The role of IFN-gamma in systemic lupus erythematosus: a challenge to the Th1/Th2 paradigm in autoimmunity

The classification of T helper cells into type 1 (Th1) and type 2 (Th2) led to the hypothesis that Th1 cells and their cytokines (interleukin [IL]-2, interferon [IFN]-γ) are involved in cell-mediated autoimmune diseases, and that Th2 cells and their cytokines (IL-4, IL-5, IL-10, IL-13) are involved in autoantibody(humoral)-mediated autoimmune diseases. However, this paradigm has been refuted by recent studies in several induced and spontaneous mouse models of systemic lupus erythematosus, which showed that IFN-γ is a major effector molecule in this disease. These and additional findings, reviewed here, suggest that these two cross-talking classes of cytokines can exert autoimmune disease-promoting or disease-inhibiting effects without predictability or strict adherence to the Th1-versus-Th2 dualism.     

Interleukin-13: A promising therapeutic target for autoimmune disease

Interleukin-13 (IL-13) was previously thought to be a redundant presence of IL-4, but in recent years its role in immunity, inflammation, fibrosis, and allergic diseases has become increasingly prominent. IL-13 can regulate several subtypes of T helper (Th) cells and affect their transformation, including Th1, Th2, T17, etc., thus it may play an important role in immune system. Previous studies have revealed that IL-13 is implicated in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), systemic sclerosis (SSc), ulcerative colitis (UC), type 1 diabetes (T1D), sjogren's syndrome (SS), etc. In this review, we will briefly discuss the biological features of IL-13 and summarize recent advances in the role of IL-13 in the development and pathogenesis of autoimmune diseases. This information may provide new perspectives and suggestions for the selection of therapeutic targets for autoimmune diseases.     

In vivo study: Th1–Th17 reduction in pristane-induced systemic lupus erythematosus mice after treatment with tolerogenic Lactobacillus probiotics

Uncontrolled inflammation in systemic lupus erythematosus (SLE) could cause dysfunction in multiple organs. T helper 17 (Th17) cells are a main branch of inflammatory responses in the pathogenesis of SLE, and by producing interleukin 17 (IL-17), represent a major functional tool in the progression of inflammation. Animal models provide a special field for better studies of the pathogenesis of diseases. Tolergenic probiotics could decrease inflammation in autoimmune diseases by modulating the immune system and maintaining homeostasis. The aim of this project was to evaluate the effects of Lactobacillus rhamnosus and Lactobacillus delbrueckii on Th17 cells and their related mediators in a pristane-induced BALB/c mice model of SLE. The mice were divided into pretreatment groups, which received probiotics or prednisolone at Day 0, and treatment groups, which received probiotics and prednisolone 2 months after injection. The presence of antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA), and anti-ribonucleoprotein (anti-RNP) and lipogranuloma was evaluated; also, the population of Th1–Th17 cells as well as interferon γ (IFN-γ), IL-17, and IL-10 levels, and the expression of RAR-related orphan related receptor gamma (RORγt) and IL-17 were determined. We observed that probiotics and prednisolone could delay SLE in pretreatment and treatment mice groups, with a reduction in ANA, anti-dsDNA, anti-RNP, and mass of lipogranuloma. Probiotics and prednisolone decreased the population of Th1–Th17 cells and reduced IFN-γ and IL-17 as inflammatory cytokines in the pretreatment and treatment groups in comparison with SLE-induced mice. Our results indicated that, due to their anti-inflammatory properties and reduction of Th17, Th1, and cytotoxic T lymphocyte (CTL) cells, the use of these probiotics could probably represent a new tool for the better management of SLE.     

