辅助性T细胞17与相关疾病发生的研究进展

辅助性T细胞17(T helper cells 17,Th17)是新近发现的一种辅助性T细胞,该类细胞在机体的抗微生物免疫中起非常重要的作用,也与很多自身免疫性疾病的发生有一定的关系,如过敏、糖尿病、类风湿性关节炎等。Th17细胞是与Th1及Th2细胞不同的T细胞亚类,可分泌IL-17A、IL-17F、IL-21、IL-22等细胞因子。本文就Th17细胞的基本生物学功能、与感染性疾病及自身免疫性疾病发生的相关性作一综述。     

Reduced Dendritic Cells Expressing CD200R1 in Children with Inflammatory Bowel Disease: Correlation with Th17 and Regulatory T Cells

Loss of tolerance of the adaptive immune system towards indigenous flora contributes to the development of inflammatory bowel diseases (IBD). Defects in dendritic cell (DC)-mediated innate and adoptive immune responses are conceivable. The aim of this study was to investigate the expression of the inhibitory molecules CD200R1 and their ligand CD200 on DCs, to clarify the role of the DCs in the pathogenesis of IBD. Thirty-seven pediatric IBD patients (23 with Crohn’s disease (CD) and 14 with ulcerative colitis (UC)) with mean age 13.25 ± 2.9 years were included. Fourteen age-matched healthy pediatric volunteers (five males and nine females) served as a control group (HC). The percentage of CD11c⁺ myeloid dendritic cells (mDCs) and CD123⁺ plasmacytoid DCs (pDCs) expressing CD200R1 and CD200 were evaluated in peripheral blood using flow cytometry and were correlated with routine biochemical, serological markers, serum levels of cytokines and with the percentages of circulating regulatory T cells (Treg) and CD4⁺ producing IL-17 (Th17). IBD patients showed a significant decrease in the percentage of pDCs and mDCs expressing CD200R1 compared to that of HC. Patients with UC showed increased expressions of the CD200 molecule on pDCs as compared to HC. DCs expressing CD200R1 were found to be correlated positively with Treg and negatively with TH17 and erythrocyte sedimentation rate (ESR). Our findings suggest that IBD is associated with dysregulation in the CD200R1/CD200 axis and that the decrease in DCs expressing CD200R1 may contribute to the imbalance of Th17 and Treg cells and in the pathogenesis of IBD.     

Therapeutic Advances in Gut Microbiome Modulation in Patients with Inflammatory Bowel Disease from Pediatrics to Adulthood

There is mounting evidence that the gut microbiota plays an important role in the pathogenesis of inflammatory bowel disease (IBD). For the past decade, high throughput sequencing-based gut microbiome research has identified characteristic shifts in the composition of the intestinal microbiota in patients with IBD, suggesting that IBD results from alterations in the interactions between intestinal microbes and the host’s mucosal immune system. These studies have been the impetus for the development of new therapeutic approaches targeting the gut microbiome, such as nutritional therapies, probiotics, fecal microbiota transplant and beneficial metabolic derivatives. Innovative technologies can further our understanding of the role the microbiome plays as well as help to evaluate how the different approaches in microbiome modulation impact clinical responses in adult and pediatric patients. In this review, we highlight important microbiome studies in patients with IBD and their response to different microbiome modulation therapies, and describe the differences in therapeutic response between pediatric and adult patient cohorts.     

Effect of Microbiome on Non-Alcoholic Fatty Liver Disease and the Role of Probiotics,Prebiotics, and Biogenics

Non-alcoholic fatty liver disease (NAFLD) is a leading cause of liver cirrhosis and hepatocellular carcinoma. NAFLD is associated with metabolic disorders such as obesity, insulin resistance, dyslipidemia, steatohepatitis, and liver fibrosis. Liver-resident (Kupffer cells) and recruited macrophages contribute to low-grade chronic inflammation in various tissues by modulating macrophage polarization, which is implicated in the pathogenesis of metabolic diseases. Abnormalities in the intestinal environment, such as the gut microbiota, metabolites, and immune system, are also involved in the pathogenesis and development of NAFLD. Hepatic macrophage activation is induced by the permeation of antigens, endotoxins, and other proinflammatory substances into the bloodstream as a result of increased intestinal permeability. Therefore, it is important to understand the role of the gut–liver axis in influencing macrophage activity, which is central to the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH). Not only probiotics but also biogenics (heat-killed lactic acid bacteria) are effective in ameliorating the progression of NASH. Here we review the effect of hepatic macrophages/Kupffer cells, other immune cells, intestinal permeability, and immunity on NAFLD and NASH and the impact of probiotics, prebiotics, and biogenesis on those diseases.     

