Joint pain. Not an uncommon problem as you grow older. Is it due to normal wear and tear on the joints? Possibly. But rheumatoid arthritis is an autoimmune disease, which means the body's immune system mistakenly attacks healthy tissue.
Autoimmune diseases occur when the immune system fails to recognize the body’s own molecules as “self,” or belonging to the person. Instead, it attacks body cells as though they were dangerous pathogens. There are more than 80 known autoimmune diseases. Recall that regulatory T cells help regulate the immune system. When autoimmune disorders occur, these regulatory T cells fail in their function. This results in damage to various organs and tissues. The type of autoimmune disorder depends on the type of body tissue that is affected.
Some relatively common autoimmune diseases are listed in Table below. These diseases cannot be cured, although they can be treated to relieve symptoms and prevent some of the long-term damage they cause.
|Name of Disease||Tissues Attacked by Immune System||Results of Immune System Attack|
|Rheumatoid arthritis||tissues inside joints||joint damage and pain|
|Type 1 diabetes||insulin-producing cells of the pancreas||inability to produce insulin, highblood sugar|
|Multiple sclerosis||myelin sheaths of central nervous system neurons||muscle weakness, pain, fatigue|
|Systemic lupus erythematosus||joints, heart, other organs||joint and organ damage and pain|
Why does the immune system attack body cells? In some cases, it’s because of exposure to pathogens that have antigens similar to the body’s own molecules. When this happens, the immune system not only attacks the pathogens, it also attacks body cells with the similar molecules.
- Autoimmune diseases occur when the immune system fails to distinguish self from non-self. As a result, the immune system attacks the body’s own cells.
- What is an autoimmune disease? Name an example.
- Rheumatic fever is caused by a virus that has antigens similar to molecules in human heart tissues. When the immune system attacks the virus, it may also attack the heart. What type of immune system disease is rheumatic fever? Explain your answer.
- Can autoimmune disease be cured?
The Role of IL-17 and Related Cytokines in Inflammatory Autoimmune Diseases
Interleukin-17 (IL-17) induces the production of granulocyte colony-stimulating factor (G-CSF) and chemokines such as CXCL1 and CXCL2 and is a cytokine that acts as an inflammation mediator. During infection, IL-17 is needed to eliminate extracellular bacteria and fungi, by inducing antimicrobial peptides such as defensin. This cytokine also plays an important role in chronic inflammation that occurs during the pathogenesis of autoimmune diseases and allergies such as human rheumatoid arthritis (RA) for which a mouse model of collagen-induced arthritis (CIA) is available. In autoimmune diseases such as RA and multiple sclerosis (MS), IL-17 is produced by helper T (Th) cells that are stimulated by IL-1β and IL-6 derived from phagocytes such as macrophages and from tissue cells. IL-17 contributes to various lesions that are produced by Th17 cells, one subset of helper T cells, and by γδ T cells and innate lymphoid cells. It strongly contributes to autoimmune diseases that are accompanied by chronic inflammation. Thus, a functional understanding of Th17 cells is extremely important. In this review, we highlight the roles of cytokines that promote the development and maintenance of pathogenic Th17 cells in autoimmune diseases.
The immune system is a defense mechanism in the body that involves various types of blood cells derived from the bone marrow such as T cells and B cells, macrophages, and dendritic cells (DCs). The function of the immune system is to eliminate infectious microorganisms that have invaded the body and cancer cells that have been produced by mutations. The immune reaction leads to cell death under certain circumstances. Thus, excessive elimination of targets in chronic inflammatory reactions is harmful and is the cause of autoimmune diseases. Therefore, strict regulation is crucial to maintain immunological homeostasis. CD4-positive T cells, one type of T cell, are called helper T cells because they regulate the function of other immune cells. These helper T cells play a central role in the elimination of foreign microorganisms and in self-tolerance. Helper T cells produce cytokines that help activate immune cells in the microenvironment. IL-17 is an important cytokine not only for protective immunity against extracellular pathogens [1, 2], but also for the clearance of intracellular pathogens [3, 4]. In addition to its important role in protective immunity, IL-17 plays a critical role in the pathogenesis of various autoimmune inflammatory diseases. IL-17-producing cells, including γδT cells, natural killer T cells, and innate lymphoid cells, are characterized by the expression of the transcription factor, retinoic acid receptor-related orphan receptor-γt (RORγt) [5–7]. Dysregulation of protective immune responses causes autoimmune diseases. Self-reactive T cells are usually suppressed. When the balance of the self-reactive T cells and regulatory T cells is disturbed, the risk for autoimmune disease onset increases. High amount of production of IL-17 accompanied by excessive generation of Th17 cells may lead to autoimmune diseases. Although several types of cells produce IL-17, accumulated evidence has implicated an important role for Th17 cells in autoimmune diseases. This review summarizes the current knowledge on cytokines that control Th17 cell differentiation and cytokines that regulate Th17 cell functions by focusing on multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS), and the corresponding mouse model of experimental autoimmune encephalomyelitis (EAE).
