T cell development and memory precursor effector T cell maintenance with the downregulation of transcription factor T cell factor-1. Peripheral T cell numbers increased in IL-7R-M452L mice with enhanced survival and homeostatic proliferation. Furthermore, although wild type and IL-7R-Y449F mice showed comparable Th1/Th2 differentiation, IL-7R-M452L mice exhibited impaired Th17 differentiation. We conclude that PI3K competes with STAT5 under IL-7Rα and maintains an appropriate signal balance for modulating T cell development and homeostasis. To our knowledge, this study provides a new insight into complex regulation of IL-7Rα signaling, which supports immune development and responses. [ABSTRACT FROM AUTHOR]

Objectives: To retrospectively evaluate the long-term results of cementless total hip arthroplasty (THA) in patients with rheumatoid arthritis (RA) and postoperative patient mortality after THA. Methods: This study included 191 hips in 149 RA patients who underwent cementless THA between 1998 and 2005. Mean age at surgery was 54.2 years, and mean follow-up was 12.6 years. Implant and patient survivorships were determined using the Kaplan-Meier method, and the associated influencing factors were determined. Results: Implant survivals at 17 years were 99.5% for stems, 93.9% for cups, and 90.8% for liners. Among the liners used, THAs with highly cross-linked polyethylene showed better survivals compared with those with conventional polyethylene and alumina-bearing surface (93.4%, 90.9%, and 52.2%, respectively). A total of 64 deaths occurred; 45 patients died within 10 years and 19 patients died between 10 and 17 years. Malignancy (25.0%) was the leading cause of death, followed by pneumonia (20.8%) and sepsis (20.8%). The patient survival rate was 36.9% at 17 years after THA. Multivariate analysis exhibited that older age at operation and greater dose of concomitant corticosteroid resulted in shorter patient survivals. Conclusions: Cementless THA worked well in patients with RA. Mortality remained high among RA patients who needed THA. [ABSTRACT FROM AUTHOR]

Objectives: This study was conducted to evaluate the period from symptom onset to diagnosis of ankylosing spondylitis (AS) in Japanese patients and to examine possible reasons for delayed diagnosis. Methods: Seventy-two consecutive patients with AS were studied. Diagnostic delay was defined as the gap between the first spondyloarthropathic symptom and diagnosis of AS according to the modified New York criteria. Results: The mean patient ages at disease onset and diagnosis were 25.6 ± 11.3 and 33.3 ± 13.2 years old, respectively, resulting in diagnostic delay of 6.7 years. The number of medical institutions to which patients were referred before diagnosis was 2.4, and orthopedic surgeons were most commonly visited (62%). Non-specific low back pain or lumbar spondylitis (33%) and degenerative arthritis (28%) were the primary diagnoses preceding that of AS. Absence of articular symptoms significantly correlated with diagnostic delay. The patients with disease onset on year 2000 or later had significantly shorter periods until diagnosis than those before 2000 (3.6 vs. 7.5 years). Conclusions: The present study showed a marked diagnostic delay among Japanese patients with AS. Although it has been improved, continuing medical education focusing on inflammatory back pain in adolescent is required for early diagnosis of AS. [ABSTRACT FROM AUTHOR]

Murine experimental autoimmune uveitis (EAU) is a model for human autoimmune uveitis, whose pathogenesis is caused by both Th1 and Th17 cell responses. Epstein-Barr virus-induced gene 3 (EBI3) is a component of the heterodimeric cytokines: interleukin (IL)-27 and IL-35. Although IL-27 was shown to initiate Th1 cell development, it is also recognized as a negative regulator of fully activated CD4+ T cells, including Th17 cells. Recently, IL-35 also has also been reported to play immunosuppressive roles in autoimmunity. To investigate the roles of EBI3 in EAU, EBI3-/- mice were immunized with human interphotoreceptor retinoid binding protein peptide 1-20 (IRBP) to induce EAU. We observed that the clinical score in EBI3-/- mice was diminished compared with that in EBI3+/+ mice up to day 22 after immunization, whereas the score in EBI3-/- mice reached the same levels as that of EBI3+/+ mice after day 28. Histological analysis revealed a significant reduction of cellular infiltration into the retina in EBI3-/- mice on day 16. Although Th1 cell responses and IRBP-specific IL-10 production were reduced in EBI3-/- mice, the development of Th17 cell responses was unaffected on day 9. On day 21, Th1 cell responses and IRBP-specific IL-10 production was restored to the same levels as that in EBI3+/+ mice, and Th17 cell responses significantly increased in EBI3-/- mice. Furthermore, Foxp3 expression in CD4+ T cells was comparable between EBI3+/+ and EBI3-/- mice on days 9 and 21. Therefore, these results indicate that EBI3 may be important in EAU initiation by Th1 cell responses and may suppress EAU by inhibition of both Th1 and Th17 cell responses in the late/maintenance phase. [ABSTRACT FROM AUTHOR]

IL-12, which is produced in response to intracellular bacteria, such as Listeria monocytogenes, promotes the development of pathogen-specific Th1 cells that play an important role in host defense. However, it has also been known that CD44high memory-phenotype CD4 T cells with Th1 functions naturally occur in naive mice, and that lymphopenia-induced proliferation of naive CD4 T cells generates memory-phenotype CD4 T cells with Th1 functions, although their differentiation mechanism and contribution to host defense are unclear. In this study, we analyzed the development and the functions of the different subsets of Th1 cells by using mice lacking tyrosine kinase 2 (Tyk2), a member of the Janus kinase family critically involved in IL-12 signaling. In contrast with the case of conventional Ag-specific Th1 cells, the development of naturally occurring Th1 cells was not impaired in Tyk2-deficient mice. In addition, Th1 cells were normally generated from Tyk2-deficient naive CD4 T cells via lymphopenia-induced proliferation. Nevertheless, all these Th1 subsets, including conventional Ag-induced Th1 cells, produced IFN-γ in response to IL-12 in a Tyk2-dependent manner. Importantly, such Tyk2-dependent bystander IFN-γ production of any Th1 subsets conferred early protection against L. monocytogenes infection. Thus, Tyk2-mediated IL-12 signaling is differentially required for the development of different Th1 cell subsets but similarly induces their bystander IFN-γ production, which contributes to innate host defense against infection with intracellular bacteria. [ABSTRACT FROM AUTHOR]