Eosinophils Contribute to Oral Tolerance via Induction of RORγt-Positive Antigen-Presenting Cells and RORγt-Positive Regulatory T Cells.

Oral tolerance has been defined as the specific suppression of immune responses to an antigen by prior oral administration of the antigen. It has been thought to serve to suppress food allergy. Previous studies have shown that dendritic cells (DCs) and regulatory T cells (Tregs) are involved in the induction of oral tolerance. However, the detailed mechanisms of Treg induction in oral tolerance remain largely unknown. Eosinophils have been recognized as effector cells in allergic diseases, but in recent years, the diverse functions of tissue-resident eosinophils have been reported. Eosinophils in the intestine have been reported to induce Tregs by releasing TGF-ß, but the role of eosinophils in oral tolerance is still controversial. In this study, we analyzed the roles of eosinophils in oral tolerance using eosinophil-deficient ΔdblGATA mice (mice lacking a high-affinity GATA-binding site in the GATA1 promoter). ΔdblGATA mice showed impaired antigen-induced oral tolerance compared to wild-type mice. The induction of RORγt+ Tregs in mesenteric lymph nodes (MLNs) by oral tolerance induction was impaired in ΔdblGATA mice compared to wild-type mice. An increase in RORγt+ antigen-presenting cells (APCs), which are involved in RORγt+ Treg differentiation, in the intestine and MLNs was not seen in ΔdblGATA mice. Notably, the expansion of group 3 innate lymphoid cells (ILC3s), a subset of RORγt+ APCs, by oral tolerance induction was seen in wild-type mice but not ΔdblGATA mice. These results suggest that eosinophils are crucial in the induction of oral tolerance, possibly via the induction of RORγt+ APCs and RORγt+ Tregs.

IL-21 is required for the maintenance and pathogenesis of murine Vγ4+ IL-17-producing γδT cells.

Murine IL-17-producing γδT (γδT17) cells are divided into two subsets: natural γδT17 (nγδT17) cells, whose development is restricted to the fetal thymus, and inducible γδT17 cells, which require antigen exposure for their IL-17 production and are presumed to develop from Rorc + Il17a - CCR9 + immature γδT17 cells in the adult thymus and whose T cell receptor (TCR) is biased toward Vγ4. Although IL-23 is known to be involved in developing γδT17 cells, the roles of other cytokines, such as IL-21, which is involved in developing Th17 cells like IL-23, in the development, maintenance, and pathophysiology of γδT17 cells remain unknown. Here, we show that IL-21 is dispensable for the fetal thymic development of nγδT17 cells but is required for the peripheral maintenance of Vγ4+nγδT17 cells. Upon stimulation with γδTCR, IL-1 plus IL-21 induces the proliferation of Vγ4+nγδT17 cells via STAT3 as effectively as IL-1 plus IL-23. Using bone marrow chimeric mice, we demonstrated that immature γδT17 cells are produced de novo in the adult mice from donor adult bone marrow cells and that IL-21 is dispensable for their development. Instead, IL-21 is required to expand newly induced Vγ4+γδT17 cells in the periphery upon immunization. Finally, using adoptive transfer experiments of γδT17 cells, we found that IL-21 receptors on γδT17 cells are involved in maintaining Vγ4+γδT17 cells, subsequent infiltration of Th17 cells into the spinal cord, and exacerbation of experimental autoimmune encephalomyelitis. Collectively, IL-21 plays a vital role in the maintenance and pathogenesis of Vγ4+γδT17 cells.

A custom-made vitreoretinal surgical simulator using a silicone mold.