2. IL-17-Producing Helper T Cells
2.1. Helper T Cells
Various hematopoietic and lymphoid progenitors are mobilized from the bone marrow and initiate T cell development in the thymus. During this process, they express an antigen receptor (the T cell receptor, TCR), and most cells differentiate into CD4-positive T cells or CD8-positive T cells. After completion of the maturation process, CD8-positive T cells circulate throughout the body, acquiring cytotoxic functions. They contribute to immunological homeostasis by killing cells that have been infected by viruses as well as cancer cells. On the other hand, CD4-positive T cells are helper T cells. They exhibit an immunological regulatory function. Helper T cells have previously been divided into mainly two subsets (Figure 1) . Th1 cells differentiate under the influence of IL-12 and mainly produce interferon-γ (IFN-γ). IFN-γ strongly activates macrophages, promoting the elimination of intracellular pathogens. In other words, it supports cellular immunity in the acquired immune system. On the other hand, Th2 cells differentiate under the influence of IL-4. Th2 cells support B cells through IL-4 production. As a result, the antibodies produced by B cells switch their class from IgM to IgG or IgE. By inducing the production of IgG or IgE, elimination of extracellular parasites (such as nematodes) is promoted. While cellular immunity is performed by Th1 cells, Th2 cells support humoral immunity. Thus, although derived from the same precursor cells, when activated by antigen stimuli, helper T cells differentiate into subsets with different properties due to the surrounding environmental factors (in particular, cytokines). The mechanism of differentiation has been previously analyzed in detail to clarify their mutually exclusive properties. Namely, IFN-γ suppresses the differentiation of Th2 cells, while IL-4 inhibits Th1 differentiation. Therefore, the functional imbalance between Th1 and Th2 is at the origin of various immunological diseases. For example, when there is a bias toward Th1, autoimmune diseases such as MS and RA are more likely to occur, while if Th2 is dominant then allergic reactions represented by pollinosis are provoked. However, energetic research in recent years identified subsets other than Th1 and Th2 cells . Among these, the Th17 cell subset, which produces IL-17, contributes to autoimmune diseases accompanied by chronic immune and inflammatory reactions, working together with Th1 cells.
IL-17 is a cytokine whose gene was isolated from a rat-mouse T cell hybridoma in 1993. Since it displayed a high degree of homology with the HVS13 Herpes virus gene, it was thought to be a subtype of the cytotoxic T-lymphocyte-associated protein (CTLA) family of proteins and called CTLA-8 . In 1995, it was recognized as a new cytokine and named IL-17, and, today, six homologous molecules are known (IL-17A through IL-17F). To date, most studies focused on IL-17A, IL-17E, and IL-17F. IL-17A and IL-17F are highly homologous and share receptors. Thus, they have extremely similar functions. IL-17E is also known as IL-25, and because it presents low homology with other molecules of the family and contributes to the induction of allergies, it is thought to have functions different from those of IL-17A . This review focuses on IL-17A. Several types of immune cells produce IL-17A, and Th17 cells, the newly established subset of helper T cells, have received particular attention [12–14]. Through the analysis of the function of Th17 cells in autoimmune diseases, there has been significant progress in the understanding of the biological significance of IL-17.
2.3. IL-17 Receptors and Their Signaling
IL-17 receptor A (IL-17RA) was identified as a new cytokine receptor for IL-17A and was found to be a member of the cytokine receptor family . The IL-17 receptor family now consists of five members (IL-17RA, IL-17RB, IL-17RC, IL-17RD, and IL-17RE), all of which share sequence homology. All these receptors contain a fibronectin III-like domain in their extracellular region and a SEF/IL-17R (SEFIR) domain in their intracellular region . IL-17RA had been long considered as the receptor of IL-17. However, newly emerged evidence suggests that IL-17RA is likely a common receptor used by the IL-17 family cytokines. Other receptors including IL-17RB, IL-17RC, and IL-17RE have been identified as specific receptors for IL-17E, IL-17A, and IL-17F and IL-17C, respectively. IL-17RD, originally identified as a negative regulator in fibroblast growth factor signaling, has recently been found to regulate IL-17A signaling [17, 18]. Recent studies have shown that IL-17A and IL-17F, believed to be predominantly expressed in Th17 cells, signal through a heteromeric receptor complex. This complex consists of IL-17RA and IL-17RC, which are single transmembrane proteins and ubiquitously expressed in various cell types, including epithelial cells, fibroblasts, and astrocytes [19–22]. It has been well documented that IL-17A and IL-17F can induce proinflammatory gene expression both alone and in synergy with TNFα, IL-6, G-CSF, IL-1, CXCL1, CCL20, and matrix metalloproteases [23–25]. IL-17 upregulates these proinflammatory genes through the activation of NF-κB, MAPK, and C/EBP cascades . Other studies demonstrated that IL-17 also activates the Jak-Stat and Jak-PI3 K pathways [27, 28]. In addition to altering gene expression, IL-17 stimulation can stabilize mRNAs. Normally, mRNA splicing factor (SF) is bound to mRNA to mediate its degradation. Upon IL-17 stimulation, mRNA is dissociated and stabilized [29, 30].
