Primary Sjögren's syndrome (pSS) is a prevalent autoimmune disease characterized by exocrine gland dysfunction, with hallmarks of B cell and T cell overactivation, whose underlying mechanism remains largely unknown. Herein, we show that pSS plasma contained more extracellular vesicles (EVs) than HC plasma, which promoted CD4 T cell activation, Th1, and follicular T helper cell (Tfh) differentiation, aggravating pSS immunopathology. Notably, pSS plasma EVs were enriched with miR-501-3p, mediating CD4 T cell activation and Tfh cell differentiation. Furthermore, miR-501-3p downregulated special AT-rich sequence-binding protein-1 (SATB1) to promote Tfh differentiation. These findings suggested pSS plasma EVs as an important contributor to pSS pathogenesis, which was of potential clinical interest in managing pSS.

Here, we investigate how autoantibodies against G protein-coupled receptors (GPCRs) on endothelial cells, which are present in patients with scleroderma renal crisis (SRC) impact on endothelin-1 (ET-1) production in human microvascular endothelial cells (HMECs). To this end, serum IgG fraction was isolated from SRC patients and applied to HMECs in culture. Compared to cells treated with either plain control medium or serum IgG from healthy individuals, exposure of HMECs to SRC-IgG resulted in a time- and concentration-dependent increase in ET-1 expression and release. This effect could be blocked by the protease activated receptor 1 (PAR1) inhibitor and mimicked by thrombin, the PAR1 activator. Transcription factor C-FOS/AP-1 and tissue factor (TF) were identified as mediators of these responses. Thus, it can be concluded that serum IgG fraction from SRC patients stimulates endothelial cells to produce ET-1, acting through PAR1 in cooperation with TF.

Clinical data and animal models have provided compelling evidence supporting the pathogenic role of complement activation in the progression of focal segmental glomerulosclerosis (FSGS). However, the mechanisms underlying complement-induced podocyte injury and parietal epithelial cell (PEC) activation are not well understood.

Primary Sjögren's syndrome (pSS) is a complex autoimmune disease characterized by diverse clinical manifestations. While xerophthalmia and xerostomia are hallmark symptoms, the disease often involves multiple organ systems, including the kidneys, lungs, nervous system, and gastrointestinal tract, leading to systemic morbidity in severe cases. Despite extensive research, the precise pathogenesis of pSS remains unclear, likely involving infectious, hormonal, and genetic factors. Emerging evidence highlights the microbiome as a key contributor to autoimmune diseases, including pSS. Dysbiosis in the oral, ocular, gut, and genital microbiomes plays a critical role in disease onset, progression, and variability. This review summarizes current findings on microbiome alterations in pSS, emphasizing their role in pathogenesis and clinical features, and explores microbiome-targeted therapies. Understanding the role of the microbiome in pSS pathophysiology could advance disease management and inspire targeted therapeutic strategies.

Acute rejection is the main contributor to early allograft failure. Current immunosuppressive regimens have shortcomings, such as toxicity and minimal inhibitory effects on B cells. Hence, developing novel, effective, and selective anti-acute rejection drugs is crucial. Therefore, this study aimed to investigate the inhibitory effect of ritlecitinib (PF-06651600), a new janus kinase 3 inhibitor, on T and B cells, as well its preventive effects on acute allograft rejection. A murine cardiac transplantation model coupled with cell culture- and immunohistochemistry-based techniques was used. In vitro assays demonstrated that ritlecitinib inhibits naïve CD4 T cell differentiation into T helper (Th)1 and Th17 cells, reduces relative inflammatory cytokines, and suppresses CD4 and CD8 T cell proliferation. Furthermore, ritlecitinib inhibited B cell activation and differentiation and antibody production. In vivo experiments revealed that ritlecitinib significantly prolongs allograft survival, decreases serum donor-specific antibody immunoglobulin G levels, alleviats allograft damage, and reduces C4d deposition and T, B, and plasma cell infiltration in allografts. Moreover, B and plasma cell percentages and counts were significantly decreased in recipient spleen, lymph nodes, bone marrow, and blood. Overall, ritlecitinib prevented acute rejection in cardiac transplantation by inhibiting T and B cells, suggesting its potential as a novel clinical immunosuppressant.

Patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5 DM) are prone to infections, but there is a lack of rapid methods to assess infection risk, which greatly affects patient prognosis. This study aims to analyze the clinical features of MDA5 DM patients systematically and develop a predictive model for infections.

The antibody response to SARS-CoV-2 does not follow the immunoglobulin isotype pattern of primary responses, conflicting with the current interpretation of COVID-19.

Viral infections, including respiratory diseases such as Coronavirus disease 2019 (COVID-19), are hypothesized to contribute to the onset of autoimmune disorders. Although elevated levels of autoantibodies have been observed following COVID-19, the role of specific autoantibodies linked to autoimmune diseases and their correlation with disease severity remains poorly defined. In this study, we used a comprehensive autoantibody panel to assess the autoantibody production across different cohorts of COVID-19 patients, categorized by disease severity. We also compared patients with severe COVID-19 to a control group with other severe, non-COVID-related diseases. Our findings indicate that the severity of COVID-19 corresponds to the overall production of specific autoantibodies, which are particularly associated with COVID-19. This association might predispose to an increased risk for the development of autoimmune conditions after a severe course of COVID-19.

The imbalance between Tregs and proinflammatory Th17 cells in children with biliary atresia (BA) causes immune damage to cholangiocytes. Dimethyl fumarate (DMF), an immunomodulatory drug, regulates the Treg/Th17 balance in diseases like multiple sclerosis (MS). This study explores DMF's effect on Treg/Th17 balance in BA and its potential mechanism. The differential gene expression profiles in liver of BA and choledochal cyst (CC) patients were analyzed by single-cell RNA sequencing (scRNA-seq). Treg and Th17 cell frequencies in BA hilar lymph nodes (LNs) were determined by flow cytometry. CD3 T cells were isolated from BA hilar LNs and treated with DMF in vitro to observe their differentiation. The effects of DMF were evaluated on BA mouse model, and enzyme-linked immunosorbent assay to measure biochemical markers and cytokine profiles. The Treg/Th17 ratio in the liver was determined by flow cytometry. Nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream antioxidant genes solute carrier family 7 member 1 (Slc7a11), heme oxygenase - 1 (Hmox1) was validated by q-PCR and Western blot. ScRNA-seq showed CD4 T cells in BA liver were enriched in antioxidant pathways. The Treg/Th17 ratio in BA hilar LNs was significantly reduced compared to CC. In vitro, DMF promoted Treg differentiation and inhibited Th17 differentiation. In vivo, the Treg/Th17 ratio increased in the liver of the DMF 40 mg/kg group. In the 40 mg/kg DMF group, interleukin-17 A (IL-17 A) expression decreased as seen in pathological staining. DMF increased Nrf2, Hmox1, Slc7a11 mRNA and protein levels in DMF 40 mg/kg group. There is a Treg/Th17 imbalance in BA patients' hilar LNs, which DMF can restore in vitro. DMF improves the survival rate of BA mice and corrects the Treg/Th17 imbalance, possibly via the Nrf2/antioxidant response elements (ARE) pathway.

The association between chromatin accessibility in CD4 T cells and Immunoglobulin A nephropathy (IgAN) remains unclear.

Patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) have a high risk of serious infection, in particular severe pneumonia. This study aimed to investigate the transcriptional landscape, lower respiratory tract (LRT) microbiome and metabolomic profiles in the lung of RA-ILD patients with pneumonia.

Rheumatoid arthritis (RA) is a chronic inflammatory disease linked to epigenetic changes, particularly DNA methylation. While LDLRAD4 has been implicated in RA through GWAS, its role in RA via methylation remains unclear.