IL-21 promotes lupus-like disease in chronic graft-versus-host disease through both CD4 T cell- and B cell-intrinsic mechanisms

T cell-driven B cell hyperactivity plays an essential role in driving autoimmune disease development in systemic lupus erythematosus. IL-21 is a member of the type I cytokine family with pleiotropic activities. It regulates B cell differentiation and function, promotes T follicular helper (T(FH)) cell and Th17 cell differentiation, and downregulates the induction of T regulatory cells. Although IL-21 has been implicated in systemic lupus erythematosus, the relative importance of IL-21R signaling in CD4(+) T cells versus B cells is not clear. To address this question, we took advantage of two induced models of lupus-like chronic graft-versus-host disease by using wild-type or IL-21R(-/-) mice as donors in the parent-into-F1 model and as hosts in the Bm12→B6 model. We show that IL-21R expression on donor CD4(+) T cells is essential for sustaining T(FH) cell number and subsequent help for B cells, resulting in autoantibody production and more severe lupus-like renal disease, but it does not alter the balance of Th17 cells and regulatory T cells. In contrast, IL-21R signaling on B cells is critical for the induction and maintenance of germinal centers, plasma cell differentiation, autoantibody production, and the development of renal disease. These results demonstrate that IL-21 promotes autoimmunity in chronic graft-versus-host disease through both CD4(+) T cell- and B cell-intrinsic mechanisms and suggest that IL-21 blockade may attenuate B cell hyperactivity, as well as the aberrant T(FH) cell pathway that contributes to lupus pathogenesis.     

Zinc deficiency drives Th17 polarization and promotes loss of Treg cell function

A high number of illnesses and disorders are connected to zinc deficiency. Equally, T cell polarization and a balance between different T helper (Th) cell subsets are essential. Therefore, in this study, the influence of zinc deficiency on T cell polarization and on respective signaling pathways was investigated. We uncovered a significantly increased number of regulatory T cells (Treg) and Th17 cells in expanded T cells during zinc deficiency after 3 days of combined treatment with IL-2 and TGF-β1 (Treg) or IL-6 and TGF-β1 (Th17). No difference in Th1 and Th2 cell polarization between zinc-deficient and zinc-adequate status was prominent. On the molecular level, Smad signaling was significantly enhanced by stimulation with TGF-β1/IL-6 during zinc deficiency compared to adequate zinc condition. This represents an explanation for the elevated Th17 cell numbers associated with autoimmune disease especially during zinc deficiency. Moreover, Treg cell numbers are increased during zinc deficiency as well. However, those cells might be nonfunctional since a lower expression of miR-146a was uncovered compared to normal zinc concentrations. In summary, an adequate zinc homeostasis is fundamental to slow down or probably stop the progression of autoimmune diseases and infections. Therefore, supplementing zinc might be a therapeutic approach to dampen autoimmune diseases connected to Th17 cells.     

Targeting prohibitins at the cell surface prevents Th17‐mediated autoimmunity

T helper (Th)17 cells represent a unique subset of CD4⁺ T cells and are vital for clearance of extracellular pathogens including bacteria and fungi. However, Th17 cells are also involved in orchestrating autoimmunity. By employing quantitative surface proteomics, we found that the evolutionarily conserved prohibitins (PHB1/2) are highly expressed on the surface of both murine and human Th17 cells. Increased expression of PHBs at the cell surface contributed to enhanced CRAF/MAPK activation in Th17 cells. Targeting surface‐expressed PHBs on Th17 cells with ligands such as Vi polysaccharide (Typhim vaccine) inhibited CRAF‐MAPK pathway, reduced interleukin (IL)‐17 expression and ameliorated disease pathology with an increase in FOXP3⁺‐expressing Tregs in an animal model for multiple sclerosis (MS). Interestingly, we detected a CD4⁺ T cell population with high PHB1 surface expression in blood samples from MS patients in comparison with age‐ and sex‐matched healthy subjects. Our observations suggest a pivotal role for the PHB‐CRAF‐MAPK signalling axis in regulating the polarization and pathogenicity of Th17 cells and unveil druggable targets in autoimmune disorders such as MS.     

