Immunity In Autoimmune Diseases Research Articles

Gut microbiota and relevant abundances of<i> Prevotella copri, Lachnospiraceae, Collinsella, Helicobacter cinaedi, Desulfovibrio</i>, and <i>Escherichia coli</i> among cats with <i>Pemphigus foliaceus</i>

The cat gut-inhabitant conjoint microbiota is a peculiar ecosystem in relationship with several bodily functions and immunity. Gut microbiota dysbiosis could participate within autoimmune disease pathogenesis, whereas its niche, whether causative or influencing role regarding systemic immunity in autoimmune diseases, remains fugitive. The purpose of the present study was to identify gut microbiota alterations and probable mechanisms that participated in the development of Pemphigus foliaceus for a better understanding of future effective therapeutical armamentarium based on gut microbiota. In the present article, the authors investigated gut microbiota alterations to those of eight cats diagnosed with Pemphigus foliaceus. Furthermore, the study thoroughly analyzed pathogenic bacteria species as triggers of autoimmunity. The diagnostic algorithm involved two distinct sides: i) on referral with the first criteria was proof of evidence for possible autoimmunity, and ii) Pemphigus foliaceus diagnosis with relevant analytes. A total of eight cats were enrolled, and gut microbiomes were detected by the use of the MIDOG All-in-One Microbial Test targeting Next-Generation DNA Sequencing. By this methodology, we analyzed the dysbiosis network for bacterial kingdoms and determined the relationship between disease activity related to Pemphigus foliaceus and gut microbiota. The data showed increasing abundances of Collinsella, Lachnospiroceae, and Escherichia coli and decreasing Desulfovibrio piger, Prevotella copri, and Helicobacter cianedi among cats with pemphigus foliaceus. For the first time in Turkey, the gut microbiota of cats with pemphigus foliaceus were detected, the results of which could be cautiously taken into consideration for novel and effective therapeutical approaches.

CD177 drives the transendothelial migration of Treg cells enriched in human colorectal cancer.

Regulatory T (Treg) cells regulate immunity in autoimmune diseases and cancers. However, immunotherapies that target tumor-infiltrating Treg cells often induce unwanted immune responses and tissue inflammation. Our research focussed on exploring the expression pattern of CD177 in tumor-infiltrating Treg cells with the aim of identifying a potential target that can enhance immunotherapy effectiveness. Single-cell RNA sequencing (scRNA-seq) data and survival data were obtained from public databases. Twenty-one colorectal cancer patient samples, including fresh tumor tissues, peritumoral tissues and peripheral blood mononuclear cells (PBMCs), were analysed using flow cytometry. The transendothelial activity of CD177+ Treg cells was substantiated using in vitro experiments. ScRNA-seq and flow cytometry results indicated that CD177 was exclusively expressed in intratumoral Treg cells. CD177+ Treg cells exhibited greater activation status and expressed elevated Treg cell canonical markers and immune checkpoint molecules than CD177- Treg cells. We further discovered that both intratumoral CD177+ Treg cells and CD177-overexpressing induced Treg (iTreg) cells had lower levels of PD-1 than their CD177- counterparts. Moreover, CD177 overexpression significantly enhanced the transendothelial migration of Treg cells in vitro. These results demonstrated that Treg cells with higher CD177 levels exhibited an enhanced activation status and transendothelial migration capacity. Our findings suggest that CD177 may serve as an immunotherapeutic target and that overexpression of CD177 may improve the efficacy of chimeric antigen receptor T (CAR-T) cell therapy.

Exosomes in Action: Unraveling Their Role in Autoimmune Diseases and Exploring Potential Therapeutic Applications.

Exosomes are double phospholipid membrane vesicles that are synthesized and secreted by a variety of cells, including T cells, B cells, dendritic cells, immune cells, are extracellular vesicles. Recent studies have revealed that exosomes can play a significant role in under both physiological and pathological conditions. They have been implicated in regulation of inflammatory responses, immune response, angiogenesis, tissue repair, and antioxidant activities, particularly in modulating immunity in autoimmune diseases (AIDs). Moreover, variations in the expression of exosome-related substances, such as miRNA and proteins, may not only offer valuable perspectives for the early warning, and prognostic assessment of various AIDs, but may also serve as novel markers for disease diagnosis. This article examines the impact of exosomes on the development of AIDs and explores their potential for therapeutic application.

Cell division control 42 elevates during infliximab therapy, and its increment relates to treatment response in ulcerative colitis patients.