This study aimed to investigate whether the polarization of monocyte-derived macrophages towards an anti-inflammatory phenotype could be hindered by modulating cellular metabolism. Several metabolic drugs were selected: Perhexiline (PerHx) and Nitazoxanide (NTZ) targeting fatty acid oxidation, CB839 (Telaglenastat) targeting glutaminolysis and Metformin (Metf) targeting the mitochondrial electron transport chain.

NLRX1 is an important regulator of inflammatory signaling in innate immune cells. Recent studies indicate NLRX1 activation may be a novel mechanism for inflammatory diseases, however, it has not been explored in atopic dermatitis (AD). Our study aims to investigate the potential role of NLRX1 in the pathogenesis of AD. We observed a significant decrease in NLRX1 expression in AD skin lesions and MC903-indued AD dermatitis. NLRX1 deficiency exacerbated AD inflammation, characterized by increased skin thickness, exacerbated inflammatory infiltration, and compromised skin barrier function. Mechanistically, NLRX1 regulated TSLP expression through Parkin-PINK1-mediated mitophagy in keratinocytes. Furthermore, topical application of NLRX1 agonist alleviated AD progression, including reduced ear thickness, diminished redness, and improved skin barrier function. This study provides novel insights into the regulatory role of NLRX1 in skin inflammation in AD, highlighting the potential therapeutic implications of targeting NLRX1 and mitophagy in AD treatment.

IKAROS, encoded by IKZF1, is a crucial transcription factor regulating hematopoiesis and B cell development. While IKZF1 haploinsufficiency variants are associated with various immunological disorders, inflammatory bowel disease (IBD) has been rarely reported. We report a case of IKZF1 haploinsufficiency presenting with an atypical IBD phenotype and its response to filgotinib. The patient was previously diagnosed with IKZF1 haploinsufficiency and presented with chronic diarrhea, fatigue and anemia. Laboratory findings indicated folate deficiency-induced megaloblastic anemia and malabsorption syndrome. Endoscopic examination showed inflammation with erythema in the colon and extensive villous blunting of the small intestine. Immunohistochemical analysis revealed increased pSTAT3/5 in the colon. Considering the clinical features and increased JAK-STAT cascade, treatment with filgotinib was initiated. At 10 weeks post-treatment, we observed improvement in endoscopic findings and suppression of pSTAT3/5. This case extends the clinical spectrum of IKZF1 haploinsufficiency. A JAK1 inhibitor is considered to be useful for IKZF1 haploinsufficiency-associated IBD.

Henoch-Schönlein purpura (HSP) is an autoimmune vasculitis affecting multiple organs, and the understanding of circulating immune cell types and their states associated with disease subtypes of HSP remains incomplete. Here, we performed a comprehensive assessment of peripheral blood mononuclear cells of healthy donors and HSP patients, using both single-cell RNA sequencing and multiparameter flow cytometry. We revealed that HSP patients exhibited broad immune activation, evidenced by increased proportions of Effector memory CD8+ T, CD14+ monocytes, Tfh, Th2, Th17, Plasma, and B cells and decreased proportions of Naïve CD4+ T, Treg, Th1, and NK cells. Notably, we identified that cytotoxic effector T cell subsets were enriched in skin and renal type of HSP, whereas Plasma, B, and Tfh cells were expanded in joint and abdominal type of HSP. In conclusion, our findings highlight the dynamic nature of immune responses throughout the progression of HSP with different clinical manifestations.

IKAROS, encoded by IKZF1, is a six zinc-finger (ZF) transcription factor integral to lymphocyte development and function. IKZF1 mutations affecting DNA-binding (ZF1-4) and dimerization (ZF5-6) have been extensively reported and result in human disease. Herein, we investigated IKZF1 mutations affecting protein stability. We identified ten individuals in three families carrying IKZF1 mutations mapping either to the pre-ZF1 area (D22N), or the dimerization domain (M494Vfs*86, Y503*) presenting with infections, immune dysregulation and/or lymphoproliferation with incomplete clinical penetrance. IKAROS expression was reduced in all mutation-carrier evaluated. Protein stability was decreased for D22N, V52L (another pre-ZF1 variant reported in COSMIC), Y503* and Del1-116, a laboratory-designed mutant encompassing the pre-ZF1 area. Mutants Y503* and Del1-116 also exhibited other impaired functions. IKAROS N-terminal pre-ZF1 area, encompassing a previously uncharacterized protein stability-associated region (PSAR), is crucial for IKAROS stability. Variants in the IKAROS PSAR leading to decreased protein stability and IKAROS haploinsufficiency seem sufficient to result in immune defects and IKAROS-associated diseases.