PURPOSE: We constructed a custom-made vitreoretinal surgical simulator using a silicone mold and described its practicality. METHODS: We obtained spherical silicone molds, mannequins, and spray material from an internet-based vendor and combined them with expired surgical instruments to complete the simulator. Vitreoretinal experts confirmed the practicality of the simulator after simulated vitrectomy, and the results of the questionnaires were confirmed by nonvitreoretinal experts. RESULTS: Vitreoretinal experts observed that the simulated eyeball and the actual eyeball were similar in size and rigidity and that the intraocular practice swing seemed to be useful for the prevention of complications. The semitransparency and open-sky structure of the silicone material ensured visibility. The simulated membrane, which was spray glue, provided an excellent peeling sensation. In the results of the nonvitreoretinal experts' questionnaires, the average scores of all items were generally high, which supported the claims of the simulator's usefulness. CONCLUSION: This report describes the simplicity and cost-effectiveness of our custom-made simulator and its contribution in creating an ideal training environment that does not necessitate travel to special facilities that offer a large number of pig eyes and vitreous surgical machines. The simple shape seems to allow many possibilities, and further verification at multiple facilities is necessary.

CCR4 predicts the efficacy of abatacept in rheumatoid arthritis patients through the estimation of Th17 and Treg cell abundance.

OBJECTIVE: Predicting the efficacy of biological disease-modifying anti-rhematic drugs (bDMARDs) is challenging. In this study, we aimed to explore markers that predict the efficacy of abatacept in rheumatoid arthritis (RA) patients. METHODS: Thirty RA patients receiving abatacept were recruited, and peripheral blood mononuclear cells (PBMCs) from the participants were subjected to DNA microarray analysis. The expression of CCR4, which was selected by the result of DNA microarray, was determined by flow cytometry in 16 newly diagnosed treatment-naïve RA patients. CCR4 expression on each helper T cell subset was also measured. RESULTS: CCR4 was upregulated in the abatacept responder. The expression levels of CCR4 were significantly correlated with the improvement of clinical disease activity index (CDAI). CCR4 expression was predominantly observed in CD4+ T cells in PBMCs. The percentage of CCR4-expressing CD4+ T cells was significantly higher in RA patients than in healthy individuals. Interestingly, Th17 and Treg cells expressed high levels of CCR4 compared to non-Th17-related helper T cells. CONCLUSION: CCR4 is a Th17- and Treg-related gene, and the high CCR4 expression in peripheral blood samples may predict the efficacy of abatacept in RA.

A role of Achaete-scute complex homolog 2 in T follicular regulatory cell development.

T follicular regulatory (Tfr) cells, a subset of CD4+ Foxp3+ regulatory T (Treg) cells, locate to the lymphoid follicle and germinal center (GC) and regulate antibody responses. Tfr cells express the functional molecules of follicular helper T (Tfh) cells, including CXCR5 and Bcl6. CD25- mature Tfr cells differentiate from CD25+ Treg cells through CD25+ immature Tfr cells. Others and we have shown that Achaete-scute complex homolog 2 (Ascl2) plays a role in Tfh cell development; however, the role of Ascl2 in the development of Tfr cells remains unclear. Here, we found that Ascl2 was highly and preferentially expressed in CD25+ Tfr cells and CD25- Tfr cells, and that the differentiation from CD25+ Tfr cells to CD25- Tfr cells was impaired by the absence of Ascl2. Furthermore, the forced Ascl2 expression in Treg cells downregulated CD25 expression and suppressed IL-2-induced phosphorylation of STAT5, which is known to suppress CD25- Tfr cell development. Finally, we found that the downregulation of CD25 by Ascl2 in Treg cells is independent of Bach2, which also regulates CD25 downregulation in CD25+ Tfr cells. These results suggest that Ascl2 plays a vital role in developing Tfr cells, possibly by downregulating CD25 expression in a Bach2-independent mechanism.

TAp63, a methotrexate target in CD4+ T cells, suppresses Foxp3 expression and exacerbates autoimmune arthritis.