Cell division control 42 (CDC42) regulates multiple processes of inflammation and/or immunity in autoimmune diseases and also relates to the treatment efficacy of biologic regimens clinically. This study aimed to explore the longitudinal change in CDC42 during infliximab (IFX) treatment and its correlation with IFX response in ulcerative colitis (UC) patients. Active UC patients (N=48) who received IFX were recruited, and their CDC42 expressions in peripheral blood mononuclear cells (PBMCs) were detected before treatment (W0) and at 12weeks after treatment (W12) using RT-qPCR. Also, CDC42 in PBMCs from UC patients with remission (N=20) and health controls (HCs) (N=20) were detected. CDC42 was reduced in active UC patients compared with UC patients with remission (p=0.014) and HCs (p<0.001). Besides, CDC42 was negatively correlated with CRP (p=0.025), TNF-α (p=0.024), IL-1β (p=0.045), IL-17A (p=0.039), and Mayo score (p=0.015) in active UC patients, but did not relate to ESR, disease duration, or IL-6 (all p>0.05), while CDC42 was only negatively related to CRP in UC patients with remission (p=0.046). Interestingly, CDC42 was increased at W12 after IFX treatment in active UC patients (p<0.001). Specifically, CDC42 was elevated during treatment in active UC patients with IFX response (p<0.001), but did not obviously change in those without IFX response (p=0.061). Furthermore, CDC42 at W12 was higher in active UC patients with IFX response compared with those without IFX response (p=0.049). Cell division control 42serves as a potential biomarker for monitoring disease progression and IFX response in UC patients.

NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases.

Autoimmune diseases are a broad spectrum of human diseases that are characterized by the breakdown of immune tolerance and the production of autoantibodies. Recently, dysfunction of innate and adaptive immunity is considered to be a key step in the initiation and maintenance of autoimmune diseases. NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome is a multimeric protein complex, which can detect exogenous pathogen irritants and endogenous danger signals. The main function of NLRP3 inflammasome is to promote secretion of interleukin (IL)-1β and IL-18, and pyroptosis mediated by caspase-1. Served as a checkpoint in innate and adaptive immunity, aberrant activation and regulation of NLRP3 inflammasome plays an important role in the pathogenesis of autoimmune diseases. This paper reviewed the roles of NLRP3 inflammasome in autoimmune diseases, which shows NLRP3 inflammasome may be a potential target for autoimmune diseases deserved further study.

The Immunopathology of Complement Proteins and Innate Immunity in Autoimmune Disease

The complement is a powerful cascade of the innate immunity and also acts as a bridge between innate and acquired immune defence. Complement activation can occur via three distinct pathways, the classical, alternative and lectin pathways, each resulting in the common terminal pathway. Complement activation results in the release of a range of biologically active molecules that significantly contribute to immune surveillance and tissue homeostasis. Several soluble and membrane-bound regulatory proteins restrict complement activation in order to prevent complement-mediated autologous damage, consumption and exacerbated inflammation. The crucial role of complement in the host homeostasis is illustrated by association of both complement deficiency and overactivation with severe and life-threatening diseases. Autoantibodies targeting complement components have been described to alter expression and/or function of target protein resulting in a dysregulation of the delicate equilibrium between activation and inhibition of complement. The spectrum of diseases associated with complement autoantibodies depends on which complement protein and activation pathway are targeted, ranging from autoimmune disorders to kidney and vascular diseases. Nevertheless, these autoantibodies have been identified as differential biomarkers for diagnosis or follow-up of disease only in a small number of clinical conditions. For some autoantibodies, a clear relationship with clinical manifestations has been identified, such as anti-C1q, anti-Factor H, anti-C1 Inhibitor antibodies and C3 nephritic factor. For other autoantibodies, the origin and the functional consequences still remain to be elucidated, questioning about the pathophysiological significance of these autoantibodies, such as anti-mannose binding lectin, anti-Factor I, anti-Factor B and anti-C3b antibodies. The detection of autoantibodies targeting complement components is performed in specialized laboratories; however, there is no consensus on detection methods and standardization of the assays is a real challenge. This review summarizes the current panorama of autoantibodies targeting complement recognition proteins of the classical and lectin pathways, associated proteases, convertases, regulators and terminal components, with an emphasis on autoantibodies clearly involved in clinical conditions.

The Dynamic Interplay between the Gut Microbiota and Autoimmune Diseases.

