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TL1A, also called TNFSF15, is a member of tumor necrosis factor family. It is expressed in different immune cell, such as monocyte, macrophage, dendritic cell, T cell and non-immune cell, for example, synovial fibroblast, endothelial cell. TL1A competitively binds to death receptor 3 or decoy receptor 3, providing stimulatory signal for downstream signaling pathways, and then regulates proliferation, activation, apoptosis of and cytokine, chemokine production in effector cells. Recent findings showed that TL1A was abnormally expressed in autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus and ankylosing spondylitis. In vivo and in vitro studies further demonstrated that TL1A was involved in development and pathogenesis of these diseases. In this study, we comprehensively discussed the complex immunological function of TL1A and focused on recent findings of the pleiotropic activity conducted by TL1A in inflammatory autoimmune disease. Finish of the study will provide new ideas for developing therapeutic strategies for these diseases by targeting TL1A.

Although initially described as an anti-tumor mediator, tumor necrosis factor-alpha (TNF) is generally considered as the master pro-inflammatory cytokine. It plays a crucial role in the pathogenesis of inflammatory diseases, such as rheumatoid arthritis (RA), inflammatory bowel disease, ankylosing spondylitis (AS), and psoriasis. Consequently, anti-TNF therapy has become mainstay treatment for autoimmune diseases. Historically, anti-inflammatory agents were developed before the identification of TNF. Salicylates, the active components of spp., were identified in the mid-19th century for the alleviation of pain, fever, and inflammatory responses. Study of this naturally occurring compound led to the discovery of aspirin, which was followed by the development of non-steroidal anti-inflammatory drugs (NSAIDs) due to the chemical advances in the 19th-20th centuries. Initially, the most of NSAIDs were organic acid, but the non-acidic compounds were also identified as NSAIDs. Although effective in the treatment of inflammatory diseases, NSAIDs have some undesirable and adverse effect, such as ulcers, kidney injury, and bleeding in the gastrointestinal tract. In the past two decades, anti-TNF biologics were developed. Drugs belong to this class include soluble TNF receptor 2 fusion protein and anti-TNF antibodies. The introduction of anti-TNF therapeutics has revolutionized the management of autoimmune diseases, such as RA, psoriatic arthritis (PsA), plaque psoriasis (PP), AS, CD and ulcerative colitis (UC). Nevertheless, up to 40% of patients have no response to anti-TNF treatment. Furthermore, this treatment is associated with some adverse effects such as increased risk of infection, and even triggered the development of autoimmune diseases. Such harmful effect of anti-TNF treatment is likely caused by the global inhibition of TNF biological functions. Therefore, specific inhibition of TNF receptor (TNFR1 or TNFR2) may represent a safer and more effective treatment, as proposed by some recent studies. In this review article, the historical development of anti-inflammatory drugs after World War II as briefly described above will be reviewed and analyzed. The future trend in the development of novel TNF receptor-targeting therapeutics will be discussed in the context of latest progress in the research of TNF biology.

A crucial factor for the development of inflammatory autoimmune diseases is the occurrence of antibodies directed against self-tissues and structures, which leads to damage and inflammation. While little is known about the cause of the development of mis-directed, disease-specific T and B cells and resulting IgG autoantibody responses, there is increasing evidence that their induction can occur years before disease symptoms appear. However, a certain proportion of healthy individuals express specific IgG autoantibodies without disease symptoms and not all subjects who generate autoantibodies may develop disease symptoms. Thus, the development of inflammatory autoimmune diseases seems to involve two steps. Increasing evidence suggests that harmless self-directed T and B cell and resulting IgG autoantibody responses in the pre-autoimmune disease stage might switch to more inflammatory T and B cell and IgG autoantibody responses that trigger the inflammatory autoimmune disease stage. Here, we summarize findings on the transition from the pre-disease to the disease stage and vice versa, e.g. by pregnancy and treatment, with a focus on low-/anti-inflammatory versus pro-inflammatory IgG autoantibody responses, including IgG subclass and Fc glycosylation features. Characterization of biomarkers that identify the transition from the pre-disease to the disease stage might facilitate recognition of the ideal time point of treatment initiation and the development of therapeutic strategies for re-directing inflammatory autoimmune conditions.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that may involve any organ in the body. Inflammation of the bowel wall as a presenting symptom of SLE is uncommon and can lead to delays in diagnosis and treatment. Here, we discuss the case of an adolescent male who presented with weight loss, intermittent fevers, abdominal pain, vomiting, and diarrhea. Initially, inflammatory bowel disease (IBD) was suspected, but endoscopic evaluation did not support this diagnosis. A computed tomography scan of the abdomen revealed signs of serositis, concerning for an inflammatory process and the patient was referred to Rheumatology for further evaluation. Autoimmune serologies were obtained and combined with clinical findings confirmed a diagnosis of SLE. This case advances our understanding of SLE as a multisystemic disease and highlights an unusual presentation involving the gastrointestinal tract, which can mimic IBD and potentially delay the diagnosis and treatment process.