Methotrexate (MTX) is a standard, first-line therapy for rheumatoid arthritis (RA); however, its precise mechanisms of action other than antifolate activity are largely unknown. We performed DNA microarray analyses of CD4+ T cells in patients with RA before and after MTX treatment and found that TP63 was the most significantly downregulated gene after MTX treatment. TAp63, an isoform of TP63, was highly expressed in human IL-17-producing Th (Th17) cells and was suppressed by MTX in vitro. Murine TAp63 was expressed at high levels in Th cells and at lower levels in thymus-derived Treg cells. Importantly, TAp63 knockdown in murine Th17 cells ameliorated the adoptive transfer arthritis model. RNA-Seq analyses of human Th17 cells overexpressing TAp63 and those with TAp63 knockdown identified FOXP3 as a possible TAp63 target gene. TAp63 knockdown in CD4+ T cells cultured under Th17 conditions with low-dose IL-6 increased Foxp3 expression, suggesting that TAp63 balances Th17 cells and Treg cells. Mechanistically, TAp63 knockdown in murine induced Treg (iTreg) cells promoted hypomethylation of conserved noncoding sequence 2 (CNS2) of the Foxp3 gene and enhanced the suppressive function of iTreg cells. Reporter analyses revealed that TAp63 suppressed the activation of the Foxp3 CNS2 enhancer. Collectively, TAp63 suppresses Foxp3 expression and exacerbates autoimmune arthritis.

Relationship of systemic type I interferon activity with clinical phenotypes, disease activity, and damage accrual in systemic lupus erythematosus in treatment-naive patients: a retrospective longitudinal analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) is heterogeneous in organ involvement and disease severity, presenting a broad clinical phenotype. Systemic type I interferon (IFN) activity has been shown to be associated with lupus nephritis, autoantibodies, and disease activity in treated SLE patients; however, these relationships are unknown in treatment-naive patients. We aimed to determine the relationship of systemic IFN activity with clinical phenotypes, disease activity, and damage accrual in treatment-naive SLE patients before and after induction and maintenance therapy. METHODS: Forty treatment-naive SLE patients were enrolled for this retrospective longitudinal observational study to examine the relationship between serum IFN activity and clinical manifestations of EULAR/ACR-2019 criteria domains, disease activity measures, and damage accrual. As controls, 59 other treatment-naive rheumatic disease patients and 33 healthy individuals were recruited. Serum IFN activity was measured by WISH bioassay and presented as an IFN activity score. RESULTS: Treatment-naive SLE patients had significantly higher serum IFN activity than other rheumatic disease patients (score: 97.6 and 0.0, respectively, p < 0.001). High serum IFN activity was significantly associated with fever, hematologic disorders (leukopenia), and mucocutaneous manifestations (acute cutaneous lupus and oral ulcer) of EULAR/ACR-2019 criteria domains in treatment-naive SLE patients. Serum IFN activity at baseline significantly correlated with SLEDAI-2K scores and decreased along with a decrease in SLEDAI-2K scores after induction and maintenance therapy (R2 = 0.112, p = 0.034). SLE patients who developed organ damage (SDI ≥ 1) had higher serum IFN activity at baseline than those who did not (SDI = 0) (150.0 versus 57.3, p= 0.018), but the multivariate analysis did not detect its independent significance (p = 0.132). CONCLUSIONS: Serum IFN activity is characteristically high and is linked to fever, hematologic disorders, and mucocutaneous manifestations in treatment-naive SLE patients. Serum IFN activity at baseline correlates with disease activity and decreases in parallel with a decrease in disease activity after induction and maintenance therapy. Our results suggest that IFN plays an important role in the pathophysiology of SLE and that serum IFN activity at baseline may be a potential biomarker for the disease activity in treatment-naive SLE patients.

Chaperone-mediated autophagy promotes PCa survival during ARPI through selective proteome remodeling.

