OBJECTIVES:Patients with RA have a 2- to 3-fold elevated risk of psychiatric disorders, suggesting an underlying genetic link between these phenotypes. However, the shared genetic architectures and pathological mechanisms driving RA-psychiatric disorder comorbidity remain to be fully elucidated. Herein, we performed cross-trait analysis to investigate the shared genetic architecture between RA and psychiatric disorders. METHODS:Leveraging European-ancestry genome-wide association studies (GWASs) datasets of RA (n = 1 026 690) and 10 major psychiatric disorders (n = 14 307-1 222 882), we performed cross-trait pleiotropic analysis to identify the shared pleiotropic loci and genes between RA and psychiatric disorders, followed by functional annotation and Mendelian randomization analysis to explore the pathological mechanisms underlying RA-psychiatric disorder comorbidity. RESULTS:Our analysis revealed significant positive genetic correlations between RA and seven psychiatric disorders, such as major depressive disorder. From these correlations, we identified 61 pleiotropic loci jointly influencing RA and psychiatric disorder risk, along with 208 pleiotropic genes predominantly involved in immune and inflammatory response biological processes. Druggable target exploration identified 21 drug-gene interactions involving pleiotropic genes, with two genes (RHOA and TRAF3) classified in the clinically actionable category, representing potential therapeutic targets for both RA and psychiatric disorders. Mendelian randomization further demonstrated a bidirectional causal relationship between RA and schizophrenia, while supporting the causal roles of attention-deficit/hyperactivity disorder, major depressive disorder and post-traumatic stress disorder in increasing RA risk. CONCLUSION:Our findings elucidate the shared genetic architecture between RA and psychiatric disorders, providing novel insights into the pathological mechanisms underlying their comorbidity and laying the groundwork for improved comorbidity management.

Rheumatoid arthritis (RA) is a common systemic autoimmune disease characterized by progressive deterioration of bone and cartilage. Sex hormone-binding globulin (SHBG), a glycoprotein integral to the regulation of sex hormone bioavailability, may have a pivotal role in the pathogenesis of RA. This study aims to investigate the relationship between SHBG concentrations and the risk of RA, as well as the occurrence of related cardiovascular complications. The analysis included 25,051 adult participants from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2023. Frailty was assessed using a 49-item frailty index, while medical conditions were self-reported via questionnaire. Logistic regression and mediation analyses were employed to evaluate these associations. Additionally, Kaplan–Meier survival curves were constructed to compare survival probabilities across different subgroups. Elevated SHBG levels were identified as a significant risk factor for RA. Both the frailty index and C-reactive protein (CRP) levels demonstrated positive correlations with RA. Importantly, the frailty index partially mediated the association between SHBG and RA, accounting for approximately 24.47

Genome-wide association studies (GWASs) have identified over 100 loci associated with rheumatoid arthritis (RA) risk. Nonetheless, the contribution of these loci to RA risk remains largely unknown, hampering the development of new therapeutics. As proteins are direct effectors of disease processes, we conducted the first large-scale proteome-wide association study (PWAS) to prioritize RA risk genes based on their effects on plasma protein abundance. We integrated RA GWAS summary statistics (discovery: 22,350 cases and 74,823 controls; replication: 31,313 cases and 995,377 controls) with precomputed protein expression weights generated from the Atherosclerosis Risk in Communities (ARIC) study (N = 7,213) and INTERVAL study (N = 3,301). Causal inference was performed using Mendelian randomization (MR) and colocalization analyses. Druggable target exploration was conducted to identify potential therapeutic targets for RA. A total of 35 genetically regulated proteins associated with RA risk, including 10 potentially causal candidates, were identified. Notably, six potentially causal proteins (FCRL3, ICOSLG, MAPK3, WISP1, FAM213A, and IL1RN) were not implicated in the original GWASs. Druggable target exploration identified 160 drug-gene interactions, including a drug, AMG-557, targeting the PWAS protein ICOSLG, which possesses superior anti-inflammatory and anti-rheumatic activity in autoimmune diseases and may therefore be a candidate for RA treatment. Our results provide novel insights into RA pathogenesis and suggest promising targets for further mechanistic investigation and drug development.

