Single-cell profiling identifies IL1Bhi macrophages associated with inflammation in PD-1 inhibitor-induced inflammatory arthritis.

Inflammatory arthritis (IA) is a common rheumatic adverse event following immune checkpoint inhibitors treatment. The clinical disparities between IA and rheumatoid arthritis (RA) imply disease heterogeneity and distinct mechanisms, which remain elusive. Here, we profile CD45+ cells from the peripheral blood or synovial fluid (SF) of patients with PD-1-induced IA (PD-1-IA) or RA using single-cell RNA sequencing. We report the predominant expansion of IL1Bhi myeloid cells with enhanced NLRP3 inflammasome activity, in both the SF and peripheral blood of PD-1-IA, but not RA. IL1Bhi macrophages in the SF of PD-1-IA shared similar inflammatory signatures and might originate from peripheral IL1Bhi monocytes. Exhausted CD8+ T cells (Texs) significantly accumulated in the SF of patients with PD-1-IA. IL1Bhi myeloid cells communicated with CD8+ Texs possibly via the CCR1-CCL5/CCL3 and CXCL10-CXCR3 axes. Collectively, these results demonstrate different cellular and molecular pathways in PD-1-IA and RA and highlight IL1Bhi macrophages as a possible therapeutic target in PD-1-IA.

Clinical features and prognosis of systemic lupus erythematosus complicated by active cytomegalovirus infection: a retrospective cohort study.

Objective: The aim of this study was to investigate the clinical traits and consequences of systemic lupus erythematosus (SLE) complicated by active cytomegalovirus (CMV) infection. Methods: This retrospective review involved the examination of medical records for patients diagnosed with SLE who had an active CMV infection at the time of their discharge from Peking Union Medical College Hospital between June 2016 and December 2022. The consistency between plasma CMV deoxyribonucleic acid (DNA) viral load and pp65 antigenemia was analyzed using the chi-square test. Related factors for CMV disease in SLE complicated by active CMV infection patients were analyzed by univariate analysis and multivariable stepwise logistic regression. Cox hazards regression analysis was used to determine predictors for all-cause mortality and CMV recurrence within 3 months. Results: A total of 206 patients were enrolled in this study. Of the 123 patients who were detected with both plasma CMV DNA viral load and pp65 antigenemia within an interval not exceeding 72 h, the consistency between plasma CMV DNA viral load and pp65 antigenemia was not good (Kappa = -0.304, p < 0.001). Plasma CMV DNA viral load ≥ 1,600 copies/mL [odds ratio (OR) 4.411, 95% CI 1.871-10.402, p = 0.001], current glucocorticoids dose (equivalent to prednisolone) ≥60 mg/d (OR 2.155, 95% CI 1.071-4.334, p = 0.031), and elevated alanine transaminase (OR 3.409, 95% CI 1.563-7.435, p = 0.002) were significant clinical clues indicating CMV disease in SLE. Multivariable Cox hazards regression analysis showed that CMV organ involvement [hazard ratio (HR) 47.222, 95% CI 5.621-396.689, p < 0.001], SLE multi-system involvement (HR 1.794, 95% CI 1.029-3.128, p = 0.039), and elevated hypersensitive C-reactive protein (hsCRP) (HR 5.767, 95% CI 1.190-27.943, p = 0.030) were independent risk factors for 3-month all-cause mortality. CMV organ involvement (HR 3.404, 95% CI 1.074-10.793, p = 0.037) was an independent risk factor for CMV recurrence within 3 months. Conclusion: In SLE patients, plasma CMV DNA viral load seemed to have a higher value in the diagnosis of CMV disease; patients with CMV organ involvement, SLE multi-system involvement, and elevated hsCRP might have a higher risk of 3-month all-cause mortality; and patients with CMV organ involvement might have a higher risk of CMV recurrence within 3 months.

Involvement of expanded cytotoxic and proinflammatory CD28null T cells in primary Sjögren's syndrome.