The androgen receptor (AR) plays an important role in PCa metabolism, with androgen receptor pathway inhibition (ARPI) subjecting PCa cells to acute metabolic stress caused by reduced biosynthesis and energy production. Defining acute stress response mechanisms that alleviate ARPI stress and therefore mediate prostate cancer (PCa) treatment resistance will help improve therapeutic outcomes of patients treated with ARPI. We identified the up-regulation of chaperone-mediated autophagy (CMA) in response to acute ARPI stress, which persisted in castration-resistant PCa (CRPC); previously undefined in PCa. CMA is a selective protein degradation pathway and a key stress response mechanism up-regulated under several stress stimuli, including metabolic stress. Through selective protein degradation, CMA orchestrates the cellular stress response by regulating cellular pathways through selective proteome remodeling. Through broad-spectrum proteomic analysis, CMA coordinates metabolic reprogramming of PCa cells to sustain PCa growth and survival during ARPI; through the upregulation of mTORC1 signaling and pathways associated with PCa biosynthesis and energetics. This not only promoted PCa growth during ARPI, but also promoted the emergence of CRPC in-vivo. During CMA inhibition, PCa metabolism is compromised, leading to ATP depletion, resulting in a profound anti-proliferative effect on PCa cells, and is enhanced when combined with ARPI. Furthermore, CMA inhibition prevented in-vivo tumour formation, and also re-sensitized enzalutamide-resistant cell lines in-vitro. The profound anti-proliferative effect of CMA inhibition was attributed to cell cycle arrest mediated through p53 transcriptional repression of E2F target genes. In summary, CMA is an acute ARPI stress response mechanism, essential in alleviating ARPI induced metabolic stress, essential for ensuring PCa growth and survival. CMA plays a critical role in the development of ARPI resistance in PCa.

Epithelial cell-derived cytokine TSLP activates regulatory T cells by enhancing fatty acid uptake.

Epithelial cells control a variety of immune cells by secreting cytokines to maintain tissue homeostasis on mucosal surfaces. Regulatory T (Treg) cells are essential for immune homeostasis and for preventing tissue inflammation; however, the precise molecular mechanisms by which epithelial cell-derived cytokines function on Treg cells in the epithelial tissues are not well understood. Here, we show that peripheral Treg cells preferentially respond to thymic stromal lymphoprotein (TSLP). Although TSLP does not affect thymic Treg differentiation, TSLP receptor-deficient induced Treg cells derived from naïve CD4+ T cells are less activated in an adoptive transfer model of colitis. Mechanistically, TSLP activates induced Treg cells partially through mTORC1 activation and fatty acid uptake. Thus, TSLP modulates the activation status of induced Treg through the enhanced uptake of fatty acids to maintain homeostasis in the large intestine.

Efficacy and safety of dose escalation of tofacitinib in refractory anti-MDA5 antibody-positive dermatomyositis.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is frequently complicated with rapidly progressive-interstitial lung disease (RP-ILD). The prognosis of MDA5-DM with RP-ILD is mostly poor despite intensive treatment with a combination of high-dose glucocorticoids and single conventional immunosuppressants. It was reported that the triple therapy (high-dose glucocorticoids, cyclophosphamide and tacrolimus) was more effective than a combination of high-dose glucocorticoids and stepwise addition of immunosuppressants. In addition, the efficacy of tofacitinib 10 mg/day for MDA5-DM with RP-ILD refractory to the triple therapy was suggested. However, the effect of those therapies was evaluated only in comparison to the historical control. Moreover, more importantly, there are still refractory patients even if treated with those therapies. In this case series, we report six MDA5-DM cases with RP-ILD in which the dose of tofacitinib was increased from 10 mg to 20 mg/day due to poor response to the triple therapy, followed by tofacitinib 10 mg/day. Four of six patients improved after dose escalation of tofacitinib, while two non-responders died. All six patients developed at least one infection including five cases of cytomegalovirus reactivation, one pulmonary aspergillosis, one herpes zoster and one herpes simplex keratitis. These cases suggest that the dose escalation of tofacitinib can be an option for MDA5-DM patients refractory to 10 mg/day of tofacitinib and other immunosuppressants although the risk of infection is a concern. The risk-benefit balance of the dose escalation of tofacitinib should be carefully assessed in each case.

Visceral disseminated varicella zoster virus infection during non-intensive maintenance therapy in a patient with systemic lupus erythematosus.

Visceral disseminated varicella zoster virus infection (VD-VZV) is a rare complication in immunocompromised patients. Although systemic lupus erythematosus (SLE) patients have a higher risk of VZV infection, only a few reports describe VD-VZV in SLE. Here, we report a 48-year-old woman with SLE who had received maintenance therapy. She was transferred to the hospital because of severe epigastric pain. There were no significant abnormalities in abdominal computed tomography and upper gastrointestinal endoscopy. On hospital day 4, she developed vesicular eruption on her face and abdomen. VZV antigen was detected in specimens obtained from skin lesions, and treatment with acyclovir was started. VZV DNA in blood turned out to be positive, and the epigastric pain was thought to be caused by VD-VZV. There is a risk of VD-VZV in patients with SLE, even in those receiving non-intensive maintenance therapy.