Biological aging constitutes a well-recognized risk factor for age-associated diseases; nevertheless, its specific impact on individuals with rheumatoid arthritis (RA) has not been comprehensively elucidated. This study aimed to investigate the relationships between biological aging and clinical outcomes, including reductions in life expectancy, among patients with RA. We analyzed data from 45,119 participants of the National Health and Nutrition Examination Survey (NHANES). Biological aging was quantified using the recently validated Gompertz Law-Based Biological Age (GOLD BioAge) metric. Additionally, accelerated biological aging was determined by calculating the discrepancy between biological age and chronological age. A simplified version of the GOLD BioAge, referred to as Light BioAge, was also examined. Logistic regression models were applied to assess the cross-sectional association between biological aging and RA. Longitudinal relationships between biological aging and the incidence of cardiovascular disease (CVD), heart disease, and malignancies were evaluated using Cox proportional hazards models. Furthermore, threshold effect analyses were conducted to explore potential non-linear associations. Patients with RA exhibited pronounced accelerated biological aging, which was identified as a significant risk factor for RA based on both GOLD BioAge and Light BioAge measures. GOLD BioAge demonstrated a significant association with increased all-cause mortality and cancer risk among RA patients, with threshold effect analysis revealing a non-linear relationship (p < 0.05). Moreover, RA patients exhibiting substantial acceleration in GOLD BioAge showed a proportionally increased risk of mortality attributable to CVD, heart disease, and malignancies, characterized by a linear association (p > 0.05). Biological aging is closely associated with a heightened risk of all-cause mortality and decreased life expectancy in individuals diagnosed with RA. Therefore, therapeutic interventions targeting the fundamental biological mechanisms of aging may represent a promising avenue for mitigating morbidity in this vulnerable population.

BACKGROUND:Interstitial lung disease manifests as a pulmonary complication of connective tissue diseases, significantly affecting patients' mortality and morbidity. This study aimed to investigate the roles of tacrolimus (TAC) and/or pirfenidone (PFD) in interstitial lung disease. METHODS:A mouse model of bleomycin (BLM)-induced lung fibrosis was established. Subsequently, the animals were orally administered 32 mg/kg TAC and/or 100 mg/kg PFD dissolved in distilled water. The survival rate, body weight changes, and wet-to-dry lung weight ratio were monitored. To assess lung inflammation and fibrosis, Hematoxylin-eosin staining and Masson's trichrome staining were performed. RT-qPCR and western blotting were conducted to measure expression levels of fibrotic genes. Additionally, the effects of TAC and/or PFD on the protein levels of factors involved in the TGFβ1/Smad2/3 signaling pathway were evaluated using western blotting. RESULTS:Compared with TAC or PFD treatment alone, the combination of TAC and PFD markedly improved BLM-induced changes in survival rate, body weight, and wet-to-dry lung weight ratio. Pathological analysis revealed that BLM induced inflammation and fibrosis, as evidenced by inflammatory cell infiltration, tissue edema, destruction of alveolar structure, and collagen deposition. These pathological changes were effectively attenuated by TAC and PFD treatment. The protein and mRNA expression levels of pro-fibrotic genes were elevated by BLM, and the trend was reversed by TAC and PFD. Moreover, TAC and PFD inhibited the activity of TGFβ1/Smad2/3 signaling in mouse lung tissues. CONCLUSION:Combined treatment of TAC and PFD effectively improves BLM-induced inflammatory response and pulmonary fibrosis in mice through inhibition of the TGFβ1/Smad2/3 signaling.