Deficiency of IL-27 Signaling Exacerbates Experimental Autoimmune Uveitis with Elevated Uveitogenic Th1 and Th17 Responses

Human uveitis is an autoimmune disease of the central nervous system that is characterized by ocular inflammation with the involvement of uveitogenic Th1 and Th17 responses. In experimental autoimmune uveitis (EAU), the animal model for human uveitis, both responses are proven to be critical in disease development. Therefore, targeting both Th1 and Th17 cells has therapeutic implication for disease resolution. IL-27 is a multifunctional cytokine that can either promote or inhibit T cell responses and is implicated in both autoimmune and infectious diseases. The aim of this study is to characterize the role of IL-27/IL-27R signaling in regulating uveitogenic Th1/Th17 responses in EAU. By immunizing IL-27Rα^−/− mice and their wild-type (WT) littermates for EAU, we demonstrated that IL-27 signaling deficiency exacerbated EAU with severe ocular inflammation and impairment of visual function. Furthermore, there was a significant increase in the eye-infiltrating Th1 and Th17 cells in IL-27Rα^−/− EAU mice compared to WT. Their retinal antigen-specific Th1 and Th17 responses were also significantly increased, as represented by the elevation of their signature cytokines, IFN-γ and IL-17A, respectively. We also observed the upregulation of another pathogenic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), from effector T cells in IL-27Rα^−/− EAU mice. Mechanistic studies confirmed that IL-27 inhibited GM-CSF production from Th17 cells. In addition, the induction of IL-10 producing type 1 regulatory T (Tr1) cells was impaired in IL-27Rα^−/− EAU mice. These results identified that IL-27 signaling plays a suppressive role in EAU by regulating multiple CD4⁺ cell subsets, including the effector Th1 and Th17 cells and the regulatory Tr1 cells. Our findings provide new insights for therapeutic potential in controlling uveitis by enhancing IL-27 signaling.     

Th17-Related Cytokines as Potential Discriminatory Markers between Neuromyelitis Optica (Devic’s Disease) and Multiple Sclerosis—A Review

Multiple sclerosis (MS) and Devic’s disease (NMO; neuromyelitis optica) are autoimmune, inflammatory diseases of the central nervous system (CNS), the etiology of which remains unclear. It is a serious limitation in the treatment of these diseases. The resemblance of the clinical pictures of these two conditions generates a partial possibility of introducing similar treatment, but on the other hand, a high risk of misdiagnosis. Therefore, a better understanding and comparative characterization of the immunopathogenic mechanisms of each of these diseases are essential to improve their discriminatory diagnosis and more effective treatment. In this review, special attention is given to Th17 cells and Th17-related cytokines in the context of their potential usefulness as discriminatory markers for MS and NMO. The discussed results emphasize the role of Th17 immune response in both MS and NMO pathogenesis, which, however, cannot be considered without taking into account the broader perspective of immune response mechanisms.     

