Immune Network最新文献

Gut dysbiosis is one of prominent features in inflammatory bowel diseases (IBDs) which are of an unknown etiology. Although the cause-and-effect relationship between IBD and gut dysbiosis remains to be elucidated, one area of research has focused on the management of IBD by modulating and correcting gut dysbiosis. The use of antibiotics, probiotics either with or without prebiotics, and fecal microbiota transplantation from healthy donors are representative methods for modulating the intestinal microbiota ecosystem. The gut microbiota is not a simple assembly of bacteria, fungi, and viruses, but a complex organ-like community system composed of numerous kinds of microorganisms. Thus, studies on specific changes in the gut microbiota depending on which treatment option is applied are very limited. Here, we review previous studies on microbial modulation as a therapeutic option for IBD and its significance in the pathogenesis of IBD.

T-helper-17 (Th17) cells and related IL-17-producing (type17) lymphocytes are abundant at the epithelial barrier. In response to bacterial and fungal infection, the signature cytokines IL-17A/F and IL-22 mediate the antimicrobial immune response and contribute to wound healing of injured tissues. Despite their protective function, type17 lymphocytes are also responsible for various chronic inflammatory disorders, including inflammatory bowel disease (IBD) and colitis associated cancer (CAC). A deeper understanding of type17 regulatory mechanisms could ultimately lead to the discovery of therapeutic strategies for the treatment of chronic inflammatory disorders and the prevention of cancer. In this review, we discuss the current understanding of the development and function of type17 immune cells at the intestinal barrier, focusing on the impact of microbiota-immune interactions on intestinal barrier homeostasis and disease etiology.

Autoimmune diseases are caused by a dysfunction of the acquired immune system. In a subset of autoimmune diseases, B cells escaping immune tolerance present autoantigen and produce cytokines and/or autoantibodies, resulting in systemic or organ-specific autoimmunity. Therefore, B cell depletion with monoclonal Abs targeting B cell lineage markers is standard care therapy for several B cell-mediated autoimmune disorders. In the last 5 years, genetically-engineered cellular immunotherapies targeting B cells have shown superior efficacy and long-term remission of B cell malignancies compared to historical clinical outcomes using B cell depletion with monoclonal Ab therapies. This has raised interest in understanding whether similar durable remission could be achieved with use of genetically-engineered cell therapies for autoimmunity. This review will focus on current human clinical trials using engineered cell therapies for B cell-associated autoimmune diseases.

Sjögren syndrome (SS) is a chronic autoimmune disorder that primarily targets the salivary and lacrimal glands. The pathology of these exocrine glands is characterized by periductal focal lymphocytic infiltrates, and both T cell-mediated tissue injury and autoantibodies that interfere with the secretion process underlie glandular hypofunction. In addition to these adaptive mechanisms, multiple innate immune pathways are dysregulated, particularly in the salivary gland epithelium. Our understanding of the pathogenetic mechanisms of SS has substantially improved during the past decade. In contrast to viral infection, bacterial infection has never been considered in the pathogenesis of SS. In this review, oral dysbiosis associated with SS and evidence for bacterial infection of the salivary glands in SS were reviewed. In addition, the potential contributions of bacterial infection to innate activation of ductal epithelial cells, plasmacytoid dendritic cells, and B cells and to the breach of tolerance via bystander activation of autoreactive T cells and molecular mimicry were discussed. The added roles of bacteria may extend our understanding of the pathogenetic mechanisms and therapeutic approaches for this autoimmune exocrinopathy.

As far the current severe coronavirus disease 2019 (COVID-19), respiratory disease is still the biggest threat to human health. In addition, infectious respiratory diseases are particularly prominent. In addition to killing and clearing the infection pathogen directly, regulating the immune responses against the pathogens is also an important therapeutic modality. Sirtuins belong to NAD+-dependent class III histone deacetylases. Among 7 types of sirtuins, silent information regulator type-1 (SIRT1) played a multitasking role in modulating a wide range of physiological processes, including oxidative stress, inflammation, cell apoptosis, autophagy, antibacterial and antiviral functions. It showed a critical effect in regulating immune responses by deacetylation modification, especially through high-mobility group box 1 (HMGB1), a core molecule regulating the immune system. SIRT1 was associated with many respiratory diseases, including COVID-19 infection, bacterial pneumonia, tuberculosis, and so on. Here, we reviewed the latest research progress regarding the effects of SIRT1 on immune system in respiratory diseases. First, the structure and catalytic characteristics of SIRT1 were introduced. Next, the roles of SIRT1, and the mechanisms underlying the immune regulatory effect through HMGB1, as well as the specific activators/inhibitors of SIRT1, were elaborated. Finally, the multitasking roles of SIRT1 in several respiratory diseases were discussed separately. Taken together, this review implied that SIRT1 could serve as a promising specific therapeutic target for the treatment of respiratory diseases.

Tobacco smoking (TS) has been known as one of the most potent risk factors for airway inflammatory diseases. However, there has been a paucity of information regarding the immunologic alteration mediated by TS in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). To identify the effect of TS, we harvested human tissue samples (never smoker: n=41, current smoker: n=22, quitter: n=23) and analyzed the expression of epithelial-derived cytokines (EDCs) such as IL-25, IL-33, and thymic stromal lymphopoietin. The expressions of Th2 cytokines and total serum IgE showed a type-2 inflammatory alteration by TS. In addition, the epithelial marker E-cadherin and epithelial-mesenchymal transition (EMT)-associated markers (N-cadherin, α-SMA, and vimentin) were evaluated. Histological analysis showed that EDC expressions were upregulated in the current smoker group and downregulated in the quitter group. These expression patterns were consistent with mRNA and protein expression levels. We also found that the local Th2 cytokine expression and IgE class switching, as well as serum IgE levels, were elevated in the current smoker group and showed normal levels in the quitter group. Furthermore, the expressions of E-cadherin decreased while those of N-cadherin, α-SMA, and vimentin increased in the current smoker group compared those in the never smoker group. Taken together, these results indicate that TS contributes to the deterioration of pathogenesis by releasing local EDCs and Th2 cytokines, resulting in EMT in patients with CRSwNP. We verified that alterations of immunological response by TS in sinonasal epithelium can play a vital role in leading to CRSwNP.

Suppressors of cytokine signaling (SOCS) have emerged as potential regulators of macrophage function. We have investigated mechanisms of SOCS3 action on type 2 macrophage (M2) differentiation induced by glucocorticoid using human monocytic cell lines and mouse bone marrow-derived macrophages. Treatment of THP1 monocytic cells with dexamethasone (Dex) induced ROS generation and M2 polarization promoting IL-10 and TGF-β production, while suppressing IL-1β, TNF-α and IL-6 production. SOCS3 over-expression reduced, whereas SOCS3 ablation enhanced IL-10 and TGF-β induction with concomitant regulation of ROS. As a mediator of M2 differentiation, glucocorticoid-induced leucine zipper (GILZ) was down-regulated by SOCS3 and up-regulated by shSOCS3. The induction of GILZ and IL-10 by Dex was dependent on ROS and p38 MAPK activity. Importantly, GILZ ablation led to the inhibition of ROS generation and anti-inflammatory cytokine induction by Dex. Moreover, GILZ knock-down negated the up-regulation of IL-10 production induced by shSOCS3 transduction. Our data suggest that SOCS3 targets ROS- and p38-dependent GILZ expression to suppress Dex-induced M2 polarization.