Th1/Th2/Th17/Treg cytokines in Guillain–Barré syndrome and experimental autoimmune neuritis

Guillain–Barré syndrome (GBS) is an immune-mediated acute inflammatory disorder in the peripheral nervous system (PNS) of humans characterized by inflammatory infiltration and damage to myelin and axon. Experimental autoimmune neuritis (EAN) is a useful animal model for GBS. Although GBS and EAN have been widely studied, the pathophysiological basis of GBS/EAN remains largely unknown. Immunocompetent cells together with cytokines produced by various cells contribute to the inflammatory process of EAN by acting as mediators or effectors. Both GBS and EAN have hitherto been attributed to T helper (Th)1 cells-mediated disorders, however, some changes in GBS and EAN could not be explained by the pathogenic role of Th1 cells and a disturbance of the Th1/Th2 balance, which has previously been considered to be important for the homeostatic maintenance of the immune responses and to explain the adaptive immunity and autoimmune diseases. The Th1/Th2 paradigm in autoimmune diseases has been greatly challenged in recent years, with the identification of a particular T cell subset Th17 cells. Studies on the associations between Th17 cells/cytokines and GBS/EAN are reviewed. But some of them occasionally yield conflicting results, indicating an intricate network of cytokines in immune response.     

Lower frequency of IL-17F sequence variant (His161Arg) in chronic fatigue syndrome patients

Chronic fatigue syndrome (CFS) is characterized by immune dysfunctions including chronic immune activation, inflammation, and alteration of cytokine profiles. T helper 17 (Th17) cells belong to a recently identified subset of T helper cells, with crucial regulatory function in inflammatory and autoimmune processes. Th17 cells are implicated in allergic inflammation, intestinal diseases, central nervous system inflammation, disorders that may all contribute to the pathophysiology of CFS. IL-17F is one of the pro-inflammatory cytokines secreted by Th17 cells. We investigated the association between CFS and the frequency of rs763780, a C/T genetic polymorphism leading to His161Arg substitution in the IL-17F protein. The His161Arg variant (C allele) antagonizes the pro-inflammatory effects of the wild-type IL-17F. A significantly lower frequency of the C allele was observed in the CFS population, suggesting that the His161Arg variant may confer protection against the disease. These results suggest a role of Th17 cells in the pathogenesis of CFS.     

Emerging role of immune cell network in autoimmune skin disorders: An update on pemphigus,vitiligo and psoriasis

Autoimmune skin diseases are a group of disorders that arise due to a deregulated immune system resulting in skin tissue destruction. In the majority of these conditions, either autoreactive immune cells or the autoantibodies are generated against self-antigens of the skin. Although the etiology of these diseases remains elusive, biochemical, genetic, and environmental factors such as infectious agents, toxins damage the skin tissue leading to self-antigen generation, autoantibody attack and finally results in autoimmunity of skin. Immune dysregulation, which involves predominantly T helper 1/17 (Th1/Th17) polarization and the inability of regulatory T cells to regress immune response, is implicated in autoimmune skin diseases.The emerging roles of immune cells, cytokines, and chemokines in the pathogenesis of common autoimmune skin diseases like pemphigus, vitiligo, and psoriasis are discussed in this review. The main focus is on the interplay between immune cell network including the innate and adaptive immune system, regulatory cells, immune checkpoints and recently identified tissue-resident memory cells (TRMs) in disease pathogenesis and relapse. We also attempt to highlight on the immune mechanisms common to these diseases which can be targeted for designing novel therapeutics.     

A gradient of glucocorticoid sensitivity among helper T cell cytokines

Helper T (Th) cells secret specific cytokines that promote immune responses whereas glucocorticoids limit the extent of immune responses by inhibiting cytokine secretion and other functions of Th cells. However, glucocorticoid resistance develops in subgroups of patients with Th cell-driven diseases such as asthma and Crohn’s disease. Recent evidence supports that Th1, Th2, and Th17 cells have distinct glucocorticoid sensitivity. Th1 cells are sensitive to glucocorticoid-induced apoptosis and cytokine suppression while Th2 cells are sensitive to the latter but not the former and Th17 cells are resistant to both. This gradient of glucocorticoid sensitivity of Th cells corresponds to the glucocorticoid sensitivity of the diseases they underlie. We identify the mechanisms contributing to distinct glucocorticoid sensitivity of Th cells and their cytokines in the literature, as this information is useful to improve treatment strategies for glucocorticoid resistant immunological disorders.     