Diet–Microbiota Interplay: An Emerging Player in Macrophage Plasticity and Intestinal Health

Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract with an increasing prevalence worldwide. Targeted therapies for IBD are limited by several factors, including the therapeutic ceiling and the high incidence of non-responders or loss-of-response. In order to improve therapeutic efficacy, there is critical need to decipher disease pathogenesis, currently not well understood. Macrophages, innate immune cells that exhibit high plasticity, perpetuate inflammatory signalling in IBD through excessive release of inflammatory mediators. In recent years, pioneering research has revealed the importance of the interplay between macrophages and gut microbiota in maintaining intestinal homeostasis. Particular attention is focusing on microbiota-derived metabolites, believed to possess immunomodulatory properties capable of manipulating macrophage plasticity. Microbiota-derived short-chain fatty acids (SCFAs) and indole compounds, along with dietary sourced omega-3 (ω-3) polyunsaturated fatty acids (PUFA), exert anti-inflammatory effects, attributable to interactions with macrophages. Before we can effectively incorporate these metabolites into IBD therapies, a deeper understanding of microbiota–macrophage interactions at a molecular level is necessary. Therefore, the aim of this review is firstly to detail current knowledge regarding how diet and microbiota-derived metabolites modify macrophage plasticity. Later, we discuss the concept of therapeutic strategies directed at microbiota–macrophage interactions, which could be highly valuable for IBD therapies in the future.     

Cytosolic Phospholipase A2 Is Required for Fexofenadine’s Therapeutic Effects against Inflammatory Bowel Disease in Mice

Inflammatory Bowel Disease (IBD) is an autoimmune condition with complicated pathology and diverse clinical signs. TNFα is believed to play a crucial role in the pathogenesis of IBD. We recently identified fexofenadine, a well-known antagonist of histamine H1 receptor, as a novel inhibitor of TNFα signaling. Additionally, cytosolic phospholipase A2 (cPLA2) was isolated as a binding target of fexofenadine, and fexofenadine-mediated anti-TNF activity relied on cPLA2 in vitro. The objective of this study is to determine whether fexofenadine is therapeutic against chemically-induced murine IBD model and whether cPLA2 and/or histamine H1 receptor is important for fexofenadine’s anti-inflammatory activity in vivo by leveraging various genetically modified mice and chemically induced murine IBD models. Both dextran sulfate sodium- and 2, 4, 6-trinitrobenzene sulfonic acid-induced murine IBD models revealed that orally delivered fexofenadine was therapeutic against IBD, evidenced by mitigated clinical symptoms, decreased secretions of the proinflammatory cytokine IL-6 and IL-1β, lowered intestinal inflammation, and reduced p-p65 and p-IĸBα. Intriguingly, Fexofenadine-mediated protective effects against IBD were lost in cPLA2 deficient mice but not in histamine H1 receptor-deficient mice. Collectively, these findings demonstrate the therapeutic effects of over-the-counter drug Fexofenadine in treating DSS-induced IBD murine and provide first in vivo evidence showing that cPLA2 is required for fexofenadine’s therapeutic effects in murine IBD model and probably other inflammatory and autoimmune diseases as well.     

Dysbiosis in Inflammatory Bowel Disease: Pathogenic Role and Potential Therapeutic Targets

Microbe–host communication is essential to maintain vital functions of a healthy host, and its disruption has been associated with several diseases, including Crohn’s disease and ulcerative colitis, the two major forms of inflammatory bowel disease (IBD). Although individual members of the intestinal microbiota have been associated with experimental IBD, identifying microorganisms that affect disease susceptibility and phenotypes in humans remains a considerable challenge. Currently, the lack of a definition between what is healthy and what is a dysbiotic gut microbiome limits research. Nevertheless, although clear proof-of-concept of causality is still lacking, there is an increasingly evident need to understand the microbial basis of IBD at the microbial strain, genomic, epigenomic, and functional levels and in specific clinical contexts. Recent information on the role of diet and novel environmental risk factors affecting the gut microbiome has direct implications for the immune response that impacts the development of IBD. The complexity of IBD pathogenesis, involving multiple distinct elements, suggests the need for an integrative approach, likely utilizing computational modeling of molecular datasets to identify more specific therapeutic targets.     

Dopaminergic Receptor Targeting in Multiple Sclerosis: Is There Therapeutic Potential?

Dopamine is a neurotransmitter that mediates neuropsychological functions of the central nervous system (CNS). Recent studies have shown the modulatory effect of dopamine on the cells of innate and adaptive immune systems, including Th17 cells, which play a critical role in inflammatory diseases of the CNS. This article reviews the literature data on the role of dopamine in the regulation of neuroinflammation in multiple sclerosis (MS). The influence of dopaminergic receptor targeting on experimental autoimmune encephalomyelitis (EAE) and MS pathogenesis, as well as the therapeutic potential of dopaminergic drugs as add-on pathogenetic therapy of MS, is discussed.     

