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.     

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.     

Interleukin-10 prevents experimental allergic encephalomyelitis in rats

Experimental allergic encephalomyelitis (EAE) is an autoimmune disease mediated by myelin protein-specific CD4⁺ T lymphocytes of the T_h1-like phenotype. In rats, the disease is characterized by a monophasic clinical manifestation, followed by a subsequent spontaneous remission and the establishment of life-long resistance to reinduction of disease. Recent data indicate that intracerebral cytokine production, in particular synthesis of interleukin(IL)-10, is selectively up-regulated during the recovery phase of disease. This led us to assess the effects of IL-10 on different rat lymphoid cell functions in vitro and to consider the possibility of an IL-10-mediated treatment to prevent the induction of central nervous system (CNS) autoimmune disease in vivo. Human recombinant IL-10 suppressed interferon-γ induced major histocompatibility complex class II up-regulation in rat peritoneal macrophages, exhibited pleiotropic effects on thymocytes and totally abrogated tumor necrosis factor production of encephalitogenic T lymphocytes in vitro, without simultaneously affecting proliferative responses of the cells. Upon systemic administration during the initiation phase of disease, IL-10 was effective in markedly suppressing the subsequent induction of EAE in Lewis rats. This suppression of clinical disease coincided with a significant and specific elevation of myelin basic protein-specific autoantibody production, a sustained T cell proliferative response to myelin basic protein and a diminution of CNS infiltrations and thymic involutions in diseased animals. These data implicate IL-10 as a possible candidate for treatment of T_h1-mediated CNS (auto-) immune diseases.     

Targeting the B7 Family of Co-Stimulatory Molecules

As more patient data is cross-referenced with animal models of disease, the primary focus on T_h1 autoreactive effector cell function in autoimmune diseases, such as rheumatoid arthritis and multiple sclerosis, has shifted towards the role of T_h17 autoreactive effector cells and the ability of regulatory T cells (T_reg) to modulate the pro-inflammatory autoimmune response. Therefore, the currently favored hypothesis is that a delicate balance between T_h1/17 effector cells and T_reg cell function is critical in the regulation of inflammatory autoimmune disease. An intensive area of research with regard to the T_h1/17:T_reg cell balance is the utilization of blockade and/or ligation of various co-stimulatory or co-inhibitory molecules, respectively, during ongoing disease to skew the immune response toward a more tolerogenic/regulatory state. Currently, FDA-approved therapies for multiple sclerosis patients are all aimed at the suppression of immune cell function. The other favored method of treatment is a modulation or deletion of autoreactive immune cells via short-term blockade of activating co-stimulatory receptors via treatment with fusion proteins such as CTLA4-Ig and CTLA4-FasL. Based on the initial success of CTLA4-Ig, there are additional fusion proteins that are currently under development. Examples of the more recently identified B7/CD28 family members are PD-L1, PD-L2, inducible co-stimulatory molecule-ligand (ICOS-L), B7-H3, and B7-H4, all of which may emerge as potential fusion protein therapeutics, each with unique, yet often overlapping functions. The expression of both stimulatory and inhibitory B7 molecules seems to play an essential role in modulating immune cell function through a variety of mechanisms, which is supported by findings that suggest each B7 molecule has developed its own indispensable niche in the immune system. As more data are generated, the diagnostic and therapeutic potential of the above B7 family-member-derived fusion proteins becomes ever more apparent. Besides defining the biology of these B7/CD28 family members in vivo, additional difficulty in the development of these therapies lies in maintaining the normal immune functions of recognition and reaction to non-self-antigens following viral or bacterial infection in the patient. Further complicating the clinical translation of these therapies, the mechanism of action identified for a particular reagent may depend upon the method of immune-cell activation and the subset of immune cells targeted in the study.     

Aetiopathogenesis of autoimmune hepatitis

Interface hepatitis, histological hallmark of autoimmune hepatitis (AIH), is a dense portal mononuclear cell infiltrate invading the parenchyma, consisting of CD4 and CD8 T-lymphocytes, monocytes/macrophages and plasma cells. What triggers AIH is unknown, but there is evidence that failure of immune homeostasis plays a permissive role allowing liver autoantigen-specific cells to attack hepatocytes. Damage is likely to be orchestrated by CD4 T-lymphocytes recognizing an autoantigenic liver peptide. For autoimmunity to arise, the peptide, embraced by an HLA class II molecule, must be presented to naïve CD4 T-helper (T_H0) cells by professional antigen-presenting cells. Once activated, T_H0 cells can differentiate into T_H1 cells, which are pivotal to macrophage activation, enhance HLA class I expression, rendering liver cells vulnerable to CD8 T-cell attack, and induce HLA class II expression on hepatocytes; or into T_H2 cells producing IL-4, IL-10 and IL-13, cytokines favouring autoantibody production by B-lymphocytes. Autoantigen recognition is tightly controlled by regulatory mechanisms, such as those exerted by CD4+CD25+ regulatory T-cells (T-regs). Numerical and functional T-reg impairment characterizes AIH, particularly during active disease. Advances in the study of autoreactive T-cells stem mostly from AIH type 2, where the main autoantigen, CYP2D6, is known enabling characterization of antigen-specific immune responses. Monocyte involvement in the autoimmune liver attack has been recently reported.     

