TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin

Celiac disease (CD) is an immunological disorder caused by intolerance to ingested gliadin and other cereal prolamins that has been included in the T_H1-dominated group of diseases, where IL-12 induced IFNγ is the major proinflamatory signal. Recently, another linage of T cells has been described, namely T_H17, characterized by production of IL-17, that differentiate in response to TGFβ and IL-6 and participate in the pathogenesis of several autoimmune diseases. Using RT-PCR analysis of gene expression, we analyzed the presence of T_H1 (IL-12 and IFNγ) and T_H17 (TGFβ, IL-6, IL-17A, IL-17F and IL-23) related cytokines in intestinal biopsies from CD patients with active disease compared to remission and from treated patients after acute, in vitro re-exposure to gliadin. Potent T_H1 and T_H17 responses were present in the active stage of the disease, whereas short incubation of normalized biopsies with gliadin did not increase the expression of the effector cytokines, although a tendency of upregulation for both T_H1 and T_H17 promoting factors was observed, suggestive of a reactivation of proinflammatory pathways. These results place CD into the group of autoimmune disorders in which T_H17 cells also participate, although the relative importance of each T cell response and their role in the initial events of the disease need further investigation.     

Sjögren’s syndrome: An old tale with a new twist

Sjögren’s syndrome (SjS) is chronic autoimmune disease manifested by the loss of saliva and/or tear secretion by salivary and/or lacrimal glands, respectively. The pathogenesis of the disease remains elusive, perhaps due to the multiple triggers of the disease. However, substantial advances have been made in attempting to resolve the complexity of SjS using both animal models and human subjects. The primary objectives of this review are to provide a better understanding of the disease processes with major emphasis on the use of mouse models, how genetic predisposition plays a role in the natural history of the disease, as well as a presentation of new findings pertaining to the role of T_H1, T_H2, and T_H17 cells in the pathogenesis of SjS.     

TH17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine

T_H17 cells are major drivers of inflammation and involved in several autoimmune diseases. Tissue inflammation is a beneficial host response to infection, but it can also contribute to autoimmunity. The crosstalk between a tissue and the immune system during an inflammatory response is key for preserving tissue integrity and restoring physiological processes. However, how the inflamed tissue regulates the magnitude of an immune response by controlling pro-inflammatory T cells is not well characterized so far. Here we show that T_H17 cells accumulating in the small intestine upon inflammation express the IL-33 receptor (ST2) and intestinal epithelial cells (IEC) are the main source of the alarmin interleukin-33 (IL-33). We show that pro-inflammatory T_H17 cells acquire a regulatory phenotype with immunosuppressive properties in response to IL-33. Absence of ST2 signaling promotes the secretion of pro-inflammatory cytokines by T_H17 cells and dampens the secretion of IL-10. Our results provide new insights into the mechanisms by which IEC, via IL-33/ST2 axis, may control pro-inflammatory T_H17 cells in the small intestine to sustain homeostasis.     

Targeting IL-17 in psoriasis: From cutaneous immunobiology to clinical application

Psoriasis vulgaris is a chronic, immune-mediated inflammatory skin disease associated with complex genetic susceptibility. Although the hallmark of psoriasis is characterized by cutaneous inflammation and keratinocyte hyperproliferation, recent studies show that the pathologic features observed in psoriasis arises as a result of innate and adaptive immune activation in genetically prone individuals. Studies focused on the microenvironment in the skin of psoriasis lesions have revealed novel cellular and cytokine abnormalities of the immune system. One pathway important is the role of the T_H17/IL-17 dysregulation. The recent development of biologics that target the IL-17 cytokine pathway has confirmed the importance of T_H17 and IL-17 homeostasis in the skin and yielded potent therapies in the treatment of psoriasis, and potentially other autoimmune diseases.     