Objective: Chronic obstructive pulmonary disease (COPD) is intricately linked to pulmonary fibrosis, yet the underlying mechanisms remain unclear. This study investigates whether CH25H/25-hydroxycholesterol (25-HC) promotes pulmonary fibrosis in COPD by modulating AMPK/STAT6-dependent M2 macrophage polarization. Methods: Using GEO datasets and a cigarette smoke-induced COPD mouse model, we analyzed CH25H expression and fibrotic pathology. CH25H was silenced via adeno-associated virus (AAV)-delivered shRNA. Histopathology, flow cytometry, qPCR, and Western blotting assessed fibrosis, macrophage polarization (M1/M2), and AMPK/STAT6 pathway activity. Bone marrow-derived macrophages (BMDMs) were employed to validate polarization mechanisms. The role of the AMPK/STAT6 pathway was investigated using the specific activator. Results: Analysis of the GEO database and experimental verification showed significantly increased CH25H expression in both lung tissues and macrophages from COPD mice. CH25H knockdown alleviated alveolar damage, airway remodeling, and pulmonary fibrosis in COPD mice, evidenced by reduced expression of fibrosis-related proteins, improved lung function, and attenuated inflammatory responses. Moreover, CH25H knockdown inhibited M2 macrophage polarization and decreased the proportion of M2-type macrophages. Importantly, decreased levels of 25-HC following CH25H knockdown were asso ciated with suppressed activation of the AMPK/STAT6 pathway. Rescue experiments demonstrated that the protective effects of CH25H knockdown could be reversed by adding the AMPKα activator GSK621. Conclusion: Our findings demonstrate that CH25H/25-HC exacerbates COPD-associated pulmonary fibrosis by promoting AMPK/STAT6-dependent M2 macrophage polarization. Targeting CH25H may represent a novel therapeutic strategy for mitigating fibrosis in COPD.

Rheumatoid arthritis (RA) is a systemic chronic autoimmune disease that primarily affects the joints and surrounding soft tissues, characterized by chronic inflammation and proliferation of the synovium. Various immune cells are involved in the pathophysiology of RA. The complex interplay of factors such as chronic inflammation, genetic susceptibility, dysregulation of serum antibody levels, among others, contribute to the complexity of the disease mechanism, disease activity, and treatment of RA. Recently, the cytokine storm leading to increased disease activity in RA has gained significant attention. Interleukin-33 (IL -33), a member of the IL -1 family, plays a crucial role in inflammation and immune regulation. ST2 (suppression of tumorigenicity 2 receptor), the receptor for IL -33, is widely expressed on the surface of various immune cells. When IL -33 binds to its receptor ST2, it activates downstream signaling pathways to exert immunoregulatory effects. In RA, IL -33 regulates the progression of the disease by modulating immune cells such as circulating monocytes, tissue -resident macrophages, synovial fibroblasts, mast cells, dendritic cells, neutrophils, T cells, B cells, endothelial cells, and others. We have summarized and analyzed these findings to elucidate the pathways through which IL -33 regulates RA. Furthermore, IL -33 has been detected in the synovium, serum, and synovial fluid of RA patients. Due to inconsistent research results, we conducted a meta -analysis on the association between serum IL -33, synovial fluid IL -33, and the risk of developing RA in patients. The pooled SMD was 1.29 (95% CI: 1.15 -1.44), indicating that IL -33 promotes the onset and pathophysiological progression of RA. Therefore, IL -33 may serve as a biomarker for predicting the risk of developing RA and treatment outcomes. As existing drugs for RA still cannot address drug resistance in some patients, new therapeutic approaches are needed to alleviate the significant burden on RA patients and healthcare systems. In light of this, we analyzed the potential of targeting the IL -33/ ST2-related signaling pathway to modulate immune cells associated with RA and alleviate inflammation. We also reviewed IL -33 and RA susceptibility -related single nucleotide polymorphisms, suggesting potential involvement of IL -33 and macrophage -related drug -resistant genes in RA resistance therapy. Our review elucidates the role of IL -33 in the pathophysiology of RA, offering new insights for the treatment of RA.

CD147 is a T cell activation-associated molecule which is closely involved in the formation of the immune synapse (IS). However, the precise role of CD147 in T cell activation and IS formation remains unclear. In the present study, we demonstrated that CD147 translocated to the IS upon T cell activation and was primarily distributed in the peripheral super molecular cluster (p-SMAC). The knock down of CD147 expression in T cells, but not in B cells, impaired IS formation. CD147 participated in IS formation between T cells and different types of antigen-presenting cells (APCs), including macrophages and dendritic cells. Ligation of CD147 with its monoclonal antibody (mAb) HAb18 effectively inhibited T cell activation and IL-2 secretion. CD98, a critical molecule interacting with CD147, was distributed in IS in a CD147-dependent way. Phosphorylation levels of T cell receptor (TCR) related molecules, like ZAP-70, ERK, and cJun, were down-regulated by CD147 ligation, which is crucial for the interaction of CD147 and TCR signaling transduction. CD147 is indispensable for the formation of immune synapses and plays an important role in the regulation of its function.