OBJECTIVE: The absence of CD28 is a feature of antigen-experienced, highly differentiated and aged T cells. The pathogenicity of CD28null T cells remains elusive in primary Sjögren's syndrome (pSS). Therefore, this study was performed to explore the characteristics of CD28null T cells in both peripheral blood and minor salivary glands (MSGs) of pSS patients. METHODS: pSS patients and paired healthy controls (HCs) were enrolled. The phenotype of peripheral CD28null T cells was analyzed using flow cytometry. In vitro functional assays were performed to evaluate the cytotoxic and proinflammatory effects of peripheral CD28null T cells. In addition, polychromatic immunofluorescence staining was performed to investigate infiltrating CD28null T cells in MSGs. RESULTS: A significant expansion of peripheral CD28null T cells was observed in pSS patients compared with HCs (p < 0.001), which were primarily CD8+CD28null T cells. The proportion of peripheral CD8+CD28null T cells moderately correlated with the erythrocyte sedimentation rate (r = 0.57, p < 0.01) and IgG levels (r = 0.44, p < 0.01). Peripheral CD28null T cells had stronger capacities to secrete granzyme B and perforin, but comparable capacities to secrete IFN-γ and TNF-α than their CD28+ counterparts. An abundant amount of cytotoxic and pro-inflammatory CD28null T cells was also found in MSGs. Moreover, a high expression of the chemokine receptor CXCR3 was found on peripheral and tissue-resident CD28null T cells, with its ligands CXCL9/10 abundantly present in MSGs. CONCLUSION: Increasing CD28null T cells with strong cytotoxicity and proinflammatory effects were observed in both peripheral blood and MSGs from pSS patients. The precise mechanism of action and migration still needs further investigation.

Withdrawal of immunosuppressants and low-dose steroids in patients with stable IgG4-RD (WInS IgG4-RD): an investigator-initiated, multicentre, open-label, randomised controlled trial.

OBJECTIVES: IgG4-related disease (IgG4-RD) is an immune-mediated, fibroinflammatory disease. Induction treatment with glucocorticoid (GC) is usually effective, but its tendency of relapse makes the strategy for maintenance treatment a challenge. The WInS IgG4-RD (withdraw immunosuppressants (IMs) and steroid in stable IgG4-RD) trial tested whether discontinuation of GC and IM was feasible in stable IgG4-RD. METHODS: The WInS IgG4-RD trial was a multicentre, open-label, randomised controlled trial. Patients with IgG4-RD receiving GC+IM as maintenance treatment with clinically quiescent disease for at least 12 months were randomised (1:1:1) into three groups: group 1: withdraw GC+IM; group 2: withdraw GC but maintain IM; group 3: maintain GC+IM. The primary outcome was the relapse rate of disease within 18 months. The secondary outcomes included the changes of IgG4-RD Responder Index (RI), Physician's Global Assessment (PGA), serum IgG4 and IgG, as well as adverse events. RESULTS: One hundred and forty-six patients were randomised, with 48 patients in group 1, 49 patients in group 2 and group 3, respectively. Within the 18-month follow-up period, disease relapse occurred in 25 out of 48 (52.1%) patients in group 1 vs 7 out of 49 (14.2%) in group 2 and 6 out of 49 (12.2%) in group 3 (p<0.001). The changes in RI and PGA were significantly higher in group 1 than in group 2 (p<0.001) or group 3 (p<0.001). CONCLUSIONS: The maintenance of IMs, with or without low-dose GC, was found to be superior to withdraw GC+IM in preventing relapse for long-time stable IgG4-RD. TRIAL REGISTRATION NUMBER: NCT04124861.

Successful treatment of anti-PTX3 positive seronegative rheumatoid arthritis with upadacitinib.

Seronegative rheumatoid arthritis (SNRA) can be a rapid-progressing and highly disabling disease. Anti-PTX3 autoantibody may be a potential biomarker in SNRA diagnosis. SNRA patients could respond well to upadacitinib.

Lupus hands mimicking psoriatic arthritis.

We report a case of a 68-year-old woman with chronic and severely destructive arthritis for 8 years with imaging features mimicking psoriatic arthritis (PsA) but serological evidence of systemic lupus erythematosus. Both the lupus panniculitis-like rash and the presence of interstitial lung disease were considered manifestations of systemic involvement of SLE.

Complement factor H attenuates TNF-α-induced inflammation by upregulating EIF3C in rheumatoid arthritis.