Stress as an endogenous adjuvant: augmentation of the immunization phase of cell-mediated immunity

Stress is thought to be immunosuppressive but paradoxically exacerbates inflammatory and autoimmune diseases. We initially showed that acute stress enhances skin immunity. Such immunoenhancement could promote immunoprotection in case of wounding, infection or vaccination but could also exacerbate immunopathological diseases. Here we identify the molecular and cellular mediators of the immunoenhancing effects of acute stress. Compared with non-stressed mice, acutely stressed animals showed significantly greater pinna swelling and leukocyte infiltration, and up-regulated macrophage chemoattractant protein-1, macrophage inflammatory protein-3alpha, IL-1alpha, IL-1beta, IL-6, tumor necrosis factor-alpha and IFN-gamma, but not IL-4 gene expression at the site of primary antigen exposure. Stressed animals also showed enhanced maturation and trafficking of dendritic cells (DCs) from skin to lymph nodes (LNs), higher numbers of activated macrophages in skin and LNs, increased T cell activation in LNs, and enhanced recruitment of surveillance T cells to skin. These findings show that important interactive components of innate (DCs and macrophages) and adaptive (surveillance T cells) immunity are mediators of the stress-induced enhancement of a primary immune response. Such enhancement during primary immunization may induce a long-term increase in immunologic memory resulting in subsequent augmentation of the immune response during secondary antigen exposure. Thus, the evolutionarily adaptive fight-or-flight stress response may protectively prepare the immune system for impending danger (e.g. infection and wounding by a predator), but may also contribute to stress-induced exacerbation of inflammatory and autoimmune diseases.     

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.     

Regulation of T helper cell cytokine expression: functional dichotomy of antigen-presenting cells

A bias to either cell-mediated or antibody-mediated effector mechanisms is induced in an immune response against a pathogen, if activated T helper cells (T_h) predominantly express T_h1 [interleukin (IL)-2, interferon (IFN)-γ, and tumor necrosis factor (TNF)-β] or T_h2 (IL-4, IL-5, IL-6 and IL-10) cytokines. Here we provide evidence that, due to the capability to secrete IL-1, macrophages, but not B cells, as antigen-presenting cells (APC) induce production of IFN-γ in resting T_h cells. Normal murine splenic Th cells were activated in vitro with the superantigen Staphylococcus aureus enterotoxin B (SEB) presented by macrophages as compared to other APC from murine spleen. As determined by immunofluorescence, T_h cells producing IL-2 but almost none producing IL-4 and IL-5 are generated, irrespective of the type of APC. Generation of IFN-γ-producing T_h cells is largely dependent on presentation of SEB by macrophages. The requirement for macrophages, however, is overcome if IL-1 is provided. Expression of IFN-y by T_h cells is not induced, if production of IL-1 by macrophages is inhibited by IL-10. Our results suggest a functional dichotomy of APC: normal resting T_h cells differentiate into IL-2 and IFN-γ secreting cells (T_h1 cells) if antigen is presented by macrophages, whereas presentation by B cells generates T_h cells secreting IL-2, which might differentiate into T_h2 cells upon re-stimulation.     

Phosphodiesterase inhibitor pentoxifylline,a selective suppressor of T helper type 1- but not type 2-associated lymphokine production,prevents induction of experimental autoimmune encephalomyelitis in Lewis rats