Regulation of IL-10 and IL-17 mediated experimental autoimmune encephalomyelitis by S-nitrosoglutathione

In this study, we investigated IL-10 and IL-17 specific immunomodulatory potential of S-nitrosoglutathione (GSNO), a physiological nitric oxide carrier molecule, in experimental autoimmune encephalomyelitis (EAE). In active EAE model, GSNO treatment attenuated EAE severity and splenic CD4⁺ T cells isolated from these mice exhibited decreased IL-17 expression without affecting the IFN-γ expression compared to the cells from untreated EAE mice. Similarly, adoptive transfer of these cells to nave mice resulted in reduction in IL-17 expression in the spinal cords of recipient mice with milder EAE severity. CD4⁺ T cells isolated from GSNO treated EAE mice, as compared to untreated EAE mice, still expressed lower levels of IL-17 under T_H17 skewing conditions, but expressed similar levels of IFN-γ under T_H1 skewing condition. Interestingly, under both T_H17 and T_H1 skewing condition, CD4⁺ T cells isolated from GSNO treated EAE mice, as compared to untreated EAE mice, expressed higher levels of IL-10 and adoptive transfer of these T_H17 and T_H1 skewed cells seemingly exhibited milder EAE disease. In addition, adoptive transfer of CD4⁺ T cells from GSNO treated EAE mice to active EAE mice also ameliorated EAE disease with induction of spinal cord expression of IL-10 and reduction in of IL-17, thus suggesting the participation of IL-10 mechanism in GSNO mediated immunomodulation. GSNO treatment of mice passively immunized with CD4⁺ T cells either from GSNO treated EAE mice or untreated mice further ameliorated EAE disease, supporting efficacy of GSNO for prophylaxis and therapy in EAE. Overall, these data document a modulatory role of GSNO in IL-17/IL-10 axis of EAE and other autoimmune diseases.     

Protective role of R381Q (rs11209026) polymorphism in IL-23R gene in immune-mediated diseases: A comprehensive review

Interleukin-23 (IL-23) is a regulator of cellular immune responses involved in controlling infection and autoimmune diseases. Strong evidence has shown that IL-23 plays a role in the maintenance of immune responses by influencing the proliferation and survival of IL-17-producing T-helper (T_H)-17 cells. The critical role of the IL-23/T_H17 axis in immune-mediated diseases has emerged from different studies. It has also been seen that polymorphisms in the IL-23 receptor (IL-23R) gene might influence IL-23 responses. Interestingly, a functional single nucleotide polymorphism (SNP) in the IL-23 receptor gene (IL-23R; rs11209026, 1142 G wild-type A reduced function, Arg381Gln, R381Q) seems to confer a measure of protection against development of inflammatory bowel disease (IBD; Crohn’s disease, ulcerative colitis), ankylosing spondylitis, rheumatoid arthritis, psoriasis, thyroiditis, recurrent spontaneous abortion and asthma, suggesting that a perturbation in the IL-23 signaling pathway is likely to be relevant to the pathophysiology of these diseases. The aim of this review was to provide an evaluation of what is currently known about the protective role of R381Q variant in IL-23R gene in immune-based diseases.     

Interleukin-27: Biological Properties and Clinical Application

Interleukin (IL)-27 is a novel cytokine secreted by stimulated antigen-presenting cells. Initial studies on the biology of IL-27 provided evidence for its role in the initiation of T_H1 responses; however, subsequent work has indicated that IL-27 has broad inhibitory effects on T_H1, T_H2, and T_H17 subsets of T cells as well as the expansion of inducible regulatory T cells. The involvement of IL-27 in the regulation of angiogenesis and antiviral response has also recently been reported. The aim of this review is to highlight the potential areas of IL-27 clinical application, especially the management of neoplastic and viral diseases as well as autoimmune disorders, including rheumatoid arthritis and multiple sclerosis. The review will also serve to elaborate on the molecular mechanisms involved in the expression of this cytokine and signaling from the IL-27 receptor.     