OBJECTIVE: To explore the role and underlying mechanism of Complement Factor H (CFH) in the peripheral and joint inflammation of RA patients. METHODS: The levels of CFH in the serum and synovial fluid were determined by ELISA. The pyroptosis of monocytes was determined by western blotting and flow cytometry. The inflammation cytokine release was tested by ELISA. The cell migration and invasion ability of fibroblast-like synoviocytes (FLS) were tested by Wound healing Assay and transwell assay, respectively. The potential target of CFH was identified by RNA sequencing. RESULTS: CFH levels were significantly elevated in the serum and synovial fluid from RA and associated with high sensitivity C-reactive protein (hs-CRP), erythrocyte sedimentation rate (ESR), and disease activity score 28 (DAS28). TNF-α could inhibit CFH expression, and CFH combined with TNF-α significantly decreased cell death, cleaved-caspase 3, gasdermin E N-terminal (GSDME-N), and inflammatory cytokines release (IL-1ß and IL-6) of RA-derived monocytes. Stimulated with TNF-α increased CFH levels in RA FLS and CFH inhibits the migration, invasion, and TNF-α-induced production of inflammatory mediators, including proinflammatory cytokines (IL-6, IL-8) as well as matrix metalloproteinases (MMPs, MMP1 and MMP3) of RA FLSs. The RNA-seq results showed that CFH treatment induced upregulation of eukaryotic translation initiation factor 3 (EIF3C) in both RA monocytes and FLS. The migration of RA FLSs was promoted and the expressions of IL-6, IL-8, and MMP-3 were enhanced upon EIF3C knockdown under the stimulation of CFH combined with TNF-α. CONCLUSION: In conclusion, we have unfolded the anti-inflammatory roles of CFH in the peripheral and joints of RA, which might provide a potential therapeutic target for RA patients.

Oxidized galectin-1 in SLE fails to bind the inhibitory receptor VSTM1 and increases reactive oxygen species levels in neutrophils.

Inhibitory immune receptors set thresholds for immune cell activation, and their deficiency predisposes a person to autoimmune responses. However, the agonists of inhibitory immune receptors remain largely unknown, representing untapped sources of treatments for autoimmune diseases. Here, we show that V-set and transmembrane domain-containing 1 (VSTM1) is an inhibitory receptor and that its binding by the competent ligand soluble galectin-1 (Gal1) is essential for maintaining neutrophil viability mediated by downregulated reactive oxygen species production. However, in patients with systemic lupus erythematosus (SLE), circulating Gal1 is oxidized and cannot be recognized by VSTM1, leading to increased intracellular reactive oxygen species levels and reduced neutrophil viability. Dysregulated neutrophil function or death contributes significantly to the pathogenesis of SLE by providing danger molecules and autoantigens that drive the production of inflammatory cytokines and the activation of autoreactive lymphocytes. Interestingly, serum levels of glutathione, an antioxidant able to convert oxidized Gal1 to its reduced form, were negatively correlated with SLE disease activity. Taken together, our findings reveal failed inhibitory Gal1/VSTM1 pathway activation in patients with SLE and provide important insights for the development of effective targeted therapies.

Study of Finite Element Simulation on the Mechano-Bactericidal Mechanism of Hierarchical Nanostructure Arrays.

Biomimetic nanostructures with bactericidal performance have become the research focus in constructing sterilization surfaces, but the mechano-bactericidal mechanism is still not fully understood, especially for the hierarchical nanostructure arrays with different heights. Herein, the interaction between Escherichia coli cells and nanostructure arrays was simulated by finite element, and the initial rupture points, i.e., critical action sites, of bacterial cells and the effects of nanostructure geometries on the cell rupture speed were analyzed based on the mechano-response of Escherichia coli cells on flat (identical heights) and hierarchical nanostructure arrays. The critical action sites of bacterial cells on nanostructure arrays are all at the three-phase junction zone of cell-liquid-nanostructure, but they are slightly shifted by the height difference ΔH of nanostructures on hierarchical nanopillar (NP)/nanosheet (NS) arrays, where the NP is higher than the NS. When ΔH < 20 nm, the site nears the NS corners, and when ΔH ≥ 20 nm, the site is consistent with that of the NP/NP array, i.e., the site locates at the three-phase junction zone of cell-liquid-high NP. In addition, except for decreasing the NP diameter, the NS thickness/width, or properly increasing the nanostructure spacing, the cell rupture can be accelerated via increasing the ΔH of nanostructures. ΔH = 40 nm is distinguished as the boundary for the effect of nanostructure ΔH on the cell rupture speed. When ΔH < 40 nm, the cell rupture speed rapidly increases as the ΔH increases; when ΔH ≥ 40 nm, the cell rupture speed reaches the maximum value and remains stable. This study provides a new strategy on how to design high-efficiency bactericidal surfaces.