Interleukin (IL)-38, a newly discovered IL-1 family cytokine, is expressed in several tissues and secreted by various cells. IL-38 has recently been reported to exert an anti-inflammatory function by binding to several receptors, including interleukin-36 receptor (IL-36R), interleukin-1 receptor accessory protein-like 1 (IL-1RAPL1), and interleukin-1 receptor 1 (IL-1R1) to block binding with other pro-inflammatory cytokines and inhibit subsequent signaling pathways; thereby regulating the differentiation and function of T cells, peripheral blood mononuclear cells, macrophages, and dendritic cells. Inflammatory autoimmune diseases, which are common immune-mediated inflammatory syndromes, are characterized by an imbalance between T helper cells (Ths), especially Th1s and Th17s, and regulatory T cells (Tregs). Recent findings have shown that abnormal expression of IL-38 in inflammatory autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, primary Sjogren’s syndrome, psoriasis, inflammatory bowel disease, hidradenitis suppurativa, ankylosing spondylitis, and glaucoma, involves Th1s, Th17s, and Tregs. In this review, the expression, regulation, and biological function of IL-38 are discussed, as are the roles of IL-38 in various inflammatory autoimmune disorders. Current data support that the IL-38/IL-36R and/or IL-38/IL-1RAPL1 axis primarily play an anti-inflammatory role in the development and resolution of inflammatory autoimmune diseases and indicate a possible therapeutic benefit of IL-38 in these diseases.

Myelodysplastic syndrome (MDS) is well known to be complicated by systemic inflammatory autoimmune disease (SIADs). However, it remains unclear how the prognosis after allogenic hematopoietic stem cell transplantation (allo-HSCT) in patients with MDS is impacted by SIADs that occur before allo-HSCT. Therefore, we hypothesized that SIADs before allo-HSCT may be a risk factor for negative outcomes after allo-HSCT in patients with MDS. We conducted a single-center, retrospective, observational study of sixty-nine patients with MDS or chronic myelomonocytic leukemia who underwent their first allo-HCT. Fourteen of the patients had SIADs before allo-HSCT. In multivariate analysis, the presence of SIADs before allo-HSCT was an independent risk factor for overall survival (HR, 3.36, 95% confidence interval: 1.34–8.42, p = 0.009). Endothelial dysfunction syndrome was identified in five of 14 patients with SIADs who required immunosuppressive therapy or intensive chemotherapy, and notably, all patients with uncontrollable SIADs at allo-HSCT developed serious endothelial dysfunction syndrome and died in the early phase after allo-HSCT. The development of SIADs in the context of MDS is thought to reflect the degree of dysfunction of hematopoietic cells in MDS and suggests a higher risk of disease progression. In addition, MDS patients with SIADs before allo-HSCT are considered to be at higher risk of endothelial dysfunction syndrome because of preexisting vascular endothelial dysfunction due to SIADs. In conclusion, SIADs before allo-HSCT constitute an independent risk factor for death in MDS patients undergoing allo-HSCT.

A series of biopsies and reports showed autoimmune diseases might be involved in the process of local inflammation related to spontaneous cervicocranial arterial dissection (SCCAD) occurrence. This retrospective case-control study examined the association between SCCADs and autoimmune diseases in patients and control subjects from 2014 to 2020. SCCAD patients and age/sex-matched control subjects were recruited, and clinical data were collected. SCCAD was confirmed by digital subtraction angiography or high-resolution magnetic resonance imaging. The study included 215 SCCAD patients and 430 control subjects. Totally, 135 (62.8%) of the 215 cases were found SCCAD in the anterior circulation, 26 (12.0%) patients involved multiple vessels. Autoimmune disease occurred in 27 (12.6%) cases with SCCAD and 4 (0.9%) control subjects (p<0.001). A conditional multivariable logistic regression model was used to calculate the odds ratio for SCCAD among patients with a history of autoimmune disease, adjusting for hypertension, diabetes, hyperlipidemia, and smoking. After adjustment, autoimmune diseases were associated with SCCAD (p<0.001). After sub-analysis by a similar modeling strategy, significant associations were still observed in different subgroups, such as female group and male group as well as intramural hematoma (IMH) group and Non-IHM group. The association of SCCAD with autoimmune disease suggested that autoimmune mechanisms may be involved in some etiologies of SCCAD.