BACKGROUND:Limited research exists on the laboratory characteristics of coexistent primary biliary cholangitis (PBC) and Sjögren's syndrome (SS). This study aimed to investigate the laboratory risk factors for the coexistence of PBC in patients with SS. METHODS:Eighty-two patients with coexistent SS and PBC (median age 52.50 years) and 82 age- and sex-matched SS controls were retrospectively enrolled between July 2015 and July 2021. The clinical and laboratory characteristics of the two groups were compared. Laboratory risk factors for the coexistence of PBC in patients with SS were analyzed using logistic regression analysis. RESULTS:Both groups had a similar prevalence of hypertension, diabetes, thyroid disease, and interstitial lung disease. Compared with the SS group, patients in the SS + PBC group had higher levels of liver enzymes, immunoglobulins M (IgM), G2, and G3 (P < 0.05). The percentage of patients with an antinuclear antibody (ANA) titre > 1:10000 in the SS + PBC group was 56.1%, higher than that in the SS group (19.5%, P < 0.05). Additionally, cytoplasmic, centromeric, and nuclear membranous patterns of ANA and positive anti-centromere antibody (ACA) were observed more frequently in the SS + PBC group (P < 0.05). Logistic regression analysis showed that elevated IgM levels, high ANA titre, cytoplasmic pattern, and ACA were independent risk factors for PBC coexistence in SS. CONCLUSIONS:In addition to established risk factors, elevated IgM levels, positive ACA, and high ANA titre with cytoplasmic pattern provide clues to clinicians for the early screening and diagnosis of PBC in patients with SS.

目的 本研究旨在探讨巨噬细胞亚型在类风湿关节炎相关间质性肺疾病(RA-ILD)患者外周血中的意义.方法 选取2017年1月至2021年12月在医院随访的158例RA-ILD患者入组本研究.RA-ILD患者分为活动组(n=63)和非活动组(n=65).活动组中,包括新诊断的RA-ILD和未治疗的受试者;非活动组中,符合缓解期的RA-ILD患者.30例单纯类风湿关节炎(RA)作为对照组.所有患者均采集外周血.流式细胞术检测巨噬细胞亚型:M1(CD14+CD86+CD80+)、M2a(CD14+CD206+CD301+)、M2b(CD14+CD206+CD86+)和 M2c(CD14+CD206+CD163+),还检测了细胞因子淋巴细胞亚群含量,包括白细胞介素(IL)(IL-1 β、IL-2、IL-4、IL-5、IL-6、IL-8、IL-10和IL-17)、干扰素(IFN)-α、IFN-γ和肿瘤坏死因子(TNF)-α.结果 M1标记CD80和M2标记CD163、CD301在活动性RA-ILD患者中高表达.活动组巨噬细胞以M1和M2a为主(P＜0.05).在非活动组中,M2倾向于极化为M2b和M2c(P＜0.05).与对照组相比,活动组IL-6显著升高(P＜0.05),非活动组IL-10、IL-4和IL-17显著升高(P＜0.05).结论 在活动的RA-ILD中,M1激活促进炎症,而M2a快速反应抑制炎症;在非活动组RA-ILD中,M2b和M2c在抑制炎症中起主要作用.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive disease characterized by excessive proliferation of fibroblasts and excessive accumulation of extracellular matrix (ECM). Ferroptosis is a novel form of cell death characterized by the lethal accumulation of iron and lipid peroxidation, which is associated with many diseases. Our study addressed the potential role played by ferroptosis and iron accumulation in the progression of pulmonary fibrosis. We found that the inducers of pulmonary fibrosis and injury, namely, bleomycin (BLM) and lipopolysaccharide (LPS), induced ferroptosis of lung epithelial cells. Both the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) alleviated the symptoms of pulmonary fibrosis induced by bleomycin or LPS. TGF-β stimulation upregulated the expression of transferrin receptor protein 1 (TFRC) in the human lung fibroblast cell line (MRC-5) and mouse primary lung fibroblasts, resulting in increased intracellular Fe2+, which promoted the transformation of fibroblasts into myofibroblasts. Mechanistically, TGF-β enhanced the expression and nuclear localization of the transcriptional coactivator tafazzin (TAZ), which combined with the transcription factor TEA domain protein (TEAD)-4 to promote the transcription of TFRC. In addition, elevated Fe2+ failed to induce the ferroptosis of fibroblasts, which might be related to the regulation of iron export and lipid metabolism. Finally, we specifically knocked out TFRC expression in fibroblasts in mice, and compared with those in the control mice, the symptoms of pulmonary fibrosis were reduced in the knockout mice after bleomycin induction. Collectively, these findings suggest the therapeutic potential of ferroptosis inhibitors and iron chelators in treating pulmonary fibrosis.