Corrigendum: The potential role of RNA N6-methyladenosine in primary Sjögren's syndrome.

[This corrects the article DOI: 10.3389/fmed.2022.959388.].

Association of growth hormone deficiency with an increased number of preadipocytes in subcutaneous fat.

The inhibitory effect of growth hormone (GH) on adipose tissue growth is well known, but the underlying mechanism is not fully understood. In this study, we determined the possibility that GH inhibits adipose tissue growth by inhibiting adipogenesis, the process of formation of adipocytes from stem cells, in the lit/lit mice. The lit/lit mice are GH deficient because of a spontaneous mutation to the GH releasing hormone receptor (ghrhr) gene, and they have more subcutaneous fat despite being smaller than the lit/+ mice at the same age. We found that cells of the stromal vascular fraction (SVF) of subcutaneous fat from the lit/lit mice had greater adipogenic potential than those from the lit/+ mice, as evidenced by forming greater numbers of lipid droplets-containing adipocytes and having greater expression of adipocyte marker genes during induced adipocyte differentiation in culture. However, addition of GH to the culture did not reverse the superior adipogenic potential of subcutaneous SVF from the lit/lit mice. Through florescence-activated cell sorting and quantification of mRNAs of preadipocyte markers, including CD34, CD29, Sca-1, CD24, Pref-1, and PPARγ, we found that subcutaneous SVF from the lit/lit mice contained more preadipocytes than that from the lit/+ mice. These results support the notion that GH inhibits adipose tissue growth in mice at least in part by inhibiting adipogenesis. Furthermore, these results suggest that GH inhibits adipogenesis in mice not by inhibiting the terminal differentiation of preadipocytes into adipocytes, rather by inhibiting the formation of preadipocytes from stem cells or the recruitment of stem cells to the fat depot.

Dietary patterns and life-styles of patients with gastrointestinal involvement of systemic lupus erythematosus: Questionnaire survey from a tertiary center of China.

OBJECTIVE: To investigate the dietary patterns and lifestyles of patients with lupus gastrointestinal (GI) involvement and to reveal the possible role of organ-specific involvement of systemic lupus erythematosus (SLE) on daily diet. METHODS: Patients with SLE complicated with gastrointestinal involvement (SLE-GI) admitted to Peking Union Medical College Hospital (PUMCH) from January 2010 to September 2021 were enrolled. Age- and sex-matched SLE patients with lupus nephritis (SLE-LN) but free of other internal organs involvement who were admitted during the same period were enrolled as disease controls at the ratio of 1:1. In addition, a group of age- and sex-matched healthy people were also included as healthy controls (HCs). Questionnaires were distributed to these patients and HC to collect their dietary patterns and lifestyle information. Clinical features, dietary and lifestyle habits were compared between the two groups of patients and HC. RESULTS: The questionnaire survey showed that compared with HC, the SLE-GI group had higher proportions of vegetarians (p = 0.014) and a lower proportion of omnivores (p = 0.058). A higher percentage of SLE-GI patients reported a traditional Chinese medicine (p = 0.018) taken history and surgical history (p = 0.014). They also less likely to take fried/pickled food (p = 0.042) and dietary supplements (p = 0.024) than HC. Higher percentages of SLE-GI patients and SLE-LN patients preferred self-catering (87.5% and 94.3%) over take-out food than HC (70.8%) (p = 0.127 and p = 0.016). No significant difference on drinking preference among the three groups, but it seemed more SLE-GI patients consumed yogurt than HC (p = 0.097). The SLE-LN patients were also found to have lower frequencies of staying up late (p = 0.005). The SLE-GI group also presented higher positivity rates for anti-SSA (69.6% vs. 45.7%, p = 0.020) and anti-SSB antibodies (32.6% vs. 10.9%, p = 0.011) but lower positivity rates for anti-dsDNA antibodies (30.4% vs. 82.6%, p < 0.001) compared with the SLE-LN group. CONCLUSION: The dietary patterns, life-styles and autoantibody spectrum of SLE-GI patients differed greatly from those of SLE-LN patients and healthy people. These factors may reflect the influence of disease and organ involvement modes on patients' daily life and may contribute partly to the systemic involvement in SLE.

