Journal of autoimmunity最新文献

Background

Methods

Results

Conclusions

Background

Objective

Methods

Results

Conclusion

Background and objectives

Methods

Results

Conclusions

Diverse forms of physical activities contribute to improvement of autoimmune diseases and may prevent disease burst. T regulatory cells (Tregs) maintain tolerance in autoimmune condition. Physical activity is one of the key factors causing enhancement of Tregs number and functions, keeping homeostatic state by its secrotome. Muscles secrete myokines like IL-6, PGC1α (PPARγ coactivator-1 α), myostatin, transforming growth factor β (TGF-β) superfamily), IL-15, brain derived neurotrophic factor (BDNF) and others. The current concept points to the role of exercise in induction of highly functional and stable muscle Treg phenotype. The residing-Tregs require IL6Rα signaling to control muscle function and regeneration. Skeletal muscle Tregs IL-6Rα is a key target for muscle-Tregs cross-talk. Thus, interplay between the Tregs-skeletal muscle, following exercise, contribute to the balance of immune tolerance and autoimmunity. The cargo delivery, in the local environment and periphery, is performed by extracellular vesicles (EVs) secreted by muscle and Tregs, which deliver proteins, lipids and miRNA during persistent exercise protocols. It has been suggested that this ensemble induce protection against autoimmune diseases.

Pemphigus is a severe autoimmune blistering disease characterized by acantholysis triggered by autoantibodies against desmoglein 1 and 3 (DSG1/3). Apoptosis plays a pivotal role in facilitating acantholysis, yet the precise underlying mechanism remains obscure. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is known to promote apoptosis and disrupt cell junctions, although its involvement in pemphigus pathogenesis remains ambiguous. Our study observed decreased DSG1/3 expression alongside increased TWEAK/fibroblast growth factor-inducible 14 (Fn14) expression and keratinocyte apoptosis in both lesional and perilesional skin. In vitro experiments revealed that TWEAK-stimulated keratinocytes exhibited enhanced apoptosis, STAT1 phosphorylation, and reduced intercellular DSG1/3 expression. Notably, bulk-RNA sequencing unveiled that CASPASE-3 was responsible for mediating the DSG1/3 depletion, as confirmed by direct interaction with DSG1/3 in a co-immunoprecipitation assay. Naloxone, known for preserving cellular adhesion and preventing cell death, effectively reduced apoptosis and restored DSG1/3 levels in TWEAK-stimulated keratinocytes. The anti-apoptotic properties of naloxone were further validated in a murine pemphigus model. Our findings elucidate that TWEAK facilitates keratinocyte apoptosis by augmenting caspase-3 activity, leading to DSG1/3 depletion and apoptosis in pemphigus. Importantly, naloxone can counter TWEAK-induced apoptosis in pemphigus pathogenesis, offering a potential therapeutic intervention.

Background

Alternative splicing (AS) and intron retention (IR) implicated in multiple pathophysiological processes, have rarely been reported in systemic sclerosis (SSc).

Methods

We integrated bulk RNA-seq and 4D label-free mass spectrometry to perform a multi-omics analysis of AS and IR in SSc skin tissue and fibroblasts. RMATS and iREAD were used to identify AS and IR, which were validated by real-time PCR. Spearman correlation and the LASSO method were employed to assess correlations among clinical features, introns, splicing factors (regulators of AS) and proteins.

Findings

AS profiles showed distinct alterations in SSc skin tissue, with the most pronounced changes occurring in IR. AS and IR were associated with total modified Rodnan skin score (mRSS) and local skin score. Upon TGF-β stimulation, fibroblasts exhibited significant alterations in IR profiles, affecting genes related to fibroblast proliferation and collagen fibril organization. A comprehensive integrated analysis of introns, exons, and proteome profiles revealed that IR exerted a negative impact on protein expression, with certain changes being under intronic control. RT-PCR confirmed the presence of intron and exon-derived sequences of CTTN, OGA, MED16 and PHYKPL. Additionally, notable changes were observed in the regulatory network of splicing factors in SSc skin tissues. These factors are also involved in fibrosis pathways and correlated with clinical features.

Conclusion

Totally, abnormal AS, IR profiles and splicing factors were identified in SSc, altered IRs and splicing factors participated in fibrosis-related pathways. IR exerted a negative impact on protein expression in TGF-β-stimulated fibroblasts. Clarification of the IR mechanisms will provide new insights into the pathophysiology of SSc.

