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关键词： IL-2R beta   Inborn errors of immunity   Immunodeficiency   Autoimmunity   Hematopoietic stem cell transplantation   Conditioning  

关键词： Regulatory T cells (Treg)   Autoimmunity   Cell therapy   HLA   SSA/Ro   Sjogren's disease (SjD  

摘要： Sjogren's disease (SjD) is a chronic systemic autoimmune disorder characterised by lymphocytic infiltration of the salivary and lacrimal glands, leading to the hallmark symptoms of dry eyes and dry mouth. Beyond glandular dysfunction, many patients experience systemic complications-including B cell hyperactivity, organ-specific inflammation, and a markedly increased risk of non-Hodgkin lymphoma-that are frequently underrecognised and poorly managed. Current treatments remain largely empirical and symptomatic, with limited efficacy in modifying disease progression or restoring immune tolerance. Recent advances have illuminated profound dysregulation in both innate and adaptive immunity, revealing novel therapeutic targets now under investigation in clinical trials, including type I interferon signalling, B cell activation, and co-stimulatory pathways. Central to this dysregulation is T cell-driven pathology: CD8+ T cell cytotoxicity, defective regulatory T cell (Treg) function, and HLA class II-mediated presentation of self-antigens to autoreactive CD4+ T cells are key mechanisms in disease initiation and persistence. A growing body of evidence implicates Ro autoantigens-Ro60 and Ro52-as central targets in SjD pathogenesis. Anti-Ro antibodies are present in approximately 70 % of patients and serve as both diagnostic markers and indicators of systemic involvement. Ro antigens and their corresponding antibodies are consistently detected in inflamed salivary tissues, underscoring their potential as compelling targets for antigen-specific therapy. This review examines the immunopathogenic role of Ro-specific T cell responses in SjD and outlines how engineered Treg-based therapies may enable precise immune modulation, restore tolerance, and provide durable disease control for patients with this complex autoimmune condition.

关键词： IL-6   PCR-RFLP   Parkinson’s disease   gene polymorphism  

摘要： BACKGROUND:The multifunctional cytokine interleukin 6 (IL-6) and its single nucleotide polymorphisms (SNPs) may influence the risk of Parkinson's disease (PD). AIM:To investigate the association between specific SNPs in the gene and susceptibility to PD in the northern Chinese Han population. SUBJECTS AND METHODS:A total of 800 Chinese Han subjects were enrolled in this case-control study, including 400 PD patients and 400 healthy controls. Peripheral blood of all subjects was collected for DNA extraction and genotyped for selected SNPs (rs1800796, rs1524107) using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS:We found significant differences in the allele (C vs. G,  = 0.002) and CC genotype ( = 0.012) of rs1800796 in the PD group compared to the control group. In addition, significant differences were observed between the two groups in both dominant and additive models (=0.046, =0.025). In further subgroup analysis, compared with the matched male control group, the frequency of CC genotype in male PD was higher ( = 0.035), and allele C may increase the risk of disease ( = 0.012). Similarly, when compared to the healthy control group, patients in the late-onset Parkinson's Disease (LOPD) group also exhibited a higher frequency of CC genotype and C allele ( = 0.015,  = 0.004). CONCLUSION:The rs1800796 polymorphism of the gene may be associated with susceptibility to PD in the northern Chinese Han population.

关键词： Anti-inflammatory therapy   Colchicine   Coronary artery disease   Interleukin-1 inhibitors   Interleukin-6 inhibitors   Methotrexate   NLRP3/IL-1 beta/IL-6/CRP pathway  

摘要： Background Treatment effects of anti-inflammatory therapies inhibiting the NLRP3/IL-1 beta/IL-6/CRP pathway in coronary artery disease (CAD) had conflicting results. The study aims to evaluate efficacy and safety outcomes of treatments inhibiting this pathway. Methods Cochrane Library, Embase, Pubmed, and *** were searched for randomized controlled trials evaluating therapies inhibiting the NLRP3/IL-1 beta/IL-6/CRP pathway in CAD patients. Relative risks (RR) with 95% confidence intervals (CI) were calculated. Results 32 studies and 37,056 individuals were included. Anti-inflammatory therapies inhibiting the pathway reduced the risks of myocardial infarction (MI) (RR 0.85, 95% CI 0.78-0.93) and coronary revascularization (RR 0.80, 95% CI 0.74-0.86), with no benefits in major adverse cardiovascular events (MACE), heart failure (HF), stroke, cardiovascular or all-cause mortality. Colchicine reduced the risks of MACE, MI, and coronary revascularization. IL-1 inhibitors reduced the risks of coronary revascularization, with potential benefits in MI and HF. Increased risks of infections, gastrointestinal adverse effects, and injection site reactions were found. Meta-regression analysis demonstrated that post-treatment hsCRP/CRP was correlated with MACE (p < 0.001) and MI (p = 0.048) and post-treatment IL-6 was associated with MI (p = 0.033). Conclusion Anti-inflammatory therapies inhibiting the NLRP3/IL-1 beta/IL-6/CRP pathway had satisfying safety profiles and were beneficial in preventing MI and coronary revascularization in CAD patients despite no benefits in stroke, cardiovascular, or all-cause mortality.

