Multikingdom characterization of gut microbiota in patients with rheumatoid arthritis and rheumatoid arthritis-associated interstitial lung disease.

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a serious and common extra-articular disease manifestation. Patients with RA-ILD experience reduced bacterial diversity and gut bacteriome alterations. However, the gut mycobiome and virome in these patients have been largely neglected. In this study, we performed whole-metagenome shotgun sequencing on fecal samples from 30 patients with RA-ILD, and 30 with RA-non-ILD, and 40 matched healthy controls. The gut bacteriome and mycobiome were explored using a reference-based approach, while the gut virome was profiled based on a nonredundant viral operational taxonomic unit (vOTU) catalog. The results revealed significant alterations in the gut microbiomes of both RA-ILD and RA-non-ILD groups compared with healthy controls. These alterations encompassed changes in the relative abundances of 351 bacterial species, 65 fungal species, and 4,367 vOTUs. Bacteria such as Bifidobacterium longum, Dorea formicigenerans, and Collinsella aerofaciens were enriched in both patient groups. Ruminococcus gnavus (RA-ILD), Gemmiger formicilis, and Ruminococcus bromii (RA-non-ILD) were uniquely enriched. Conversely, Faecalibacterium prausnitzii, Bacteroides spp., and Roseburia inulinivorans showed depletion in both patient groups. Mycobiome analysis revealed depletion of certain fungi, including Saccharomyces cerevisiae and Candida albicans, in patients with RA compared with healthy subjects. Notably, gut virome alterations were characterized by an increase in Siphoviridae and a decrease in Myoviridae, Microviridae, and Autographiviridae in both patient groups. Hence, multikingdom gut microbial signatures showed promise as diagnostic indicators for both RA-ILD and RA-non-ILD. Overall, this study provides comprehensive insights into the fecal virome, bacteriome, and mycobiome landscapes of RA-ILD and RA-non-ILD gut microbiota, thereby offering potential biomarkers for further mechanistic and clinical research.

MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus.

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.

Cutaneous leukocytoklastic vasculitis in a patient with ankylosing spondylitis: A case report.

Extra-articular manifestations (EAMs) in ankylosing spondylitis (AS) are common and most extra-articular manifestations such as acute iritis and inflammatory bowel disease are positively correlated with disease activity of AS. Vasculitis is an extra-articular manifestation of AS. However cutaneous leukocytoclastic vasculitis (CLV) is uncommon in AS patients. In this article, we report a case of a 66-year-old female patient who has had AS for long time. Although the patient's articular manifestations were stable, the aortic aneurysm and CLV continued to occur sequentially. This article reminds clinicians that even AS patients with stable articular manifestations should be followed up regularly. All extra-articular manifestations of AS patients should be taken seriously and treated as soon as possible under the guidance of rheumatoid immunologists.

Characteristics of primary Sjogren's syndrome with articular manifestations at initial treatment.

Objectives: Articular manifestations have been reported in 19.3%-53.5% of patients with primary Sjogren's syndrome. Our aim was to profile the clinical characteristics of Chinese patients with primary Sjogren's syndrome who presented with articular manifestations at the time of initial treatment. Methods: We conducted a retrospective study of 129 primary Sjogren's syndrome patients admitted to the second Affiliated Hospital of Dalian Medical University between April 2016 and December 2021 for initial treatment. Clinical and serological features, extra-articular involvement, and initial treatment were compared between primary Sjogren's syndrome patients with and without articular manifestations. Results: Fifty-seven (44.2%) primary Sjogren's syndrome patients had articular manifestations (mean age at diagnosis: 53.4 years), of which 42 (73.7%) presented with symmetrical distribution, 21 (36.8%) patients had rheumatoid factor positivity, and 11 (20.0%) patients had anti-cyclic citrullinated peptide antibodies positivity (mean 6.8 RU/mL); imaging examinations showed no signs of structural damage in these patients. The presence of articular manifestations showed positive correlation with anti-cyclic citrullinated peptide antibody level (odds ratio (OR) 1.01, 95% confidence interval (CI): 1.00-1.02; p = 0.049), C-reactive protein level (OR 1.15, 95% CI: 1.10-1.20; p = 0.000), and European League Against Rheumatism Sjogren syndrome disease activity index scores (OR 1.18, 95% CI: 1.11-1.25; p = 0.000). Ninety (69.8%) primary Sjogren's syndrome patients received hydroxychloroquine therapy. Hydroxychloroquine treatment was significantly less frequently used in articular manifestation patients (35 (70.0%) vs 55 (85.9%); p = 0.038). Conclusions: Symmetrical polyarthritis was the most common clinical manifestation of primary Sjogren's syndrome patients with articular manifestations in this cohort. Articular manifestations were associated with higher prevalence of C-reactive protein level, and European League Against Rheumatism Sjogren syndrome disease activity index score.

Diagnosis of neuropsychiatry disorder in patients with anti-MDA5 antibody dermatomyositis: A case report.