Emodin inhibits splenocyte proliferation and inflammation by modulating cytokine responses in a mouse model system

Emodin, an anthraquinone derivative, was investigated for potential anti-inflammatory and anti-proliferative effects in vitro. The potential to induce these outcomes was assessed using concanavalin A (ConA)-stimulated mouse splenocytes. Dose–response studies showed that emodin at 100?µM was not cytotoxic to naive cells, and that the same dose caused proliferation to be significantly reduced in ConA-stimulated cells. In addition, emodin significantly reduced ConA-induced nitric oxide (NO) production and the formation/release of T_H1 (IL-2, IFNγ, TNFα) and T_H17 (IL-6 and IL-17) cell cytokines, but induced those of T_H2 (IL-4) and T_reg (IL-10) cells. From the results, it is concluded that earlier-reported immunomodulatory effects imparted by emodin may have been attributable, in part, to anti-proliferative effects on lymphocytes, as well as a shift within the T_H1/T_H2 and T_H17/T_reg balance (towards T_H2 and Treg). These findings, while providing evidence of mechanisms of emodin immunomodulation, are also potentially important for sparking studies that ultimately may result in the potential use of this agent in preventive and/or corrective strategies against autoimmune and other inflammatory diseases.     

Tissue-resident memory Th17 cells maintain stable fungal commensalism in the oral mucosa

Keeping a stable equilibrium between the host and commensal microbes to which we are constantly exposed, poses a major challenge for the immune system. The host mechanisms that regulate homeostasis of the microbiota to prevent infection and inflammatory disorders are not fully understood. Here, we provide evidence that CD4⁺ tissue-resident memory T (T_RM) cells act as central players in this process. Using a murine model of C. albicans commensalism we show that IL-17 producing CD69⁺CD103⁺CD4⁺ memory T cells persist in the colonized tissue long-term and independently of circulatory supplies. Consistent with the requirement of Th17 cells for limiting fungal growth, IL-17-producing T_RM cells in the mucosa were sufficient to maintain prolonged colonization, while circulatory T cells were dispensable. Although T_RM cells were first proposed to protect from pathogens causing recurrent acute infections, our results support a central function of T_RM cells in the maintenance of commensalism.     

A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis

Homeostasis in the ileum, which is commonly disrupted in patients with Crohn's disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4⁺T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4⁺T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of T_H17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by T_H17 and T_H1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia. By contrast, adult mice with normal growth continued to exhibit T_H17-associated ileal crypt hyperplasia and additionally accumulated ileal-reactive Treg cells. Both IL-17A and IFNγ were protective, as their deficiency precluded ileal-reactive Treg accumulation and exacerbated colitic disease. IL-23R blockade prevented progression to colitis, whereas nTreg cell transfers prevented colitic disease, ileal crypt hyperplasia and ileal-reactive Treg accumulation. Thus, our studies identify an IL-17A and IFNγ-dependent homeostatic process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.     

Autoimmune effector memory T cells: the bad and the good

Immunological memory is a hallmark of adaptive immunity, a defense mechanism endowed to vertebrates during evolution. However, an autoimmune pathogenic role of memory lymphocytes is also emerging with accumulating evidence, despite reasonable skepticism on their existence in a chronic setting of autoimmune damage. It is conceivable that autoimmune memory would be particularly harmful since memory cells would constantly “remember” and attack the body’s healthy tissues. It is even more detrimental given the resistance of memory T cells to immunomodulatory therapies. In this review, we focus on self-antigen-reactive CD4⁺ effector memory T (T_EM) cells, surveying the evidence for the role of the T_EM compartment in autoimmune pathogenesis. We will also discuss the role of T_EM cells in chronic and acute infectious disease settings and how they compare to their counterparts in autoimmune diseases. With their long-lasting potency, the autoimmune T_EM cells could also play a critical role in anti-tumor immunity, which may be largely based on their reactivity to self-antigens. Therefore, although autoimmune T_EM cells are “bad” due to their role in relentless perpetration of tissue damage in autoimmune disease settings, they are unlikely a by-product of industrial development along the modern surge of autoimmune disease prevalence. Rather, they may be a product of evolution for their “good” in clearing damaged host cells in chronic infections and malignant cells in cancer settings.     