The Ras (rat sarcoma virus) is a GTP-binding protein that is considered one of the important members of the Ras-GTPase superfamily. The Ras involves several pathways in the cell that include proliferation, migration, survival, differentiation, and fibrosis. Abnormalities in the expression level and activation of the Ras family signaling pathway and its downstream kinases such as Raf/MEK/ERK1-2 contribute to the pathogenic mechanisms of rheumatic diseases including immune system dysregulation, inflammation, and fibrosis in systemic sclerosis (SSc); destruction and inflammation of synovial tissue in rheumatoid arthritis (RA); and autoantibody production and immune complexes formation in systemic lupus erythematosus (SLE); and enhance osteoblast differentiation and ossification during skeletal formation in ankylosing spondylitis (AS). In this review, the basic biology, signaling of Ras, and abnormalities in this pathway in rheumatic diseases including SSc, RA, AS, and SLE will be discussed.

Background Thyroid eye disease (TED) is the most common orbital pathology that occurs in up to 50% of patients with Graves’ disease. Herein, we aimed at discovering the possible hub genes and pathways involved in TED based on bioinformatical approaches. Results The GSE105149 and GSE58331 datasets were downloaded from the Gene Expression Omnibus (GEO) database and merged for identifying TED-associated modules by weighted gene coexpression network analysis (WGCNA) and local maximal quasi-clique merger (lmQCM) analysis. EdgeR was run to screen differentially expressed genes (DEGs). Transcription factor (TF), microRNA (miR) and drug prediction analyses were performed using ToppGene suite. Function enrichment analysis was used to investigate the biological function of genes. Protein–protein interaction (PPI) analysis was performed based on the intersection between the list of genes obtained by WGCNA, lmQCM and DEGs, and hub genes were identified using the MCODE plugin. Based on the overlap of 497 genes retrieved from the different approaches, a robust TED coexpression network was constructed and 11 genes (ATP6V1A, PTGES3, PSMD12, PSMA4, METAP2, DNAJA1, PSMA1, UBQLN1, CCT2, VBP1 and NAA50) were identified as hub genes. Key TFs regulating genes in the TED-associated coexpression network, including NFRKB, ZNF711, ZNF407 and MORC2, and miRs including hsa-miR-144, hsa-miR-3662, hsa-miR-12136 and hsa-miR-3646, were identified. Genes in the coexpression network were enriched in the biological processes including proteasomal protein catabolic process and proteasome-mediated ubiquitin-dependent protein catabolic process and the pathways of endocytosis and ubiquitin-mediated proteolysis. Drugs perturbing genes in the coexpression network were also predicted and included enzyme inhibitors, chlorodiphenyl and finasteride. Conclusions For the first time, TED-associated coexpression network was constructed and key genes and their functions, as well as TFs, miRs and drugs, were predicted. The results of the present work may be relevant in the treatment and diagnosis of TED and may boost molecular studies regarding TED.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting the joints, with neurogenic inflammation involving the nervous system being a hallmark of the condition. Treatments include medications such as disease-modifying antirheumatic drugs (DMARDs), corticosteroids, and biologics targeting inflammatory pathways. Yet, these treatments are not curative for RA. Heat Shock Proteins (HSPs) are molecular chaperones with immunoregulatory properties; however, their role is not yet fully understood, as these molecules may play a dual, pro- and anti-inflammatory role. In this study, we evaluated the protein expression levels of HSPs 27, 60, 70, and 90 in the synovial membrane and spinal cord of the RA rats’ model to determine their roles during the disease course, both on the neurological and immunological levels. Furthermore, HSP levels have been evaluated in the spinal cord of control and RA rats’ model after high and low doses of ketamine injection. Significant changes in Hsp60, 70, and 90 expression levels were observed only in the spinal cord of RA rats. We demonstrated that blocking N-methyl-D-aspartate receptors with ketamine can modulate spinal cord HSPs expression in RA rats and subsequently impact neurogenic inflammation and adult neurogenesis. This suggests that HSPs may be a promising target for RA treatment due to their complex immunomodulatory effects and potential interactions with the nervous system. Further research is needed to explore their therapeutic potential and develop effective interventions for RA.