Anti-melanoma differentiation-associated gene 5 (MDA5) dermatomyositis (DM) is a rare disease that can be easily misdiagnosed. Anti-MDA5 dermatomyositis is a subtype of DM. It is distinguished by the presence of significant mucocutaneous characteristics, palmar papules, panniculitis, interstitial lung disease (ILD), and clinically amyopathic dermatomyositis (CADM). When combined with rapidly progressing ILD (RP-ILD), anti-MDA5 DM can be fatal. The literature indicates that nervous system involvement is uncommon in patients with anti-MDA5 DM. We report a case of anti-MDA5 DM with neuropsychiatric abnormalities and ILD. The patient suffered from persistent worsening mental disorders, while his ILD was relatively stable. The patient's neuropsychiatric abnormalities gradually subsided after receiving treatment with glucocorticoids, immunoglobulins, and immunosuppressants, leaving only a slow response and memory loss.

B1-cell-produced anti-phosphatidylserine antibodies contribute to lupus nephritis development via TLR-mediated Syk activation.

Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role of anti-phosphatidylserine (PS) autoantibodies in the development of LN. Elevated serum PS-specific IgG levels were measured in model mice and SLE patients, especially in those with LN. PS-specific IgG accumulation was found in the kidney biopsies of LN patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients. Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice, whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components, while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.

Exploratory analysis on the relationship between dietary live microbe intake and arthritis: a national population based cross-sectional study.

Objective: The pathogenesis of arthritis such as rheumatoid arthritis (RA) and osteoarthritis (OA) remains unclear. This study aims to investigate whether the intake of live dietary microbes can be used as an auxiliary means for the treatment of arthritis. Methods: Data used in the present research were originated from the US National Health and Nutrition Examination Survey (NHANES) from 2003-2018. Participants involved in the present study were categorized into three groups based on the dietary live microbe classification system, namely low, medium, and high dietary live microbe groups. The analyses utilized weighted univariate and multivariate logistic regression. The restricted cubic spline plot was used to explore the relationship between the high dietary live microbe group and the odds of arthritis. Results: 12,844 participants were included in the present study. The intake of high live dietary microbes in RA group was lower than that in healthy control group and OA group. The proportion of RA patients in the high live dietary microbe group was lower than that in the low and medium live dietary microbe group. Following the comprehensive adjustment for covariates, it was observed that participants in both the high and medium dietary live microbe groups exhibited lower odds of RA compared to those in the low dietary live microbe group (High OR: 0.71, 95% CI: 0.53-0.96; Medium OR: 0.77, 95% CI: 0.59-1.00, p = 0.02). A restricted cubic spline plot indicates a negative correlation between the quantity of dietary live microbes and the occurrence of RA within the high dietary live microbe group. Conclusion: The results of our study revealed a significant difference in dietary live microbe intake between healthy and RA patients. Higher dietary intake was correlated with a decreased odds of RA. However, no significant association was found between the occurrence of OA and the quantity of dietary live microbes.

Blockage of C-X-C Motif Chemokine Receptor 2 (CXCR2) Suppressed Uric Acid (UA)-Induced Cardiac Remodeling.

Hyperuricemia-induced cardiac remodeling is at least in part via pressure-dependent mechanisms, yet the pressure-independent mechanisms are not well understood. C-X-C motif chemokine ligand 1 (CXCL1) was upregulated in renal tubules from mice subjected to uric acid (UA)-induced nephropathy. Given that CXCL1 is a master chemokine responsible for the recruitment of macrophage by binding with its receptor C-X-C motif chemokine receptor 2 (CXCR2), we thus hypothesized that UA-induced cardiac injury is via promoting the recruitment of CXCR2 + macrophages into the heart, which enhances cardiac inflammation. Within a mouse model of UA injection (500 mg/kg, twice/day, 14 days), we measured the level of cardiac CXCL1. We also tested the efficacy of the CXCR2 antagonist on UA-induced cardiac inflammation and remodeling. We found a high plasma level of UA-induced upregulation of CXCL1 in heart tissues. CXCR2 antagonist relieved UA-induced cardiac hypertrophy and suppressed cardiac inflammation and fibrosis. The silencing of CXCR2 in human monocytes abolished the migration of UA-induced monocyte. Thus, the interventions against CXCL1/CXCR2 may be effective for the prevention and treatment of UA-induced cardiac hypertrophy and inflammatory responses.

Olfactory ecto-mesenchymal stem cell-derived exosomes ameliorate murine Sjögren's syndrome by modulating the function of myeloid-derived suppressor cells.

Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by progressive inflammation and tissue damage in salivary glands and lacrimal glands. Our previous studies showed that myeloid-derived suppressor cells (MDSCs) exhibited impaired immunosuppressive function during disease progression in patients with SS and mice with experimental Sjögren's syndrome (ESS), but it remains unclear whether restoring the function of MDSCs can effectively ameliorate the development of ESS. In this study, we found that murine olfactory ecto-mesenchymal stem cell-derived exosomes (OE-MSC-Exos) significantly enhanced the suppressive function of MDSCs by upregulating arginase expression and increasing ROS and NO levels. Moreover, treatment with OE-MSC-Exos via intravenous injection markedly attenuated disease progression and restored MDSC function in ESS mice. Mechanistically, OE-MSC-Exo-secreted IL-6 activated the Jak2/Stat3 pathway in MDSCs. In addition, the abundant S100A4 in OE-MSC-Exos acted as a key factor in mediating the endogenous production of IL-6 by MDSCs via TLR4 signaling, indicating an autocrine pathway of MDSC functional modulation by IL-6. Taken together, our results demonstrated that OE-MSC-Exos possess therapeutic potential to attenuate ESS progression by enhancing the immunosuppressive function of MDSCs, possibly constituting a new strategy for the treatment of Sjögren's syndrome and other autoimmune diseases.