Antiphospholipid antibody positivity and the thrombotic risk in Japanese patients with anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: It has been reported that 21.0-51.7% of anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) patients were antiphospholipid antibody (aPL)-positive. However, the clinical significance of aPL positivity in AAV is not fully understood. METHODS: We retrospectively assessed patients with AAV diagnosed from 2013 to 2020 at our hospital. Positivity of aPL was defined as positivity of anti-cardiolipin antibody, anti-cardiolipin ß2 glycoprotein 1 complex antibody, and/or lupus anticoagulant at least one time during the follow-up periods. The thrombotic risk of aPL positivity was examined by multivariate analyses with the Cox regression model. RESULTS: A total of 93 patients with a median age of 71.9 years were included in the study. The median follow-up period was 35.4 months. Thirty-one patients (33.3%) were aPL-positive. Twenty-two thrombotic events occurred in 17 patients (18.3%). Thrombotic events occurred more frequently in aPL-positive patients than in aPL-negative patients (P = 0.011). Multivariate analyses with two different models identified aPL positivity as a thrombotic risk factor (hazard ratios 4.302 and 5.956, 95% confidence intervals 1.546-11.968 and 1.940-18.281, respectively). CONCLUSIONS: The proportion of aPL-positive patients was 33.3%, and aPL positivity increased the thrombotic risk in Japanese patients with AAV.

Annular choroidal detachment following intravitreal aflibercept injection in a patient with nivolumab treatment: a case report.

BACKGROUND: To present a novel case that developed annular choroidal detachment after intravitreal anti-vascular endothelial growth factor antibody injection in a patient after immune checkpoint inhibitor treatment. CASE PRESENTATION: A 58-year-old Japanese man presented visual impairment in the right eye. Ophthalmological examination revealed macular edema in the right eye, which suggested the possibility of age-related macular degeneration. Following the intravitreal aflibercept injection, the annular choroidal detachment was observed in the injected eye. As hypotony or thick sclera was not observed, choroidal detachment seemed to have appeared due to enhanced inflammation by intravitreal injection. The patient had a history of stage IV paranasal cavity cancer and was treated with nivolumab, an immune checkpoint inhibitor. The immune response might have been enhanced due to the use of nivolumab so that intravitreal injection triggered inflammation. Three weeks after sub-tenon injection of triamcinolone acetonide, macular edema and choroidal detachment improved. CONCLUSIONS: Intravitreal aflibercept injection caused annular choroidal detachment in our patient, presumably because the immune system was activated after nivolumab treatment. To the best of our knowledge, this is the first case report of annular choroidal detachment that developed after intravitreal injection in a patient with a history of nivolumab therapy. With the increasing use of immune checkpoint inhibitors in patients with various cancers, clinicians should be aware of these potentially associated immune-related adverse events.

A20 (Tnfaip3) expressed in CD4+ T cells suppresses Th2 cell-mediated allergic airway inflammation in mice.

A20 (Tnfaip3), a ubiquitin-editing enzyme, inhibits NF-κB signaling pathways in response to pro-inflammatory cytokines. Previous studies have proved the anti-inflammatory roles of A20 in various cell types, including T cells, B cells, dendritic cells, and intestinal epithelial cells. Moreover, recent studies have shown that A20 expressed in lung epithelial cells is required for LPS-induced protection from asthma. In humans, a single-nucleotide polymorphism in TNFAIP3 is associated with asthma risk. However, the role of A20 expressed in T cells in asthmatic responses has not been elucidated. We addressed this point by generating mice lacking A20 expression in T cells (CD4-CreA20 fl/fl mice). We found that house dust mite (HDM)-induced allergic airway inflammation, mucus production, airway hyperresponsiveness, and Th2 cytokine production were significantly exacerbated in CD4-CreA20 fl/fl mice compared with those in control A20 fl/fl mice. In vitro differentiation of Th2 cells but not of Th1 cells or Th17 cells was enhanced in CD4+ T cells by the absence of A20. Consistently, enforced expression of A20 inhibited the differentiation of Th2 cells but not of Th1 cells or Th17 cells. Notably, the expression of GATA3 was significantly enhanced in A20-deficient CD4+ T cells, and the enhanced GATA3 expression was partly canceled by IL-2 neutralization. These results suggest that A20 functions as a stabilizing factor maintaining GATA3 levels during the induction of Th2 cells to prevent excessive Th2 cell differentiation.