Proximity-enabled covalent binding of IL-2 to IL-2Rα selectively activates regulatory T cells and suppresses autoimmunity.

Interleukin-2 (IL-2) is a pleiotropic cytokine that orchestrates bidirectional immune responses via regulatory T cells (Tregs) and effector cells, leading to paradoxical consequences. Here, we report a strategy that exploited genetic code expansion-guided incorporation of the latent bioreactive artificial amino acid fluorosulfate-L-tyrosine (FSY) into IL-2 for proximity-enabled covalent binding to IL-2Rα to selectively promote Treg activation. We found that FSY-bearing IL-2 variants, such as L72-FSY, covalently bound to IL-2Rα via sulfur-fluoride exchange when in proximity, resulting in persistent recycling of IL-2 and selectively promoting the expansion of Tregs but not effector cells. Further assessment of L72-FSY-expanded Tregs demonstrated that L72-FSY maintained Tregs in a central memory phenotype without driving terminal differentiation, as demonstrated by simultaneously attenuated expression of lymphocyte activation gene-3 (LAG-3) and enhanced expression of programmed cell death protein-1 (PD-1). Subcutaneous administration of L72-FSY in murine models of pristane-induced lupus and graft-versus-host disease (GvHD) resulted in enhanced and sustained therapeutic efficacy compared with wild-type IL-2 treatment. The efficacy of L72-FSY was further improved by N-terminal PEGylation, which increased its circulatory retention for preferential and sustained effects. This proximity-enabled covalent binding strategy may accelerate the development of pleiotropic cytokines as a new class of immunomodulatory therapies.

mTORC1-GLUT1-mediated glucose metabolism drives hyperactivation of B cells in primary Sjogren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic systemic autoimmune disease characterized by B cell hyperactivation and hypergrammaglobulinemia. Currently, the role of metabolic pathways in the B cells of pSS patients is poorly defined. Here, we showed that upon cytosine phosphate-guanine (CpG)/sCD40L/IL-4 stimulation, B cells proportionally increased glycolysis and oxygen consumption, and compared with B cells from healthy controls (HCs), B cells from pSS patients exhibited higher glycolysis capacity and maximal oxidative respiration (OXPHOS). We also found that glucose transporter 1 (GLUT1) expression in B cells from pSS patients was significantly higher than that in B cells from HCs. Treatment with 2-deoxy-d-glucose (2-DG) inhibited the activation of B cells in pSS patients. Both 2-DG and Metformin inhibited the proliferation, formation of plasma/plasmablasts and decreased the IgG and IgM levels in the supernatants of B cells from pSS patients. Furthermore, inhibition of mTORC1 by rapamycin had an effect similar to that of 2-DG, suppressing B cell activation, proliferation and antibody production. Taken together, we demonstrated that B cells from pSS patients are more metabolically active than those from HCs and suggested that the mTORC1-GLUT1 glycolysis pathways were the major drivers of B cell hyperactivation and autoantibody production in pSS patients.

Impact of different axial wall designs on the fracture strength and stress distribution of ceramic restorations in mandibular first molar.