The two sides of cytokine signaling and glaucomatous optic neuropathy

The mechanistic study of glaucoma pathogenesis has shifted to seeking to understand the effects of immune responses on retinal ganglion cell damage and protection. Cytokines are the hormonal factors that mediate most of the biological effects in both the immune and nonimmune systems. CD4-expressing T helper cells are a major source of cytokine production and regulation. Type 1 helper T (Th1) cells are characterized by the production of proinflammatory cytokines such as interferon-gamma, interleukin (IL)-2, IL-12, IL-23, and tumor necrosis factor-alpha while type 2 helper T (Th2) cells are characterized by the production of IL-4, IL-5, IL-6, and IL-10. The balance of Th1/Th2 cytokine production influences many pathological processes and plays both causative and protective roles in neuron damages. Growing evidence indicates that imbalances of Th1/Th2 cytokine production are involved in neural damage or protection in many neurological diseases. In this review, we discuss the possible roles of Th1/Th2 cytokine production and imbalance of Th1/Th2 cytokines in retina, especially glaucomatous optic neuropathy.     

The two sides of cytokine signaling and glaucomatous optic neuropathy

The mechanistic study of glaucoma pathogenesis has shifted to seeking to understand the effects of immune responses on retinal ganglion cell damage and protection. Cytokines are the hormonal factors that mediate most of the biological effects in both the immune and nonimmune systems. CD4-expressing T helper cells are a major source of cytokine production and regulation. Type 1 helper T (Th1) cells are characterized by the production of proinflammatory cytokines such as interferon-gamma, interleukin (IL)-2, IL-12, IL-23, and tumor necrosis factor-alpha while type 2 helper T (Th2) cells are characterized by the production of IL-4, IL-5, IL-6, and IL-10. The balance of Th1/Th2 cytokine production influences many pathological processes and plays both causative and protective roles in neuronal damage. Growing evidence indicates that imbalances of Th1/Th2 cytokine production are involved in neural damage or protection in many neurological diseases. In this review, we discuss the possible roles of Th1/Th2 cytokine production and imbalance of Th1/Th2 cytokines in retina, especially glaucomatous optic neuropathy.     

Prostanoid receptor 2 signaling protects T helper 2 cells from BALB/c mice against activation-induced cell death

T helper 2 (Th2) cells play a central role in the progression of many diseases such as allergic airway inflammation, autoimmune diseases, and infections caused by intracellular pathogens. Consequently, animals such as BALB/c mice, which exhibit a propensity for generating Th2 responses, are susceptible to allergic airway inflammation, type-II autoimmune diseases, and various infections induced by intracellular pathogens, namely, Leishmania. In contrast, C3H/OuJ mice have a tendency for generating T helper 1 (Th1) responses and show resistance to these diseases. Here, we show that prostaglandin endoperoxide E(2) selectively inhibits activation-induced cell death of Th2 cells by signaling through its receptor E-prostanoid receptor 2 (EP2). Consequently, Th2 cells derived from BALB/c mice expressed very high levels of EP2. On the other hand, Th2 cells derived from C3H/OuJ mice expressed very low levels of EP2, which failed to support the survival of Th2 cells. Furthermore, we found that this effect of EP2 on Th2 cells from BALB/c mice was executed by a granzyme B-mediated mechanism. EP2 belongs to a group of G-protein-coupled receptors that are amenable to therapeutic targeting. Our findings therefore identify EP2 as a promising target for small molecule-directed immunomodulation.     

Th17细胞在肺部感染免疫中的作用

Th17细胞是近年来发现的一种新的效应T细胞亚群,在自身免疫性疾病和感染中发挥重要的作用,其分泌产生几种致炎细胞因子,包括新发现的细胞因子白细胞介素17。Th17产生的细胞因子与Th1、Th2不同并且与其相互对抗。Th17细胞很可能对防御胞外病原菌的感染及自身免疫性疾病产生影响。综述了Th17细胞产生的细胞因子及其在肺部感染免疫中的作用相关方面的进展。