Efficacy and safety of dual filtration plasmapheresis combined with biological agents in active refractory rheumatod arthritis: A retrospective cohort study.

To investigate the effectiveness of dual filtration plasmapheresis (DFPP), a novel blood purification treatment, as a rapid and sustained disease-modifying therapy for active refractory rheumatoid arthritis (RA).A retrospective cohort study had been conducted. One hundred fifty three patients aged 18 years or older with active refractory RA were treated with DFPP combined with infliximab (IFX), IFX, or glucocorticoid (GC), all the above treatments were combined with methotrexate (MTX).Baseline characteristic of the 153 patients (DFPP: n = 53; IFX: n = 51; GC: n = 49) were similar across groups. The remission rate of CDAI (SDAI) in the DFPP treatment group was significantly higher than that of the IFX and GC group after 3 months of treatment. The remission rate of DFPP treatment group was above 50%, while in IFX and GC group, the rate of CDAI (SDAI) remission was 41.2% (37.3%) and 22.4% (14.2%) after 3 months of treatment.A combination of DFPP and biological agents can quickly induce remission or low disease activity of active refractory RA.

Relapsing granulomatosis with polyangiitis provoked by trauma: A case report.

RATIONALE: The precise cause of granulomatosis with polyangiitis (GPA) remains unclear. Herein we present a case of refractory GPA occurring after trauma. PATIENT CONCERNS: A 43-year-old man suffered fractures of the left orbital in an accident, and then received surgical repair. At a postoperative follow-up, he developed maxillary sinusitis. Seven months later, he was hospitalized with symptoms of cough, high-grade fever, and loss of weight. DIAGNOSIS: He was diagnosed with GPA based on the symptoms of upper and lower respiratory tract involvement, granulomas in a lung biopsy specimen, and presence of PR3-ANCA. INTERVENTIONS: Initially the patient responded well to the treatment of glucocorticoids and cyclophosphamide (CYC). Forty days later, he was hospitalized again with symptoms of fever, cephalgia, and recurrent ulcerated subcutaneous nodules, due to the vasculitic manifestations of GPA. This time he was treated with cyclophosphamide and glucocorticoids with no improvement, and then switched to rituximab. OUTCOMES: After 4 doses of rituximab, the symptom of cephalgia disappeared and subcutaneous ulcerations and conjunctival congestion diminished. LESSONS: Trauma may act as an inflammatory stimulus to affect the course of disease in GPA. The combination of glucocorticoids and cyclophosphamide is the standard therapy for GPA. Nevertheless, patients who have no response to CYC, especially with predominantly vasculitic manifestations, could resort to rituximab.

Dynamic expression of transformating growth factor-ß1 and caveolin-1 in the lung of Bleomycin-induced interstitial lung disease.

BACKGROUND: Interstitial lung disease (ILD) is a disease with high mortality worldwide. Unfortunately, its prognosis is still very poor. Therefore, developing the target molecular is very important for ILD diagnosis and treatment. Caveolin-1 (Cav-1) can regulate the formation of fibrosis by linking to the signaling pathway of transforming growth factor-ß1 (TGF-ß1), which is generally considered to be the most effective approach to solve the problem of ILD. METHODS: The rat model of ILD was induced by disposable transtracheal injection of bleomycin hydrochloride. Rats were sacrificed in batches on days 7, 14, 21 and 28 after modeling, and the lung tissues was obtained for histopathological examination (HE) and Masson staining. Expressions of TGF-ß1 and Cav-1 in the lungs were measured by western blot and real-time polymerase chain reaction (RT-PCR). RESULTS: Pulmonary inflammation was observed in lung tissue from day 7 after modeling; fibrosis was observed from day 14 after modeling; the collagen deposition reached the peak on day 21. Significant TGF-ß1 up-regulation and Cav-1 down-regulation appeared in the inflammatory phase (7d); TGF-ß1 expression level reached the peak and Cav-1 expression level reached the minimum on day 21-28 with the most obvious fibrosis. CONCLUSIONS: The rat model of bleomycin induced pulmonary fibrosis can be used to dynamically observe the progress of ILD. In the lung tissues from inflammation to fibrosis, TGF-ß1 expression was significantly up-regulated and Cav-1 expression was significantly down-regulated. The regulation of two protein expressions is closely related to the occurrence and development of ILD in rats. The regulation of TGF-ß1 and Cav-1 expressions and the balance between the two can be used as a possible target of ILD therapeutic intervention.