Immune-mediated neuropathy (IMN) is a group of heterogenous neuropathies caused by intricate autoimmune responses. For now, known mechanisms of different IMN subtypes involve the production of autoantibodies, complement activation, enhanced inflammation and subsequent axonal/demyelinating nerve damages. Recent therapeutic studies mainly focus on specific antibodies and small molecule inhibitors previously approved in rheumatoid diseases. Initial strategies based on the pathophysiologic features of IMN should be explored. Adoptive cell therapy (ACT) refers to the emerging immunotherapies in which circulating immunocytes are collected from peripheral blood and modified with killing and immunomodulatory capacities. It consists of chimeric antigen receptor-T cell therapy, T cell receptor-engineered T cell, CAR-Natural killer cell therapy, and others. In the last decade, ACT has demonstrated extraordinary potentials in treating cancers, infectious diseases and autoimmune diseases. Versatile combinations of targets, chimeric domains and effector cells greatly empower ACT to treat complicated immune disorders. In this review, we summarized the advances of ACT and envisioned suitable strategies for different IMN subtypes.

Though the exact causes of systemic lupus erythematosus (SLE) remain unknown, exposure to ultraviolet (UV) light is one of the few well-known triggers of cutaneous inflammation in SLE. However, the precise cell types which contribute to the early cutaneous inflammatory response in lupus, and the ways that UV dosing and interferons modulate these findings, have not been thoroughly dissected. Here, we explore these questions using the NZM2328 spontaneous murine model of lupus. In addition, we use iNZM mice, which share the NZM2328 background but harbor a whole-body knockout of the type I interferon (IFN) receptor, and wild-type BALB/c mice. 10-13-week-old female mice of each strain were treated with acute (300 mJ/cm² x1), chronic (100 mJ/cm² daily x5 days), or no UVB, and skin was harvested and processed for bulk RNA sequencing and flow cytometry. We identify that inflammatory pathways and gene signatures related to myeloid cells – namely neutrophils and monocyte-derived dendritic cells – are a shared feature of the acute and chronic UVB response in NZM skin greater than iNZM and wild-type skin. We also verify recruitment and activation of these cells by flow cytometry in both acutely and chronically irradiated NZM and WT mice and demonstrate that these processes are dependent on type I IFN signaling. Taken together, these data indicate a skewed IFN-driven inflammatory response to both acute and chronic UVB exposure in lupus-prone skin dominated by myeloid cells, suggesting both the importance of type I IFNs and myeloid cells as therapeutic targets for photosensitive patients and highlighting the risks of even moderate UV exposure in this patient population.

The main pathogenic features of immunoglobulin A vasculitis (IgAV) are overactive B cells and elevated production of IgA, which requires help from T follicular helper 17 (Tfh17) cells. To evaluate the pathological role of Tfh17 cells in IgAV, we investigated the mechanism responsible for Tfh17 differentiation and explored how to ameliorate IgAV by modulating Tfh17 generation.

Peripheral blood mononuclear cells from IgAV patients were analyzed by flow cytometry. In vitro culture was performed to assess the modulation of cytokine-induced phenotypes. IgAV rats were used to explore the therapeutic effects of IL-6 blockade and the regulatory functions of IL-6 in Tfh17 cells. Serum cytokine and IgA levels were measured by ELISA while histopathological changes were evaluated by H&E,PAS or immunofluorescence staining.

Frequency of CD4⁺CXCR5⁺CCR6⁺ Tfh17 cells were increased in IgAV patients and associated with disease severity. There was also a significant infiltration of Tfh17 cells in the kidney of human IgAV nephritis patients. IL-6 promoted the dendritic cell production of TGF-β and Tfh17 differentiation. In IgAV rats, the in vivo blockade of IL-6 signaling inhibited Tfh17 differentiation, resulting in reduction of the germinal center and IgA production. Suppression of Tfh17 cells using IL-6 blockade greatly ameliorated clinical symptoms such as hemorrhagic rash and bloody stool and decreased IgA deposition and mesangial proliferation in the kidney in IgAV rats.

Our findings suggest that suppression of Tfh17 differentiation can alleviate IgA-mediated vasculitis and may permit the development of tailored medicines for treating IgAV.