目的 研究类风湿性关节炎(RA)患者外周血单个核细胞(PBMC)、淋巴细胞(Lym)和单核细胞(Mo)及单核细胞亚型中锌指蛋白A20的表达情况,并分析A20的表达与疾病的相关性.方法 收集健康对照(HC)共78例,RA患者共57例,经流式细胞术检测外周血PBMC、T细胞、B细胞以及Mo和Mo亚型中A20的表达,分析患者28关节疾病活动度评分(DAS28)与A20表达的相关性.结果 RA患者Mo中A20表达较HC显著降低,中高疾病活动度组[DAS28-C反应蛋白(CRP)≥3.2]RA患者的Mo中A20的表达显著低于低疾病活动度组(2.6≤DAS28-CRP＜3.2)、缓解期组(DAS28-CRP＜2.6)和HC组,低疾病活动组(2.6≤DAS28-CRP＜3.2)的Mo中A20表达显著低于缓解期组(DAS28-CRP＜2.6)和HC组;以DAS28-红细胞沉降率(DAS28-ESR)为分组条件,经比较后各组间患者Mo中A20表达同上.活动期RA患者非经典型单核细胞(NCM)中A20的表达显著低于HC组,中高疾病活动度组(DAS28-CRP≥3.2)的NCM中A20表达显著低于其他三组,低疾病活动度组(2.6≤DAS28-CRP＜3.2)的NCM中A20表达显著低于缓解期组(DAS28-CRP＜2.6)和HC组;以DAS28-ESR为分组条件,经比较后各组间患者Mo亚型中A20表达无明显差异.RA患者外周血Mo中A20的表达与DAS28-CRP以及DAS28-ESR负相关;患者NCM中A20的表达与DAS28-CRP负相关.结论 RA患者的外周血Mo以及NCM中的A20表达降低且与疾病活动度负相关,提示A20可能与RA的发病相关.

ObjectiveInjections of proteoglycan aggrecan (PGA) have been reported to induce axial spondyloarthritis (ax-SpA) in BALB/c mice. It is considered to be a model for radiographic ax-SpA. However, evaluation of the extent of axial disease by histopathological assessment of every intervertebral space is labor-intensive. The objective of our paper is to test the feasibility of Micro Computed Tomography (Micro-CT) in rapidly enumerating the number of intervertebral spaces affected in each mouse.MethodsArthritis was induced in BALB/c mice by intraperitoneal injections of PGA. Involvement of several spinal segments, and selected sacroiliac and hip joints were evaluated by histopathology. The involvement of all intervertebral spaces, sacroiliac and hip joints was evaluated by Micro-CT.ResultsBALB/c mice injected with PGA developed histopathology of SpA-like axial lesions, including spondylitis, sacroiliac joint arthritis and hip joint arthritis. Micro-CT allowed us to clearly enumerate the number of lesions in each mouse.ConclusionMicro-CT allows quantitative assessment of the extent of axial involvement in PGA-induced mouse spondylitis. This can be a useful tool in assessing therapeutic interventions.

Innate lymphoid cells (ILCs) have roles in many diseases and immune pathways. To determine the roles of these cells in patients with rheumatoid arthritis (RA) and mice with collagen-induced arthritis (CIA), we measured ILC subsets using flow cytometry and multiplex immunofluorescence staining. Patients with stable RA had greater proportions of ILC2s and decreased proportions of ILC1s and ILC3s (all p < 0.05). The 28-joint disease activity (DAS28) score had positive correlations with the proportion of ILC1s and negative correlations with ILC2s (both p < 0.05). ILC2s of patients with RA expressed more IL-4 than healthy controls (p < 0.05). The proportions of ILC1s and ILC2s were greater in mice with CIA (both p < 0.05), especially the ILC2s in mice without arthritis after immunization and had correlations with multiple inflammatory and anti-inflammatory cytokines. Multiplex immunofluorescence staining described the distribution of ILCs in spleen tissues. Our results indicate that dysregulation of ILCs occurs during the pathogenesis of RA and CIA.