The phosphodiesterase inhibitor pentoxifylline (POX), which is known to have pharmacological effects in animal models of multiorgan failure and endotoxin-mediated shock, was tested for its immunosuppressive potential on T lymphocyte activation in vitro and in vivo. POX was found to have a profound inhibitory effect on both mitogen- and antigen-induced proliferation of CD4⁺ T cells in vitro. This inhibitory activity of the drug could be reproduced by treating T lymphocytes with cAMP analogues during stimulation. Responses of repeatedly in vitro stimulated cells were much more strongly inhibited by the drug and by cAMP analogues than responses of fresh resting lymphocytes. Furthermore, POX could drastically down-regulate tumor necrosis factor regulate production and to a lesser extent interleukin (IL)-2 secretion in activated T cells, but an excess of exogenous IL-2 did not override the antiproliferative effect of the drug. In contrast, the same doses of POX had no inhibitory effect on spontaneous or induced IL-4 and IL-6 production by short-term cultured T lymphocytes, indicating a selective sparing of T helper type 2 (T_h2)-associated lymphokine functions by the drug. To test a potential use of POX as an antiinflammatory agent in T cell-mediated autoimmune disease, the influence of POX on myelin basic protein (MBP)-induced experimental autoimmune encephalomyelitis (EAE) was assessed. The onset of EAE in Lewis rats could almost completely be abrogated by oral administration of POX during the induction phase of disease. Lack of clinical symptoms in POX-treated animals coincided with a marked suppression of MBP-specific T cell reactivity in vitro, without any evidence for a generalized impairment of T cell activity. Collectively, our data suggest the potential use of xanthine derivatives of the POX type as a supporting antiinflammatory therapeutic agent in T_h1 CD4⁺ T cell-mediated autoimmune diseases in animal models and possibly in man.     

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.     

Psychological Stress May Induce Increased Humoral and Decreased Cellular Immunity

Abstract

Stress alters immune function and affects different immune cell populations in different ways. The authors examined whether psychological stress has different effects on the production of macrophage, T-helper 1(Th1) cell, and T-helper 2(Th2) cell-derived cytokines. Forty-two college students were recruited and their blood was sampled on the day they were to take a stressful academic examination and again 4 weeks after the examination. The stress from the academic examination significantly increased IL-1β, IL-6, and IL-10 and decreased IFN-γ production. These findings suggest that examination stress may increase Th2 cell-mediated humoral immunity and macrophage activities and may decrease Th1 cell-mediated cellular immunity.     

Interleukin-12/T cell stimulating factor,a cytokine with multiple effects on T helper type 1 (Th1) but not on Th2 cells

At least two subsets of CD4⁺ T helper cell lymphocytes termed T_h1 and T _h, 2 exist in the mouse and probably in humans. They are characterized by the secretion of different lymphokines and by their functional behavior. Dysregulated expansion of one or the other subset may be one reason for the development of certain diseases. Thus, it is of importance to define the signals involved in the differentiation and activation of the two T_h cell subsets. It is known and has been confirmed in this report that the cytokine interleukin (IL)-1 acts onT_h2 cells but not on T_h1 cells. We now report that a previously identified cytokine which was provisionally termed T cell stimulating factor is identical with IL-12 and exhibits a reciprocal behaviour to IL-1. IL-12 has several effects on T_h1 cells. It can induce the proliferation of certain T_h1 cells in combination with IL-2. Synthesis of interferon (IFN)-γ by T_h1 cells can be triggered by IL-2 plus IL-12. In contrast to the IFN-γ production observed after T cell receptor (TcR) CD3 stimulation of T_h1 cells with lectin Concanavalin A the IFN-γ production induced by IL-12+IL-2 is insensitive to the immunosuppressive drug cyclosporin A. Furthermore, IL-12 enhances the TcR/CD3-induced synthesis of IFN-γ of several T_h1 clones. Finally, IL-12 (+ IL-2) induces homotypic cell aggregation of T_h1 clones. This type of cell aggregation depends on the participation of LFA-1 and ICAM-1 molecules. In all activation systems with T_h1 cells no effect of IL-1 was demonstrable. In contrast, only IL-1 but not IL-12 served as a co-stimulatory signal for several T_h2 cell lines activated via the TcR/CD3 complex.     

Psychological stress may induce increased humoral and decreased cellular immunity

Stress alters immune function and affects different immune cell populations in different ways. The authors examined whether psychological stress has different effects on the production of macrophage, T-helper 1(Th1) cell, and T-helper 2(Th2) cell-derived cytokines. Forty-two college students were recruited and their blood was sampled on the day they were to take a stressful academic examination and again 4 weeks after the examination. The stress from the academic examination significantly increased IL-1 beta, IL-6, and IL-10 and decreased IFN-gamma production. These findings suggest that examination stress may increase Th2 cell-mediated humoral immunity and macrophage activities and may decrease Th1 cell-mediated cellular immunity.     

Emerging role of IL-35 in inflammatory autoimmune diseases

Interleukin 35 (IL-35) is the recently identified member of the IL-12 family of cytokines and provides the possibility to be a target for new therapies for autoimmune, inflammatory diseases. It is composed of an α chain (p35) and a β chain (EBI3). IL-35 mediates signaling by binding to its receptors, activates subsequent signaling pathways, and therefore, regulates the differentiation, function of T, B cells, macrophages, dendritic cells. Recent findings have shown abnormal expression of IL-35 in inflammatory autoimmune diseases, such as systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes, psoriasis, multiple sclerosis, autoimmune hepatitis, experimental autoimmune uveitis. In addition, functional analysis suggested that IL-35 is critical in the onset and development of these diseases. Therefore, the present study will systematically review what had been occurred regarding IL-35 in inflammatory autoimmune disease. The information collected will help to understand the biologic role of IL-35 in immune cells, and give information about the therapeutic potential of IL-35 in these diseases.     