Native and Engineered Probiotics: Promising Agents against Related Systemic and Intestinal Diseases

Intestinal homeostasis is a dynamic balance involving the interaction between the host intestinal mucosa, immune barrier, intestinal microecology, nutrients, and metabolites. Once homeostasis is out of balance, it will increase the risk of intestinal diseases and is also closely associated with some systemic diseases. Probiotics (Escherichia coli Nissle 1917, Akkermansia muciniphila, Clostridium butyricum, lactic acid bacteria and Bifidobacterium spp.), maintaining the gut homeostasis through direct interaction with the intestine, can also exist as a specific agent to prevent, alleviate, or cure intestinal-related diseases. With genetic engineering technology advancing, probiotics can also show targeted therapeutic properties. The aims of this review are to summarize the roles of potential native and engineered probiotics in oncology, inflammatory bowel disease, and obesity, discussing the therapeutic applications of these probiotics.     

Elevated Th22 Cells Correlated with Th17 Cells in Peripheral Blood of Patients with Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a hematological tumor in which progress T helper (Th) subsets including Th22, Th17, and Th1 cells play a pivotal role. However, the role of T helper (Th) subsets in the immune pathogenesis of AML remains unclear. Here, we investigated frequencies of Th22, Th17, pure Th17, and Th1 cells in the peripheral blood (PB) of AML patients. We demonstrated that Th22, Th17, and pure Th17 in newly-diagnosed (ND) and non-complete remission (Non-CR) AML patients and plasma IL-22 in ND AML patients were significantly increased. Retinoid-related orphan receptor C (RORC) expression was significantly elevated in CR and Non-CR AML patients. However, Th1 in ND AML patients and IL-17 in ND, Non-CR or CR AML patients was significantly decreased compared with controls. Moreover, Th22 and IL-22 showed positive correlation with pure Th17, but Th22 showed negative correlation with Th1 in ND AML patients. RORC showed positive correlation with Th22 and approximately positive correlation with pure Th17 in Non-CR patients. PB blast cell showed positive correlation with Th22 and negative correlation with Th1 in ND AML patients. Our results indicate that Th22 and pure Th17 cells conjointly contribute to the pathogenesis of AML and might be promising novel clinical index for AML.     

CD147 Is Essential for the Development of Psoriasis via the Induction of Th17 Cell Differentiation

Th17 cells play an important role in psoriasis. The differentiation of naïve CD4⁺ T cells into Th17 cells depends on glycolysis as the energy source. CD147/basigin, an integral transmembrane protein belonging to the immunoglobulin superfamily, regulates glycolysis in association with monocarboxylate transporters (MCTs)-1 and -4 in cancer cells and T cells. We examined whether CD147/basigin is involved in the pathogenesis of psoriasis in humans and psoriasis-model mice. The serum level of CD147 was increased in patients with psoriasis, and the expression of CD147 and MCT-1 was elevated in their dermal CD4⁺ RORγt⁺ T cells. In vitro, the potential of naïve CD4⁺ T cells to differentiate into Th17 cells was abrogated in CD147^−/− T cells. Imiquimod (IMQ)-induced psoriatic dermatitis was significantly milder in CD147^−/− mice and bone marrow chimeric mice lacking CD147 in the hematopoietic cells of myeloid lineage. These findings demonstrate that CD147 is essential for the development of psoriasis via the induction of Th17 cell differentiation.     

Next-Generation Probiotics for Inflammatory Bowel Disease

Engineered probiotics represent a cutting-edge therapy in intestinal inflammatory disease (IBD). Genetically modified bacteria have provided a new strategy to release therapeutically operative molecules in the intestine and have grown into promising new therapies for IBD. Current IBD treatments, such as corticosteroids and immunosuppressants, are associated with relevant side effects and a significant proportion of patients are dependent on these therapies, thus exposing them to the risk of relevant long-term side effects. Discovering new and effective therapeutic strategies is a worldwide goal in this research field and engineered probiotics could potentially provide a viable solution. This review aims at describing the proceeding of bacterial engineering and how genetically modified probiotics may represent a promising new biotechnological approach in IBD treatment.     