BACKGROUND: The purpose of this study was to investigate the fracture strength and stress distribution of four ceramic restorations. METHODS: Forty human mandibular first molars were collected and randomized into four groups after establishing the distal defect: full crown group with 4 mm axial wall height (AWH) (FC4); short AWH crown group with 2 mm AWH (SC2); occlusal veneer group with 0 mm AWH (OV0); occlusal distal veneer group with only the distal surface prepared, and 4 mm AWH (OD4). The teeth were prepared according to the groups and the ceramic restorations were completed using celtra duo ceramic blocks. The ceramic thickness of the occlusal surface is about 1.5 mm and the edge is about 1 mm. The failure load values and fracture modes of each group were detected by mechanical test in vitro. According to the groups to establish three-dimensional finite element analysis (FEA) models, a 600 N loading force was applied vertically using a hemispherical indenter with a diameter of 6 mm. and compare the stress distribution under the condition of different restorations. RESULTS: In vitro mechanical tests showed that the failure load values were SC2 (3232.80 ± 708.12 N) > OD4 (2886.90 ± 338.72 N) > VO0 (2133.20 ± 376.15 N) > FC4(1635.40 ± 413.05 N). The failure load values of the short AWH crown and occlusal distal veneer were significantly higher than that of occlusal veneer and full crown (P<0.05). The fracture modes of the full crown and occlusal veneer groups were mainly ceramic fractures and some were restorable tooth fractures. The short AWH crown and occlusal distal veneer groups presented with three fracture modes, the proportion of non-restorable tooth fracture was higher. The results of FEA show that under the spherical loading condition, the stress of ceramic was concentrated in the contact area of the loading head, the maximum von Mises stress values were FC4 (356.2 MPa) > VO0 (214.3 MPa) > OD4 (197.9 MPa) > SC2 (163.1 MPa). The stress of enamel was concentrated in the area where the remaining enamel was thinner, the maximum von Mises stress values was OD4 (246.2 MPa) ≈ FC4 (212.4 MPa) > VO0 (61.8 MPa) ≈ SC2 (45.81 MPa). The stress of dentin is concentrated in the root furcation and the upper third region of the root. However, stress concentration was observed at the tooth cervix in the full crown. CONCLUSION: Under certain conditions, the occlusal distal veneer shows better performance than the full crown.

The potential role of RNA N6-methyladenosine in primary Sjögren's syndrome.

Objective: The pathogenesis of primary Sjögren's syndrome (pSS) remains incompletely understood. The N6-methyladenosine (m6A) RNA modification, the most abundant internal transcript modification, has close associations with multiple diseases. This study aimed to investigate the role of m6A in patients with pSS. Materials and methods: This study enrolled 44 patients with pSS, 50 age- and gender-matched healthy controls (HCs), and 11 age- and gender-matched patients with non-SS sicca. We detected the messenger RNA (mRNA) levels of m6A elements (including METTL3, WTAP, RBM15, ALKBH5, FTO, YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2), ISG15, and USP18 in peripheral blood mononuclear cells (PBMCs) from patients with pSS, patients with non-SS sicca, and HCs. The clinical characteristics and laboratory findings of patients with pSS and patients with non-SS sicca were also collected. We used binary logistic regression to determine if m6A elements were risk factors for pSS. Results: The mRNA levels of m6A writers (METTL3 and RBM15), erasers (ALKBH5 and FTO), and readers (YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2) were all significantly higher in PBMCs from patients with pSS than in HCs. The mRNA levels of m6A writers (METTL3 and WTAP) and readers (YTHDF2, YTHDF3, and YTHDC2) were lower in PBMCs from patients with pSS compared to patients with non-SS sicca. The expression of METTL3, RBM15, FTO, YTHDF1, YTHDF2, YTHDC1, and YTHDC2 was positively correlated with the level of C-reactive protein (CRP) of patients with pSS. The mRNA level of YTHDF1 in PBMCs from patients with pSS was negatively correlated with the EULAR Sjögren's syndrome disease activity index (ESSDAI) score. In patients with pSS, FTO, YTHDC1, and YTHDC2 were also related to white blood cells (WBCs), neutrophils, lymphocytes, and monocytes. Increased mRNA level of ALKBH5 in PBMCs was a risk factor for pSS, as determined by binary logistic regression analysis. The mRNA level of ISG15 was positively correlated with that of FTO, YTHDF2, YTHDF3, and YTHDC2 in patients with pSS. Conclusion: Compared with HCs, the expression of METTL3, RBM15, ALKBH5, FTO, YTHDF1, YTHDF2, YTHDF3, YTHDC1, and YTHDC2 was considerably higher in PBMCs from patients with pSS. In comparison with patients with non-SS sicca, the expression of METTL3, WTAP, YTHDF2, YTHDF3, and YTHDC2 was reduced in PBMCs from patients with pSS. The m6A elements correlating with clinical variables may indicate the disease activity and inflammation status of pSS. Elevated expression of ALKBH5 was a risk factor for pSS. The dynamic process of m6A modification is active in pSS. m6A elements (FTO, YTHDF2, YTHDF3, or YTHDC2) might target ISG15, stimulate the expression of ISG15, and activate the type I IFN signaling pathway, playing an active role in initiating the autoimmunity in pSS.