Involvement of brain-derived neurotrophic factor (BDNF) in MP4-induced autoimmune encephalomyelitis

The role of brain-derived neurotrophic factor (BDNF) in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) is still unclear. Here we investigate the clinical course, CNS histopathology and peripheral antigen-specific immunity in MP4-induced EAE of BDNF (−/+) mice. We demonstrate that these mice displayed less severe disease compared to BDNF (+/+) mice, reflected by decreased inflammation and demyelination. In correspondence to diminished frequencies of T and B cells in CNS infiltrates, the peripheral MP4-specific T_H1/T_H17 response was attenuated in BDNF (−/+), but not in wild-type animals. In contrast, immunization with ovalbumin triggered similar frequencies of IFN-γ- and IL-17-secreting T cells in both groups. The cytokine secretion and proliferative activity upon mitogen stimulation did not reveal any global defect of T cell function in BDNF (−/+) mice. By influencing the antigen-specific immune response in autoimmune encephalomyelitis, BDNF may support and maintain the disease in ways that go beyond its alleged neuroprotective role.     

Alterations in regulatory T-cells: Rediscovered pathways in immunotoxicology

In addition to the effector T-cells subsets, T-cells can also differentiate into cells that play a suppressive or regulatory role in adaptive immune responses. The cell types currently identified as regulatory T-cells (T_regs) include natural or thymic-derived T_regs, T-cells which express Foxp3⁺CD25⁺CD4⁺ and can suppress immune responses to autoreactive T-cells, as well as inducible T_regs, that are generated from naïve T-cells in the periphery after interaction with antigens presented by dendritic cells. Inducible T_regs include T_H3 cells, T_r1 cells, and Foxp3⁺-inducible T_regs. T_regs have been shown to be critical in the maintenance of immune responses and T-cell homeostasis. These cells play an important role in suppressing responses to self-antigens and in controlling inappropriate responses to non-self-antigens, such as commensal bacteria or food in the gut. For example, depletion of CD4⁺CD25⁺ T_regs from mice resulted in the development of multi-organ autoimmune diseases. CD4⁺CD25⁺ T_regs and/or IL-10-producing T_r1 cells are capable of suppressing or attenuating T_H2 responses to allergens. Moreover, adoptive transfer of CD4⁺CD25⁺ T_regs from healthy to diseased animals resulted in the prevention or cure of certain autoimmune diseases, and was able to induce transplantation tolerance. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma is associated with the induction of IL-10- and TGFβ-producing T_r1 cells as well as FoxP3-expressing IL-10 T-cells, with resulting suppression of the T_H2 cytokine milieu. Activation, expansion, or suppression of CD4⁺CD25⁺ T_regs in vivo by xenobiotics, including drugs, may therefore represent a relevant mechanism underlying immunotoxicity, including immunosuppression, allergic asthma, and autoimmune diseases.     

Excreted/secreted Trichuris suis products reduce barrier function and suppress inflammatory cytokine production of intestinal epithelial cells

The administration of helminths is considered a promising strategy for the treatment of autoimmune diseases due to their immunomodulatory properties. Currently, the application of the helminth Trichuris suis as a treatment for Crohn's disease is being studied in large multi-center clinical trials. The intestinal epithelium forms an efficient barrier between the intestinal lumen containing the microbial flora and helminths, and dendritic cells (DCs) present in the lamina propria that determine the T_H response. Here, we investigated how excreted/secreted (E/S) products of T. suis affect the barrier function of intestinal epithelial cells (IECs) in order to reach the DCs and modulate the immune response. We show that T. suis E/S products reduce the barrier function and the expression of the tight junction proteins EMP-1 and claudin-4 in IEC CMT93/69 monolayers in a glycan-dependent manner. This resulted in an increased passage of soluble compounds to the basolateral side that affected DC function. In addition, T. suis E/S suppressed LPS-induced pro-inflammatory cytokine production by CMT93/69 cells, whereas the production of the T_H2 response-inducing cytokine thymic stromal lymphopoietin (TSLP) was induced. Our studies indicate that T. suis E/S glycans affect the function of the intestinal epithelium in order to modulate DC function. Identification of the T. suis E/S glycans that modulate IEC and DC function may lead to a strategy to reduce symptoms of autoimmune and allergic immune diseases by orally administrated helminth-derived factors without the need of infection with live helminths.     