Currently, IgA nephropathy (IgAN) is the most common cause of chronic renal failure in patients with primary glomerulonephritis. However, IgAN diagnosis is usually performed by collecting a renal biopsy as gold standard to visualize pathological changes in the glomeruli. The randomized nature of this invasive procedure in clinical practice, together with the need to exclude patients with contraindications, often results in a limited number of eligible people. Therefore, over the past two decades, researchers have explored new biomarkers for IgAN to meet the urgent clinical need for rapid diagnosis and prognosis, as well as realistic prediction of IgAN progression. In addition to traditional common markers with low specificity to detect renal diseases, the classical antibody targeting galactose-deficient IgA1 has been progressively discovered. In addition, new types of diagnostic or prognostic biomarkers are emerging, including microRNA, complement factors, proteases, inflammatory molecules and serum or urinary metabolite profiles.

Persistent selective T-lymphocytopenia is found both in SCID and congenital athymia. Without molecular diagnosis, it is challenging to determine whether HCT or thymus transplantation ought to be performed. Ex vivo T-lymphopoiesis assays have been proposed to assist clinical decision-making for genetically undefined patients. We investigated 20 T-lymphocytopenic patients, including 13 patients awaiting first-line treatment and 7 patients with failed immune reconstitution after previous HCT or thymus transplantation. Whilst developmental blocks in ex vivo T-lymphopoiesis indicated hematopoietic cell-intrinsic defects, successful T-lymphocyte differentiation required careful interpretation, in conjunction with clinical status, immunophenotyping, and genetic investigations. Of the 20 patients, 13 proceeded to treatment, with successful immune reconstitution observed in 4 of the 6 patients post-HCT and 4 of the 7 patients after thymus transplantation, the latter including two patients who had previously undergone HCT. Whilst further validation and standardization are required, we conclude that assessing ex vivo T-lymphopoiesis during the diagnostic pathway for genetically undefined T-lymphocytopenia improves patient outcomes by facilitating corrective treatment choice.

In this case study, we used Digital Spatial Profiling to localize transcripts in a series of 4 biopsies from a single patient before, during and after treatment for acute antibody-mediated rejection that was characterized by strong C4d staining of the glomeruli. Spatial resolution demonstrated that molecular signatures of innate immune cells including NK cells and macrophages are located in glomeruli during AMR, and transcripts for HLA class II antigens were upregulated in the glomeruli. In contrast, transcripts of signature genes for podocytes were decreased during rejection. Treatment with IVIg resolved histological evidence of glomerulitis but did not restore expression of podocyte transcripts. These data demonstrate a vulnerability of podocytes in acute AMR with persistent glomerulitis. Additionally, by using a protocol biopsy from the same patient as a baseline, transcript changes for an informative set of genes were uncovered to test for podocyte dysfunction in future patients.

The study examines efgartigimod and intravenous immunoglobulin (IVIg) in elderly patients with generalized myasthenia gravis (GMG), focusing on changes in Myasthenia Gravis Activities of Daily Living (MG-ADL) scores, pyridostigmine dosage, and minimal symptom expression (MSE) over an 8-week period. Among 74 enrolled patients, efgartigimod showed greater reduction in MG-ADL scores compared to IVIg at weeks 4 and 8, with no serious adverse events, suggesting its superior efficacy and safety in elderly Chinese patients with acetylcholine receptor antibody-positive (AChR-Ab(+)) GMG.