Glucose metabolism and glycosylation link the gut microbiota to autoimmune diseases.

Carbohydrates serve as important energy sources and structural substances for human body as well as for gut microbes. As evidenced by the advances in immunometabolism, glucose metabolism and adenosine triphosphate (ATP) generation are deeply involved in immune cell activation, proliferation, and signaling transduction as well as trafficking and effector functions, thus contributing to immune response programming and assisting in host adaption to microenvironment changes. Increased glucose uptake, aberrant expression of glucose transporter 1 (e.g., GLU1), and abnormal glycosylation patterns have been identified in autoimmunity and are suggested as partially responsible for the dysregulated immune response and the modification of gut microbiome composition in the autoimmune pathogenesis. The interaction between gut microbiota and host carbohydrate metabolism is complex and bidirectional. Their impact on host immune homeostasis and the development of autoimmune diseases remains to be elucidated. This review summarized the current knowledge on the crosstalk of glucose metabolism and glycosylation in the host with intestinal microbiota and discussed their possible role in the development and progression of autoimmune diseases. Potential therapeutic strategies targeting glucose metabolism and glycosylation in modulating gut ecosystem and treating autoimmune diseases were discussed as well.

Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus.

Nucleic acid autoantibodies, increase type I interferon (IFN-α) levels, and immune cell hyperactivation are hallmarks of systemic lupus erythematosus (SLE). Notably, immune cell activation requires high level of cellular energy that is predominately generated by the mitochondria. Mitochondrial reactive oxygen species (mROS), the byproduct of mitochondrial energy generation, serves as an essential mediator to control the activation and differentiation of cells and regulate the antigenicity of oxidized nucleoids within the mitochondria. Recently, clinical trials on normalization of mitochondrial redox imbalance by mROS scavengers and those investigating the recovery of defective mitophagy have provided novel insights into SLE prophylaxis and therapy. However, the precise mechanism underlying the role of oxidative stress-related mitochondrial molecules in skewing the cell fate at the molecular level remains unclear. This review outlines distinctive mitochondrial functions and pathways that are involved in immune responses and systematically delineates how mitochondrial dysfunction contributes to SLE pathogenesis. In addition, we provide a comprehensive overview of damaged mitochondrial function and impaired metabolic pathways in adaptive and innate immune cells and lupus-induced organ tissues. Furthermore, we summarize the potential of current mitochondria-targeting drugs for SLE treatment. Developing novel therapeutic approaches to regulate mitochondrial oxidative stress is a promising endeavor in the search for effective treatments for systemic autoimmune diseases, particularly SLE.

Gut microbiota in systemic lupus erythematosus: A fuse and a solution.

Gut commensals help shape and mold host immune system and deeply influence human health. The disease spectrum of mankind that gut microbiome may associate with is ever-growing, but the mechanisms are still enigmas. Characterized by loss of self-tolerance and sustained self-attack, systemic lupus erythematosus (SLE) is labeled with chronic inflammation, production of autoantibodies and multisystem injury, which so far are mostly incurable. Gut microbiota and their metabolites, now known as important environmental triggers of local/systemic immune responses, have been proposed to be involved in SLE development and progression probably through the following mechanisms: translocation beyond their niches; molecular mimicry to cross-activate immune response targeting self-antigens; epitope spreading to expand autoantibodies spectrum; and bystander activation to promote systemic inflammation. Gut microbiota which varies between individuals may also influence the metabolism and bio-transformation of disease-modifying anti-rheumatic drugs, thus associated with the efficacy and toxicity of these drugs, adding another explanation for heterogenic therapeutic responses. Modulation of gut microbiota via diet, probiotics/prebiotics, antibiotics/phages, fecal microbiota transplantation, or helminth to restore immune tolerance and homeostasis is expected to be a promising neoadjuvant therapy for SLE. We reviewed the advances in this territory and discussed the application prospect of modulating gut microbiota in controlling SLE.