The human gut-resident commensal microbiota is a unique ecosystem associated with various bodily functions, especially immunity. Gut microbiota dysbiosis plays a crucial role in autoimmune disease pathogenesis as well as in bowel-related diseases. However, the role of the gut microbiota, which causes or influences systemic immunity in autoimmune diseases, remains elusive. Aryl hydrocarbon receptor, a ligand-activated transcription factor, is a master moderator of host-microbiota interactions because it shapes the immune system and impacts host metabolism. In addition, treatment optimization while minimizing potential adverse effects in autoimmune diseases remains essential, and modulation of the gut microbiota constitutes a potential clinical therapy. Here, we present evidence linking gut microbiota dysbiosis with autoimmune mechanisms involved in disease development to identify future effective approaches based on the gut microbiota for preventing autoimmune diseases.

Revisiting the Concept of Targeting NFAT to Control T Cell Immunity and Autoimmune Diseases.

The nuclear factor of activated T cells (NFAT) family of transcription factors, which includes NFAT1, NFAT2, and NFAT4, are well-known to play important roles in T cell activation. Most of NFAT proteins are controlled by calcium influx upon T cell receptor and costimulatory signaling results increase of IL-2 and IL-2 receptor. NFAT3 however is not shown to be expressed in T cells and NFAT5 has not much highlighted in T cell functions yet. Recent studies demonstrate that the NFAT family proteins involve in function of lineage-specific transcription factors during differentiation of T helper 1 (Th1), Th2, Th17, regulatory T (Treg), and follicular helper T cells (Tfh). They have been studied to make physical interaction with the other transcription factors like GATA3 or Foxp3 and they also regulate Th cell signature gene expressions by direct binding on promotor region of target genes. From last decades, NFAT functions in T cells have been targeted to develop immune modulatory drugs for controlling T cell immunity in autoimmune diseases like cyclosporine A, FK506, etc. Due to their undesirable side defects, only limited application is available in human diseases. This review focuses on the recent advances in development of NFAT targeting drug as well as our understanding of each NFAT family protein in T cell biology. We also discuss updated detail molecular mechanism of NFAT functions in T cells, which would lead us to suggest an idea for developing specific NFAT inhibitors as a therapeutic drug for autoimmune diseases.

Bioconjugate Strategies for the Induction of Antigen-Specific Tolerance in Autoimmune Diseases.

Antigen-specific immunotherapy (ASI) holds great promise for the treatment of autoimmune diseases. In mice, administration of major histocompatibility complex (MHC) binding synthetic peptides which modulate T cell receptor (TCR) signaling under subimmunogenic conditions induces selective tolerance without suppressing the global immune responses. However, clinical translation has yielded limited success. It has become apparent that the TCR signaling pathway via synthetic peptide antigen alone is inadequate to induce an effective tolerogenic immunity in autoimmune diseases. Bioconjugate strategies combining additional immunomodulatory functions with TCR signaling can amplify the antigen-specific immune tolerance and possibly lead to the development of new treatments in autoimmune diseases. In this review, we provide a summary of recent advances in the development of bioconjugates to achieve antigen-specific immune tolerance in vivo, with the discussion focused on the underlying design principles and challenges that must be overcome to target these therapies to patients suffering from autoimmune diseases.

Osteopontin Bridging Innate and Adaptive Immunity in Autoimmune Diseases.

Osteopontin (OPN) regulates the immune response at multiple levels. Physiologically, it regulates the host response to infections by driving T helper (Th) polarization and acting on both innate and adaptive immunity; pathologically, it contributes to the development of immune-mediated and inflammatory diseases. In some cases, the mechanisms of these effects have been described, but many aspects of the OPN function remain elusive. This is in part ascribable to the fact that OPN is a complex molecule with several posttranslational modifications and it may act as either an immobilized protein of the extracellular matrix or a soluble cytokine or an intracytoplasmic molecule by binding to a wide variety of molecules including crystals of calcium phosphate, several cell surface receptors, and intracytoplasmic molecules. This review describes the OPN structure, isoforms, and functions and its role in regulating the crosstalk between innate and adaptive immunity in autoimmune diseases.