Regulatory T cell (Treg) stability is necessary for the proper control of immune activity and tissue homeostasis. However, it remains unclear whether Treg stability must be continually reinforced or is established during development under physiological conditions. Foxp3 has been characterized as a central mediator of the genetic program that governs Treg stability. Here, we demonstrate that to maintain Foxp3 protein expression, Tregs require cell-to-cell contact, which is mediated by the CD147-CD98 interaction. As Tregs are produced, CD147, which is expressed on their surface, is stimulated by CD98, which is widely expressed in the physiological environment. As a result, CD147’s intracellular domain binds to CDK2 and retains it near the membrane, leading to Foxp3 dephosphorylation and the prevention of Foxp3 degradation. In addition, the optimal distribution of Foxp3+ Tregs under both pathological and physiological conditions depends on CD98 expression. Thus, our study provides direct evidence that Foxp3-dependent Treg stability is reinforced in the periphery by the interaction between CD147 and CD98 in the surrounding environment. More importantly, Tregs with high CD147 expression effectively inhibit inflammatory responses and maintain Foxp3 stability, which has guiding significance for the application of Tregs in immunotherapy.

Objective To develop a model of spondyloarthritis (SpA) in mice, and analyze their clinical manifestations, radiological and histological features, and inflammatory cytokines expression levels. Methods Fourteen-week-old female BALB/c mice were immunized by intraperitoneal injection of human cartilage proteoglycan (PG), with their peripheral joints observed and scored 3 times a week. 45 weeks after immunization, micro-computed tomography (micro-CT) was used to scan the axial and peripheral joints, and bone mineral density (BMD) and bone volume/total volume (BV/TV) of the vertebral body were analyzed. The pathological changes of the axial and peripheral joints were evaluated by HE and Safranin-Fast Green staining. The levels of tumor necrosis factor alpha (TNF-α) and interleukin 17A (IL-17A) in serum were tested by ELISA. Results 30% (6/20) of PG-induced SpA (PGISpA) mice exhibited peripheral joint swelling and joint stiffness. Micro-CT showed reduced BMD and BV/TV of the vertebral body and new bone formation in sacroiliac and spinal joints in PGISpA compared with the control. Histological staining showed inflammatory cell infiltration and abnormal proliferation of synovial cells and chondrocytes in the peripheral joints. It also observed chondrocytes proliferation in the sacroiliac joints, and increased chondrocytes and osteoblasts in the spinal joints in PGISpA mice. TNF-α and IL-17A increased at week 20 after induction and TNF-α decreased at week 45 in the serum of induced mice, while IL-17A continued to increase. Conclusion The established model of PGISpA showed similar imaging and pathological features to those of human SpA, suggesting a role of IL-17A in the pathogenesis. This model, together with its research platform, can serve as the cornerstone for SpA and model animal studies.

SARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants—alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 μg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a “spike protein-CD147-CyPA signaling axis”: Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

目的 探讨系统性红斑狼疮患者(systemic lupus erythematosus,SLE)中免疫球蛋白G(immunoglobulin G,IgG)正常与IgG升高的患者,其抗核抗体(antinuclear antibody,ANA)滴度、抗双链DNA(double-strand DNA,ds-DNA)抗体及抗可溶性抗原抗体谱(extractable nuclear antigen,ENA),以便深入对SLE的认识.方法 选择2019年6～12月在空军军医大学第一附属医院就诊的初诊SLE患者150例,其中狼疮性肾炎患者62例,采用速率散射比浊法分别检测SLE患者血清中免疫球蛋白IgA,IgG,IgM及补体C3,C4的水平.采用间接免疫荧光法和欧蒙印迹法检测抗核抗体ANA,抗ds-DNA抗体及ENA.比较IgG正常组与IgG升高组患者间实验室指标的差异.结果 IgG正常组SLE患者血清中免疫球蛋白IgA,IgM水平低于IgG升高组,补体C3,C4水平高于IgG升高组,其中IgA差异具有统计学意义(z=-3.64,P<0.05).IgG正常组SLE患者抗ds-DNA抗体、抗舍格伦综合征A(SSA)抗体、抗Ro-52抗体、抗核小体抗体(AnuA)阳性率均低于IgG升高组(χ2=4.985,7.479,8.974和5.637,均P<0.05);而抗核糖核蛋白/史密斯(nRNP/Sm)抗体、抗Sm抗体、抗舍格伦综合征B(SSB)抗体、抗组蛋白抗体(AHA)、抗核糖体P蛋白抗体(ARPA)在两组之间差异无统计学意义(χ2=0.005～2.050,均P>0.05).两组患者的狼疮性肾炎患病率相似,差异无统计学意义(χ2=1.129,P>0.05).结论 IgG正常SLE患者与IgG升高患者相比,其自身抗体阳性率降低,而狼疮肾炎发病率与IgG升高组无差异,提示临床IgG正常和IgG升高的SLE患者实验室指标之间存在差异,以便加深对SLE的认识.