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.     

Molecular mimicry in the pathogenesis of AIDS: The HIV/MHC/Mycoplasma triangle

The immune defects characterizing infection with the human immunodeficiency virus (HIV) and culminating in the acquired immune deficiency syndrome (AIDS) are the result of a multifactorial disease process, components of which are the occurrence of autoimmune phenomena and opportunistic infection. In this discussion, the observation that both the HIV-1 gp 120 envelope and Mycoplasma genitalium adhesin proteins share an area of significant similarity with the CD4-binding site of the class II major histocompatibility complex (MHC) proteins is placed in this perspective and mechanisms by which interaction within this triad could contribute to the T-cell dysfunction, T-cell depletion, T_h1-cell→T_h2-cell shift, B-cell proliferation, hyperglobulinemia and antigen-presenting cell dysfunction observed during the development of AIDS are proposed.     

Induction of T helper cell subsets

Conclusions Long-term murine CD4⁺ T cell clones can be classified into two distinct subsets which produce either IL-2 and IFN- (T_h1) or IL-4 and IL-5 (T_h2). This functional separation of CD4⁺ T cells has subsequently been shown to be of great biological relevance, since these T helper cell subsets can be associated with protective or pathogenic immune responses. While a large number of in vitro and in vivo experiments underlined the biological relevance of T_h1 and T_h2 phenotypes, the ontogeny of T_h1 or T_h2 cells remained unknown until recently. Experiments published during the last 3 years have shown that cytokines such as IL-2, IL-4 and IFN- can influence the LK response pattern of CD4⁺ T cells. However, further investigations demonstrated that these cytokines alone had no effect on the modulation of the LK response pattern.Prolonged TCR binding by mitogenic mAb delivered a signal required for the induction of the T_h2 phenotype. Whereas this signal cannot be replaced by soluble factors, ligation of the TCR together with LK leads to the development of T_h2. The fact that TCR-mediated induction of T_h2 in vitro takes the same time as the antigen-mediated commitment of T_h1- or T_h2-like cells in vivo underlines the role of the TCR in T helper cell subset differentiation. Since the two subsets can be derived from a common postthymic CD4⁺ precursor, the T_h1 or T_h2 phenotype of a T cell is acquired during T cell differentiation and is not secondary to the expansion of distinct subpopulations which are predetermined for the production of a specific LK pattern.The structure of the natural ligands of the TCR, i. e., antigens and MHC class II-encoded molecules, have been shown to influence the development of T helper cells with distinct LK profiles in vivo. This suggests that the TCR-ligand interaction is decisive for the commitment of a peripheral CD4⁺ T cell towards a T_h1- or a T_h2-like response pattern.     

Patients treated with high‐dose intravenous immunoglobulin show selective activation of regulatory T cells

Intravenous immunoglobulin (IVIg) is used to treat autoimmune and systemic inflammatory diseases caused by derailment of humoral and cellular immunity. In this study we investigated whether IVIg treatment can modulate regulatory T cells (T_regs) in humans in vivo. Blood was collected from IVIg-treated patients with immunodeficiency or autoimmune disease who were treated with low-dose (n = 12) or high-dose (n = 15) IVIg before, immediately after and at 7 days after treatment. Percentages and activation status of circulating CD4⁺CD25⁺forkhead box protein 3 (FoxP3⁺) T_regs and of conventional CD4⁺FoxP3⁻ T-helper cells (T_conv) were measured. The suppressive capacity of T_regs purified from blood collected at the time-points indicated was determined in an ex-vivo assay. High-dose, but not low-dose, IVIg treatment enhanced the activation status of circulating T_regs, as shown by increased FoxP3 and human leucocyte antigen D-related (HLA-DR) expression, while numbers of circulating T_regs remained unchanged. The enhanced activation was sustained for at least 7 days after infusion, and the suppressive capacity of purified T_regs was increased from 41 to 70% at day 7 after IVIg treatment. The activation status of T_conv was not affected by IVIg. We conclude that high-dose IVIg treatment activates T_regs selectively and enhances their suppressive function in humans in vivo. This effect may be one of the mechanisms by which IVIg restores imbalanced immune homeostasis in patients with autoimmune and systemic inflammatory disorders.