Semaphorin 3G exacerbates joint inflammation through the accumulation and proliferation of macrophages in the synovium.

OBJECTIVES: Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA). However, the precise mechanisms by which MTX stalls RA progression and alleviates the ensuing disease effects remain unknown. The aim of the present study was to identify novel therapeutic target molecules, the expression patterns of which are affected by MTX in patients with RA. METHODS: CD4+ T cells from 28 treatment-naïve patients with RA before and 3 months after the initiation of MTX treatment were subjected to DNA microarray analyses. The expression levels of semaphorin 3G, a differentially expressed gene, and its receptor, neuropilin-2, were evaluated in the RA synovium and collagen-induced arthritis synovium. Collagen-induced arthritis and collagen antibody-induced arthritis were induced in semaphorin3G-deficient mice and control mice, and the clinical score, histological score, and serum cytokines were assessed. The migration and proliferation of semaphorin 3G-stimulated bone marrow-derived macrophages were analyzed in vitro. The effect of local semaphorin 3G administration on the clinical score and number of infiltrating macrophages during collagen antibody-induced arthritis was evaluated. RESULTS: Semaphorin 3G expression in CD4+ T cells was downregulated by MTX treatment in RA patients. It was determined that semaphorin 3G is expressed in RA but not in the osteoarthritis synovium; its receptor neuropilin-2 is primarily expressed on activated macrophages. Semaphorin3G deficiency ameliorated collagen-induced arthritis and collagen antibody-induced arthritis. Semaphorin 3G stimulation enhanced the migration and proliferation of bone marrow-derived macrophages. Local administration of semaphorin 3G deteriorated collagen antibody-induced arthritis and increased the number of infiltrating macrophages. CONCLUSIONS: Upregulation of semaphorin 3G in the RA synovium is a novel mechanism that exacerbates joint inflammation, leading to further deterioration, through macrophage accumulation.

Epstein-Barr viral corneal stromal keratitis occurring during rheumatoid arthritis treatment: a case report.

BACKGROUND: A case of Epstein-Barr viral (EBV) corneal stromal keratitis during rheumatoid arthritis (RA) treatment is presented. CASE PRESENTATION: A 74-year-old female undergoing RA treatment was previously treated for bacterial corneal ulcer and herpetic keratitis and healed with antibiotic eye drops and topical anti-herpes ointment. At the first visit to our hospital, she presented with findings of monocular posterior interstitial keratitis with neovascularization mostly located in the inferior cornea with a corneal epithelial defect. The right eye showed no thinning of the corneal periphery and anterior uveitis. Her RA had subsided with oral steroid treatment, and infectious mononucleosis (IM) had not developed. EBV DNA could be detected in her corneal sample. After an extended but ineffective period to antibiotic treatment the corneal infiltrate responded rapidly to topical corticosteroids. CONCLUSION: EBV can cause stromal keratitis without IM during treatment for RA.

NF-κB1 Contributes to Imiquimod-Induced Psoriasis-Like Skin Inflammation by Inducing Vγ4+Vδ4+γδT17 Cells.