Cross Talk between Neuroregulatory Molecule and Monocyte: Nerve Growth Factor Activates the Inflammasome

BackgroundIncreasing evidence points to a role for the extra-neuronal nerve growth factor (NGF) in acquired immune responses. However, very little information is available about its role and underlying mechanism in innate immunity. The role of innate immunity in autoimmune diseases is becoming increasingly important. In this study, we explored the contribution of pleiotropic NGF in the innate immune response along with its underlying molecular mechanism with respect to IL-1β secretion.MethodsHuman monocytes, null and NLRP3 deficient THP-1 cell lines were used for this purpose. We determined the effect of NGF on secretion of IL-1β at the protein and mRNA levels. To determine the underlying molecular mechanism, the effect of NGF on NLRP1/NLRP3 inflammasomes and its downstream key protein, activated caspase-1, were evaluated by ELISA, immunoflorescence, flow cytometry, and real-time PCR.ResultsIn human monocytes and null THP-1 cell line, NGF significantly upregulates IL-1β at protein and mRNA levels in a caspase-1 dependent manner through its receptor, TrkA. Furthermore, we observed that NGF induces caspase-1 activation through NLRP1/NLRP3 inflammasomes, and it is dependent on the master transcription factor, NF-κB.ConclusionsTo best of our knowledge, this is the first report shedding light on the mechanistic aspect of a neuroregulatory molecule, NGF, in innate immune response, and thus enriches our understanding regarding its pathogenic role in inflammation. These observations add further evidence in favor of anti-NGF therapy in autoimmune diseases and also unlock a new area of research about the role of NGF in IL-1β mediated diseases.

Regulatory T Cells and Immune Tolerance to Coagulation Factor IX in the Context of Intramuscular AAV1 Gene Transfer

Regulatory T cells play a major role in induction and maintenance of immune tolerance and immunological homeostasis. A variety of strategies have been attempted to induce regulatory T cells for control of unwanted, adverse immunity in autoimmune diseases, transplantation as well as gene transfer. We recently reported efficient induction of immune tolerance to coagulation factor IX (FIX) following intramuscular AAV1 gene transfer. In the current study, we performed a systematic and comprehensive examination of the role and function of regulatory T cells in induction and maintenance of FIX tolerance in the context of intramuscular AAV1 gene transfer. We observed no significant upregulation of regulatory T cells in the FIX-tolerant mice. In addition, adoptive transfer of splenocytes from FIX-tolerant mice did not suppress anti-hFIX immunity in recipient mice. Both in vitro and in vivo depletion of regulatory T cells failed to reverse FIX tolerance. These observations revealed that regulatory T cells do not play a significant role in the maintenance/protection of the established FIX tolerance. Our results provide critical insight into the role and function of regulatory T cells in induction and maintenance/protection of immune tolerance in gene transfer, complementing the current paradigm of immune tolerance mechanism.

Human cardiac myosin (HCM) activates Toll-like receptors 2, 7 and 8 (B87)

Abstract Toll-like receptor (TLR) activation has been implicated as a link between innate immunity and adaptive immunity in autoimmune diseases including myocarditis. Human cardiac myosin (HCM) has long been known as an autoantigen in myocarditis. The role of HCM on innate immunity has not been studied. To test the hypothesis that HCM activates TLRs, HEK 293 cells transfected with human (h) TLR2, 3, 4, 5, 7, 8, and 9 were treated with HCM or a cryptic HCM peptide S2-16 for 72h. IL-8 levels in supernatants were measured by ELISA. HCM or S2-16 treatment resulted in 2–4 times more IL-8 from hTLR2, 7 and 8 transfected cell lines compared with media. HEK control cells treated with HCM or S2-16 showed same level of IL-8 as media. In addition, skeletal muscle myosin treated hTLR transfected cell lines showed no difference in IL-8 levels from media. To confirm this observation, human monocytes were isolated and treated with HCM and S2-16. Supernatant was harvested 24 h later and IL-8 was measured by ELISA. Both HCM and S2-16 treatment resulted in a dose-dependent increase of IL-8. Similar increase in IL-8 in human monocytic THP-1 cell line was also observed. The finding that HCM activates innate immunity through TLR 2, 7, and 8 is novel, and links innate and adaptive immunity in autoimmune myocarditis. Exposure of HCM during viral infection or after apoptosis or necrosis in the heart may lead to chronic stimulation of TLRs and autoimmune heart disease.

A protective role for innate immunity in autoimmune disease.

Systemic lupus erythematosus is an incurable autoimmune disease characterized by autoantibodies directed against highly conserved nuclear proteins and DNA. While the cause of lupus is not known, B-lymphocytes are essential for disease. Most striking is that deficiency in components of the innate immune system such as complement is a major risk factor in disease. One explanation for the involvement of complement and innate immunity is that they are important in the induction and maintenance of B cell tolerance to lupus antigens.

Cell-mediated immunity in autoimmune diseases tested by the aggregation of buffy-coat cells

Cell-mediated immunity in autoimmune diseases tested by the aggregation of buffy-coat cells