Identification of Corosolic and Oleanolic Acids as Molecules Antagonizing the Human RORγT Nuclear Receptor Using the Calculated Fingerprints of the Molecular Similarity

RORγT is a protein product of the RORC gene belonging to the nuclear receptor subfamily of retinoic-acid-receptor-related orphan receptors (RORs). RORγT is preferentially expressed in Th17 lymphocytes and drives their differentiation from naive CD4+ cells and is involved in the regulation of the expression of numerous Th17-specific cytokines, such as IL-17. Because Th17 cells are implicated in the pathology of autoimmune diseases (e.g., psoriasis, inflammatory bowel disease, multiple sclerosis), RORγT, whose activity is regulated by ligands, has been recognized as a drug target in potential therapies against these diseases. The identification of such ligands is time-consuming and usually requires the screening of chemical libraries. Herein, using a Tanimoto similarity search, we found corosolic acid and other pentacyclic tritepenes in the library we previously screened as compounds highly similar to the RORγT inverse agonist ursolic acid. Furthermore, using gene reporter assays and Th17 lymphocytes, we distinguished compounds that exert stronger biological effects (ursolic, corosolic, and oleanolic acid) from those that are ineffective (asiatic and maslinic acids), providing evidence that such combinatorial methodology (in silico and experimental) might help wet screenings to achieve more accurate results, eliminating false negatives.     

The Interplay between Immune System and Microbiota in Inflammatory Bowel Disease: A Narrative Review

The importance of the gut microbiota in human health is currently well established. It contributes to many vital functions such as development of the host immune system, digestion and metabolism, barrier against pathogens or brain–gut communication. Microbial colonization occurs during infancy in parallel with maturation of the host immune system; therefore, an adequate cross-talk between these processes is essential to generating tolerance to gut microbiota early in life, which is crucial to prevent allergic and immune-mediated diseases. Inflammatory bowel disease (IBD) is characterized by an exacerbated immune reaction against intestinal microbiota. Changes in abundance in the gut of certain microorganisms such as bacteria, fungi, viruses, and archaea have been associated with IBD. Microbes that are commonly found in high abundance in healthy gut microbiomes, such as F. prausnitzii or R. hominis, are reduced in IBD patients. E. coli, which is usually present in a healthy gut in very low concentrations, is increased in the gut of IBD patients. Microbial taxa influence the immune system, hence affecting the inflammatory status of the host. This review examines the IBD microbiome profile and presents IBD as a model of dysbiosis.     

CD4+ T-Cell Plasticity in Non-Infectious Retinal Inflammatory Disease

Non-infectious uveitis (NIU) is a potentially sight-threatening disease. Effector CD4⁺ T cells, especially interferon-γ-(IFNγ) producing Th1 cells and interleukin-17-(IL-17) producing Th17 cells, are the major immunopathogenic cells, as demonstrated by adoptive transfer of disease in a model of experimental autoimmune uveitis (EAU). CD4⁺FoxP3⁺CD25⁺ regulatory T cells (Tregs) were known to suppress function of effector CD4⁺ T cells and contribute to resolution of disease. It has been recently reported that some CD4⁺ T-cell subsets demonstrate shared phenotypes with another CD4⁺ T-cell subset, offering the potential for dual function. For example, Th17/Th1 (co-expressing IFNγ and IL-17) cells and Th17/Treg (co-expressing IL-17 and FoxP3) cells have been identified in NIU and EAU. In this review, we have investigated the evidence as to whether these ‘plastic CD4⁺ T cells’ are functionally active in uveitis. We conclude that Th17/Th1 cells are generated locally, are resistant to the immunosuppressive effects of steroids, and contribute to early development of EAU. Th17/Treg cells produce IL-17, not IL-10, and act similar to Th17 cells. These cells were considered pathogenic in uveitis. Future studies are needed to better clarify their function, and in the future, these cell subsets may in need to be taken into consideration for designing treatment strategies for disease.     