Recent studies have identified NF-κB1 as a new disease susceptibility gene for psoriasis. Although accumulating evidence has shown the importance of NF-κB signaling in various cell types in the pathogenesis of psoriasis, it remains unclear how NF-κB1 contributes to the pathogenesis of psoriasis. In this study, we examined psoriasis-like skin diseases induced by topical administration of imiquimod in Nf-κb1‒deficient (Nf-κb1-/-) mice and littermate wild-type (WT) mice. Compared with WT mice, Nf-κb1-/- mice exhibited attenuated skin inflammation. The numbers of Vγ4+Vδ4+γδT17 cells, which cause skin inflammation in this model, were significantly reduced in the skin and draining lymph nodes in imiquimod-treated Nf-κb1-/- mice. Nf-κb1 is preferentially phosphorylated in Vγ4+Vδ4+γδT17 cells in WT mice. In vitro proliferation of Vγ4+Vδ4+γδT17 cells but not conventional CD4+ T cells was significantly impaired in Nf-κb1-/- mice compared with that in WT mice. RNA-sequencing analyses revealed that the expression of E2 factor target genes was decreased in Vγ4+Vδ4+γδT cells by the absence of NF-κB1. Consistently, the cell cycle progression of Vγ4+Vδ4+γδT cells was reduced in Nf-κb1-/- mice compared with that in WT mice. These results suggest that Nf-κb1 plays a crucial role in the pathogenesis of imiquimod-induced psoriasis-like skin inflammation by promoting the proliferation of Vγ4+Vδ4+γδT17 cells.

The Efficacy of Surgical Metastasectomy for Solitary Metastasis of Renal Cell Carcinoma.

BACKGROUND: Patients with solitary metastasis of renal cell carcinoma (RCC) have shown to be ideal candidates for surgical metastasectomy (SM). However, whether SM will show more benefit than systemic therapy remains unclear. METHODS: We included 73 patients treated for solitary metastasis after nephrectomy at our institute from April 2008 to December 2018. We compared the clinical outcomes between the SM (n = 29) and no-SM (n = 44) group which were treated with only systemic therapy. RESULTS: Eleven of 29 patients in the SM group received presurgical targeted therapy (PTT). Although 13 of 29 patients in the SM group showed recurrence during the study period, a Cox proportional hazards model showed that SM was significantly associated with a favorable overall survival (hazard ratio: 0.18; p = 0.007). Patients receiving PTT prior to SM showed a longer recurrence-free survival after SM in comparison to those who underwent SM without PTT (median: not reached vs. 27.7 months; p = 0.009). CONCLUSIONS: If resection is feasible, SM may be beneficial for patients with solitary metastasis of RCC, and we showed the possibility that PTT prior to SM may be effective for avoiding recurrence after SM. Further large-scale prospective studies are needed to clarify the ideal treatment strategy for metastatic RCC.

Association between global sagittal malalignment and increasing hip joint contact force, analyzed by a novel musculoskeletal modeling system.

Patients with adult spinal deformity have various standing postures. Although several studies have reported a relationship between sagittal alignment and exacerbation of hip osteoarthritis, information is limited regarding how spinopelvic sagittal alignment changes affect hip joint loading. This study aimed to investigate the relationship between sagittal spinopelvic-lower limb alignment and the hip joint contact force (HCF) using a novel musculoskeletal model. We enrolled 20 women (78.3±6.7 years) from a single institution. Standing lateral radiographs were acquired to measure thoracic kyphosis, lumbar lordosis, the pelvic tilt, sacral slope, sagittal vertical axis (SVA), femur obliquity angle, and knee flexion angle. In the model simulation, the Anybody Modeling System was used, which alters muscle pathways using magnetic resonance imaging data. Each patient's alignment was entered into the model; the HCF and hip moment in the standing posture were calculated using inverse dynamics analysis. The relationship between the HCF and each parameter was examined using Spearman's correlation coefficient (r). The patients were divided into low SVA and high SVA groups, with a cutoff value of 50 mm for the SVA. The HCF was 168.2±60.1 N (%BW) and positively correlated with the SVA (r = 0.6343, p<0.01) and femur obliquity angle (r = 0.4670, p = 0.03). The HCF were 122.2 and 214.1 N (75.2% difference) in the low SVA and high SVA groups, respectively (p<0.01). The flexion moment was also increased in the high SVA group compared with that in the low SVA group (p = 0.03). The SVA and femur obliquity angle are factors related to the HCF, suggesting an association between adult spinal deformity and the exacerbation of hip osteoarthritis. Future studies will need to assess the relationship between the hip joint load and sagittal spinopelvic parameters in dynamic conditions.