Is TGFβ as an anti-inflammatory cytokine required for differentiation of inflammatory TH17 cells?

T-Helper 17 (T_H17) cells are a CD4⁺ T_H subset that plays a critical role in the pathophysiology of inflammatory disorders, especially chronic forms. It seems that the derivation of T_H17 cells from their precursors take place in inflammatory microenvironment. The role of transforming growth factor (TGF)-β as an anti-inflammatory cytokine in T_H17 cell differentiation is controversial. To address some of the discrepancies that exist among different studies, this study was undertaken to more clarify the TGFβ role in human T_H17 cell differentiation. Here, CD4⁺ T-cells were isolated from peripheral blood samples and cultured in X-VIVO 15 serum-free medium. Purified cells were then treated with different combinations of polarizing cytokines (interleukin [IL]1-β, -6, and -23, with or without TGFβ), neutralizing anti-interferon (IFN)-γ and anti-IL-4 antibodies and polyclonal stimulators anti-CD3 and -CD28 antibodies, and then analyzed for IL-17, IFNγ, Foxp3, and CD25 expression by flow cytometry and for release of IL-17, -21, -22, and -10 into culture media by ELISA. The effects of selective inhibition of TGFβ signaling pathway on T_H17 cell polarization were also determined by using small molecules SB-431542 and A83-01. The current study found that a combination of pro-inflammatory cytokines, including IL-1β, -6, and -23, but not TGFβ, could be used as a cytokine combination to induce development of human T_H17 cells. It was also shown that TGFβ acted as a negative regulator in this regard and also led to reduced IL-17 and IL-22 production while inducing Foxp3 expression. Indeed, blocking of TGFβ signaling pathways by selective inhibitors up-regulated T_H17 cell differentiation. From the data here, we concluded that TGFβ down-regulates human T_H17 cell differentiation and that a presence of pro-inflammatory cytokines (along with IFNγ and IL-4 neutralizing antibodies) is sufficient for optimal differentiation of human T_H17 cells.     

Cytokine and autoantibody patterns in acute liver failure

The mechanisms of idiosyncratic drug-induced liver injury (IDILI) are still a matter of dispute. Some of the characteristics of reactions that have been classed as metabolic idiosyncrasy could also be those of an immune-mediated reaction with an autoimmune component. Many auto-immune reactions appear to be mediated by T_H17 cells, which are in part characterized by the production of interleukin (IL)-17. To test the involvement of T_H17 cells in IDILI, we quantified a number of cytokines, chemokines, and autoantibodies in the serum of 39 patients with acute liver failure (ALF) due to IDILI and compared the values with those from 21 patients with acetaminophen-induced ALF and 10 patients with viral hepatitis-induced ALF. The IL-17 levels were elevated in 60% of patients with IDILI, but also in a similar number of patients with acetaminophen-induced ALF and occasionally in patients with viral hepatitis. Levels of other cytokines, such as IL-21, that are also produced by T_H17 cells were higher in patients with IDILI, but again, there was overlap with acetaminophen DILI. Autoantibodies were more frequent in patients in the IDILI group but were absent in most patients. These data provide a picture of the cytokine/chemokine profile in patients with various types of ALF. The pattern varies from patient to patient and not specifically by etiology. This suggests that different underlying disease mechanisms may be at play in different individuals, even among those demonstrating injury from the same drug. Since cytokines may originate from more than one type of cell, interpretation of results of cytokine assays remains difficult in complex disease settings.     

Immune responses to commensal and environmental microbes

The mammalian immune system discriminates among microbes, inactivating pathogens while tolerating colonization by commensal organisms. Calibrating immune responses to microbes on this basis, however, is complex, as microbial virulence is often context dependent, being influenced by the host's immune status and the microbial milieu. Many microbial pathogens infecting immunocompromised hosts, for example, are innocuous in immune-competent individuals, and other microbes cause disease only when the commensal flora is compromised by antibiotic therapy. Recent studies have begun to reveal how the immune system tips the balance in favor of some microbes, allowing commensals to persist on mucosal surfaces while eliminating disease-causing pathogens.