关键词： IL-21   Inflammation   Lymphocytes   italic>S. aureus   Septic arthritis   TGF-beta   Th17/Treg  

摘要： Septic arthritis (SA) caused by Staphylococcus aureus is a severe inflammatory joint disease, characterized by synovitis accompanied with cartilage destruction and bone erosion. The available antibiotic treatment alone is insufficient to resolve the inflammation that leads to high rates of morbidity and mortality. Among the CD4+ T helper lymphocytes, the Th17 and Tregs are key regulators of immune homeostasis. A high Th17 could lead to autoimmunity, whereas an increase in Tregs indicates immunosuppression. Depending on the external cytokine milieu, na & iuml;ve CD4+ T cells transform into either Th17 or Treg cell lineage. TGF-beta in the presence of IL-21 produces Th17 cells and drives the inflammatory cascade of reactions. We studied the effects of in vivo neutralization of TGF-beta and IL-21 in septic arthritic mice to control arthritic inflammation, which has not been studied before. The arthritic index showed maximum severity in the SA group which substantially reduced in the Ab-treated groups. Flow cytometric analyses of peripheral blood collected from mice at 9DPI revealed the highest Th17/Treg ratio in the SA group but least in the combined-antibody-treated group. TGF-beta 1 and IL-21 cytokine production from serum, spleen, and synovial tissue homogenates was significantly reduced in the dual Ab-treated group than in the untreated SA group. From the Western blot analyses obtained from splenic lymphocytes at 9 DPI, we elucidated the possible underlying mechanism of interplay in downstream signalling involving the interaction between different STAT proteins and SOCS, NF-kappa B, RANKL, mTOR, iNOS, and COX-2 in regulating inflammation and osteoclastogenesis. On endogenous blockade with TGF-beta and IL-21, the Th17/Treg ratio and resultant arthritic inflammation in SA were found to be reduced. Therefore, maintaining the Th17/Treg balance is critical to eradicate infection as well as suppress excessive inflammation and neutralization of TGF-beta and IL-21 could pr

关键词： Type 1 diabetes   Islet antigen-specific T cells   T cell epitopes   Islet-specific autoantibodies  

摘要： A proportion of patients with new-onset diabetes share similar symptoms with type 1 diabetes (T1D) patients but they are negative for islet antigen-specific autoantibodies. This study was to develop an islet antigen-specific CD8(+) T-cell assay to provide autoimmune evidence regarding these "suspected" T1D patients. HLA-A*0201 individuals with autoAbs(+) T1D, autoAbs(-) suspected T1D, and type 2 diabetes, along with HLA-A*0201 healthy controls were recruited. Using interferon-gamma enzyme-linked immunospot assays, the percentages of participants in each group with various islet antigen-specific CD8(+) T cells were determined. Sixteen out of the 28 islet antigen-specific epitopes tested were T1D specific, meaning that there was a significantly (P < 0.05) greater epitope positivity rate in the autoAbs(+) T1D cohort than in the healthy controls. Using a cutoff value of two positive epitopes, the 16-epitope panel led to a sensitivity of 75.0% and a specificity of 94.4% regarding the autoAbs(+) T1D patients. Even when using an optimized five-epitope panel, the results were highly accurate. Notably, in the application phase of the study, 77.8% of a new cohort of autoAbs(-) suspected T1D patients exhibited positivity when using the five-epitope optimized panel. This highly accurate method, especially for pediatric patients, will improve clinical diagnosis and etiological classification of autoimmune T1D.

关键词： autism spectrum disorder   contingencies of self‐worth   self‐esteem   the personal sense of power   tumor necrosis factor‐alpha  

摘要： AIM:This study aimed to explore the relationship between self-esteem and tumor necrotic factor-alpha (TNF-α) expression in individuals with autism spectrum disorder (ASD). Self-esteem was assessed using the Contingencies of Self-Worth (CSW) scale, with a focus on external and internal contingencies, and TNF-α expression was measured, given its association with both ASD pathophysiology and self-esteem in prior studies. METHODS:We enrolled 51 high-functioning individuals with ASD and 34 typically developed (TD) individuals. Self-esteem was assessed using the Japanese version of the CSW scale, which evaluates seven domains, and the Personal Sense of Power. TNF-α expression in plasma was quantified via ELISA. Correlations of CSW scores and the Personal Sense of Power with TNF-α levels were analyzed using multiple regression models adjusted for confounding factors such as age, sex, education level, and autistic symptoms. RESULTS:In ASD individuals, TNF-α expression was significantly negatively correlated with the external CSW domain of others' approval and showed a trend toward negative correlations with appearance and relationship harmony. These correlations were not observed in the TD individuals. Likewise, the Personal Sense of Power within family settings showed a trend toward positive correlations with TNF-α expression in ASD individuals, but not in TD individuals. DISCUSSION:This study highlights the implication of TNF-α levels in the self-esteem of ASD individuals, particularly in interpersonal relationships. Lower TNF-α expression was associated with higher self-esteem in social contexts, independent of the severity of autistic symptoms. These findings suggest a biological link between inflammatory pathways and self-esteem in ASD, contributing to a deeper understanding of the interplay between immune function and psychological well-being in this population.