Pertussis Toxin Inhibits Encephalitogenic T-Cell Infiltration and Promotes a B-Cell-Driven Disease during Th17-EAE

Pertussis toxin (PTX) is a required co-adjuvant for experimental autoimmune encephalomyelitis (EAE) induced by immunization with myelin antigen. However, PTX’s effects on EAE induced by the transfer of myelin-specific T helper cells is not known. Therefore, we investigated how PTX affects the Th17 transfer EAE model (Th17-EAE). We found that PTX significantly reduced Th17-EAE by inhibiting chemokine-receptor-dependent trafficking of Th17 cells. Strikingly, PTX also promoted the accumulation of B cells in the CNS, suggesting that PTX alters the disease toward a B-cell-dependent pathology. To determine the role of B cells, we compared the effects of PTX on Th17-EAE in wild-type (WT) and B-cell-deficient (µMT) mice. Without PTX treatment, disease severity was equivalent between WT and µMT mice. In contrast, with PTX treatment, the µMT mice had significantly less disease and a reduction in pathogenic Th17 cells in the CNS compared to the WT mice. In conclusion, this study shows that PTX inhibits the migration of pathogenic Th17 cells, while promoting the accumulation of pathogenic B cells in the CNS during Th17-EAE. These data provide useful methodological information for adoptive-transfer Th17-EAE and, furthermore, describe another important experimental system to study the pathogenic mechanisms of B cells in multiple sclerosis.     

The Role of CD4+ T Cells and Microbiota in the Pathogenesis of Asthma

Asthma, a chronic respiratory disease involving variable airflow limitations, exhibits two phenotypes: eosinophilic and neutrophilic. The asthma phenotype must be considered because the prognosis and drug responsiveness of eosinophilic and neutrophilic asthma differ. CD4⁺ T cells are the main determinant of asthma phenotype. Th2, Th9 and Tfh cells mediate the development of eosinophilic asthma, whereas Th1 and Th17 cells mediate the development of neutrophilic asthma. Elucidating the biological roles of CD4⁺ T cells is thus essential for developing effective asthma treatments and predicting a patient’s prognosis. Commensal bacteria also play a key role in the pathogenesis of asthma. Beneficial bacteria within the host act to suppress asthma, whereas harmful bacteria exacerbate asthma. Recent literature indicates that imbalances between beneficial and harmful bacteria affect the differentiation of CD4⁺ T cells, leading to the development of asthma. Correcting bacterial imbalances using probiotics reportedly improves asthma symptoms. In this review, we investigate the effects of crosstalk between the microbiota and CD4⁺ T cells on the development of asthma.     

The Role of the Lymphatic System in the Pathogenesis and Treatment of Inflammatory Bowel Disease

Although the number of therapeutic options for the treatment of inflammatory bowel disease (IBD) has increased in recent years, patients suffer from decreased quality of life due to non-response or loss of response to the currently available treatments. An increased understanding of the disease’s etiology could provide novel insights for treatment strategies in IBD. Lymphatic system components are generally linked to immune responses and presumably related to inflammatory diseases pathophysiology. This review aims to summarize findings on immune-mediated mechanisms in lymphoid tissues linked with IBD pathogenesis and (potential) novel treatments. Enhanced innate and adaptive immune responses were observed in mesenteric lymph nodes (MLNs) and other lymphoid structures, such as Peyer’s patches, in patients with IBD and in animal models. Furthermore, the phenomenon of lymphatic obstruction in the form of granulomas in MLNs and lymphatic vessels correlates with disease activity. There is also evidence that abnormalities in the lymphatic stromal components and lymph node microbiome are common in IBD and could be exploited therapeutically. Finally, novel agents targeting lymphocyte trafficking have been added to the treatment armamentarium in the field of IBD. Overall, gut-associated lymphoid tissue plays a key role in IBD immunopathogenesis, which could offer novel therapeutic targets.