Objective: Our study aimed to investigate the effect of Iguratimod (IGU) on bleomycin (BLM)-induced interstitial lung disease (ILD). Methods: The pulmonary fibrosis model group mice were developed by intratracheal injection of BLM. Mice were divided into two groups at random: (1) Control group (BLM group) - endotracheal BLM (BLM, 3.5 mg/kg, Kayaku, Japan) plus an intraperitoneal injection of normal saline, and (2) BLM + IGU group - intratracheal BLM (same as the control group) + IGU intraperitoneal injection (50 mg/kg/d). The alveolar lavage fluid, histopathology/immunohistochemistry, imaging, and other tests were performed on days 7, 14, 21, and 28 after injection. Results: Lung function, including Compliance (Crs),Tissue damping (G), Static compliance (Cst), Inspiratory capacity (IC), Elastance (Ers), Tissue elastance (H) and Respiratory system resistance (Rrs) in mice, was improved by IGU. IGU reduced BLM-induced changes in pulmonary fibrosis and pulmonary inflammation, as shown in histological examination.Collagen production and inflammatory damage in the lungs caused by BLM were also reduced by IGU. IGU reduced the expression of immunoglobulin IgG and type I collagen in BLM-induced pulmonary fibrosis mice by inhibiting the production of B cells and immunoglobulin, and also delayed the deterioration of imaging changes. Conclusion: IGU inhibits immunoglobulin secretion by B cells to relieve pulmonary inflammation and fibrosis. IGU also plays a protective role in the lung in ILD.

Background The therapeutic effect of immune checkpoint blockers, especially the neutralizing antibodies of programmed cell death (PD-1) and its ligand programmed death ligand 1 (PD-L1), has been well verified in melanoma. Nevertheless, the dissatisfactory response rate and the occurrence of resistance significantly hinder the treatment effect. Inflammation-related molecules like A20 are greatly implicated in cancer immune response, but the role of tumorous A20 in antitumor immunity and immunotherapy efficacy remains elusive.Methods The association between tumorous A20 expression and the effect of anti-PD-1 immunotherapy was determined by immunoblotting, immunofluorescence staining and flow cytometry analysis of primary tumor specimens from melanoma patients. Preclinical mouse model, in vitro coculture system, immunohistochemical staining and flow cytometry analysis were employed to investigate the role of A20 in regulating the effect of anti-PD-1 immunotherapy. Bioinformatics, mass spectrum analysis and a set of biochemical analyzes were used to figure out the underlying mechanism.Results We first discovered that upregulated A20 was associated with impaired antitumor capacity of CD8+T cells and poor response to anti-PD-1 immunotherapy in melanoma patients. Subsequent functional studies in preclinical mouse model and in vitro coculture system proved that targeting tumorous A20 prominently improved the effect of immunotherapy through the invigoration of infiltrating CD8+T cells via the regulation of PD-L1. Mechanistically, A20 facilitated the ubiquitination and degradation of prohibitin to potentiate STAT3 activation and PD-L1 expression. Moreover, tumorous A20 expression was highly associated with the ratio of Ki-67 percentage in circulating PD-1+CD8+T cells to tumor burden.Conclusions Together, our findings uncover a novel crosstalk between inflammatory molecules and antitumor immunity in melanoma, and highlight that A20 can be exploited as a promising target to bring clinical benefit to melanomas refractory to immune checkpoint blockade.