关键词： ADAMTS-8   Colorectal cancer   Transcriptional regulation   Inflammation   IL-6  

摘要： BackgroundADAMTSs are extracellular matrix metalloproteinases that mainly process extracellular matrix components and closely related tumorigenesis. ADAMTS-8 is an anti-angiogenic member of the family and is dysregulated in common cancers. The tumor suppressor function of the ADAMTS-8 has been demonstrated in colorectal cancer. Although ADAMTS-8 plays a critical role in tumor progression, transcriptional regulatory features haven't been studied *** and methodsThe human ADAMTS-8 promoter was cloned into the pMetLuc Reporter vector. Basal promoter activity and the effect of the IL-6 on ADAMTS-8 promoter activity were determined by transient transfection assays in SW480 cells. QRT-PCR and Western blot analyses assessed the impact of IL-6 on ADAMTS-8 mRNA and protein expressions. Functional binding of the specific transcription factors to the ADAMTS-8 promoter region was evaluated by ChIP qPCR and *** results demonstrated that the ADAMTS-8 promoter includes multiple binding sites for transcription factors that could be activated in the inflammatory pathways. IL-6 stimulation increased ADAMTS-8 promoter activity, also mRNA, and protein expressions. Pathway inhibition studies showed that IL-6-mediated induction of ADAMTS-8 was achieved through p38/MAPK, NF-kappa B, PI3K, and SAPK/JNK pathways. STATs, Elk-1, and c-Jun functionally bind to the ADAMTS-8 promoter *** can be concluded that inflammation is a strong positive regulator of the ADAMTS-8 gene.

关键词： Microchimerism   HLA   Autoimmune disease  

摘要： Naturally acquired microchimerism (Mc) is increasingly recognized as an aspect of normal biology. Maternal-fetal bi-directional exchange during pregnancy creates a Mc legacy for the long-term in both individuals. Maternal Mc in her offspring and Mc of fetal origin in women with previous births are best studied. Other sources include from a known or vanished twin, miscarriage or pregnancy termination, older sibling, or previous maternal pregnancy loss. Mc is pleotropic and protean, present in diverse forms, and changing over time as other aspects of biology. Mc acquired from multiple sources, at different lifespan times, and taking on an array of diverse forms, creates a "forward, reverse, and horizontal inheritance" Mc landscape. Mc is found in adaptive and innate immune cells, as resident tissue-specific cells in a wide variety of human tissues, and among other forms as extracellular vesicles. HLA molecules function in a myriad of ways as key determinants for health and are of central importance in interactions between genetically disparate individuals. Studies of autoimmune disease have firmly established a primary role of HLA molecules. Studies of iatrogenic chimerism have established benefit of donor-recipient HLA-disparity against recurrent malignancy after transplantation. HLA molecules and HLA-relationships of families are therefore of particular interest in seeking to understand the role(s) of Mc at the interface of auto-immunity and healthy allo-immunity. This review will begin by providing perspective on Mc in biology followed by a primary focus on persistent Mc according to the human lifespan, in healthy individuals and with illustrative examples of autoimmune diseases.

关键词： MHC polymorphism   Evolution   Bioinformatics   Primates   Selective sweep  

摘要： T cells recognize peptides displayed on the surface of cells on MHC molecules. Genetic variation in MHC genes alters their peptide-binding repertoire and thus influences the potential immune response generated against pathogens. Both gorillas and chimpanzees show reduced diversity at their MHC class I A (MHC-A) locus compared to humans, which has been suggested to be the result of a pathogen-mediated selective sweep. More specifically, gorillas lack A3 lineage alleles while chimpanzees seem to have lost the A2 lineage. While previous studies showed this using phylogenetic analysis, here, we take an in silico functional approach and use the peptide-MHC binding prediction software NetMHCpan to examine the peptide-binding repertoires of common human, chimpanzee, and gorilla MHC-A molecules. We find that both gorillas and chimpanzees lack the A02 peptide binding specificity (supertype) despite gorillas being expected to have this specificity since they kept the A2 lineage. Additionally, we show that human MHC molecules with the A02 specificity bind fewer virus-derived peptides than other MHC molecules. We also do not find differential presentation of self-peptides by the A02 supertype, making the purpose of maintaining this specificity in high frequencies in the human population unclear. Taken together, we hypothesize that poor presentation of viral peptides by A02 supertype MHC molecules could have resulted in a selective sweep in chimpanzees and/or gorillas, though we could not identify a specific virus that may have caused this sweep.