Adaptor protein Act1 and tumor necrosis factor receptor-associated factor (TRAF) regulate these molecular mechanisms after activation of IL-17R. Act1 was originally discovered as an NF-κB activator [31, 32]. Several studies demonstrated that Act1 is recruited to the IL-17 receptor complex through the homotypic interactions of the SEFIR domains upon IL-17 stimulation [33, 34]. Act1 deficiency results in loss of IL-17-dependent NF-κB activation and proinflammatory cytokine production. Following Act1 binding to the receptor complex, TRAF6 is recruited through interaction with the Act1 TRAF binding motif . TRAF6 further activates downstream TRAF6-dependent TAK1 for NF-κB activation.
IL-17-mediated mRNA stability of CXCL1 requires Act1 but not TRAF6, suggesting that Act1 mediates both TRAF6-dependent and TRAF6-independent pathways in IL-17R signaling . In the TRAF6-independent pathway, TRAF2 and TRAF5 are required for IL-17-induced mRNA stabilization of CXCL1 . Act1-TRAF5-TRAF2-SF complex formation induced by IL-17 prevents SF binding to CXCL1 mRNA for degradation. Phosphorylation of Act1 at Ser-311 was shown to be required for its association with TRAF2-TRAF5 complex. By mass spectrometry analysis, Act1 was found to be phosphorylated directly by the kinase IKKε at Ser-311 upon exposure to IL-17. Consistently, IKKε deficiency also prevented the formation of Act1-TRAF2-TRAF5 complex without disrupting interaction between TRAF6 and Act1, suggesting that phosphorylation of Act1 is necessary for the formation of the mRNA stabilization cascade. Thus, Act1 serves as a receptor proximal anchor platform for the initiation of two independent pathways activated by IL-17: (
) the TRAF6-dependent cascade for signaling and (
) TRAF2-TRAF5-dependent cascade for stabilization of mRNA.
Regulation of IL-17R pathways is important in the control of IL-17-mediated inflammation. As in intracellular mechanisms, fundamental features of inflammation have been revealed using mice lacking IL-17R subunits. IL-17RA-deficient fibroblasts failed to respond to IL-17A or IL-17F stimulation . Subsequent studies showed that IL-17RC interacts with IL-17RA and it can bind to IL-17A or IL-17F. IL-17RC-deficient mice also failed to induce downstream gene expression in response to IL-17A and IL-17F and develop much milder disease than wild-type mice in experimental autoimmune encephalomyelitis [37–39]. These results suggest that the IL-17 receptor complex has a significant role in biological and pathological functions  and is a candidate therapeutic target. Therefore, identification of new compounds to block the activation of IL-17R is a powerful approach to prevent IL-17-mediated pathology. A monoclonal antibody targeting IL-17R would be a potential treatment to investigate this therapeutic tool for autoimmune diseases. Brodalumab, previously known as AMG827, is a human monoclonal antibody that binds to the human IL-17RA and blocks the biological activities of IL-17A and IL-17F. This antibody is a broad spectrum inhibitor of IL-17-mediated signaling pathways compared to other IL-17-targeted therapy. Brodalumab is currently being investigated in different phases of clinical trials for psoriasis (phase II) and for RA (phase I/II) [40, 41]. In a phase II study, brodalumab showed significant improvement in severe psoriasis compared to placebo . In these preclinical studies, IL-17R targeted therapy did not show any major safety concern. However, further trials are warranted to confirm the safety profile of this therapy. IL-17 expresses protective properties against extracellular pathogens [42, 43]. Future trials with a large number of patients will provide more insight into the safety profile. Other therapeutic strategies against IL-17 are discussed below.
3. IL-17 and Autoimmune Diseases
Central immune tolerance is the thymic mechanism that eliminates self-reactive T cell receptor-producing cells. However, the elimination is not perfect. Thus, self-reactive T cells exist in peripheral tissues. Peripheral immune tolerance refers to the suppression of self-reactive T cells by regulatory T cells. Failure of both types of tolerance may result in autoimmunity and autoimmune diseases. In autoimmune diseases, the helper T cells that support the acquired immunity system attack tissues in an antigen-specific manner. Tissue dysfunction accompanied by localized organ damage induced by self-reactive T cells leads to diseases. In human diseases, it is difficult to identify antigens and the causes of disease. Thus, methods using mouse models of these diseases, in which the disease can be induced by the identified antigens, are often used as a strategy for studying autoimmune diseases. For example, the CIA model is often used as a model for human RA, and the EAE mouse model is often used as a model for human MS. Currently, Th17 cells have been established as having a close relationship with chronic inflammatory autoimmune diseases. In this section, the first half introduces the current knowledge on inflammatory cytokines related to Th17 cells in autoimmune diseases based on results obtained using the EAE mouse model, and the second half briefly explains the role of Th17 cells and IL-17 in RA and psoriasis.
3.1. Th17 Cells in EAE
MS is an autoimmune disease accompanied by chronic neuroinflammation that causes demyelination in the CNS. Accumulation of helper T cells is observed in the cerebrospinal fluid of patients. The EAE mouse model that recapitulates MS is an experimental system in which pathogenic helper T cells can be induced by administering antigens in the CNS tissue, resulting in limb paralysis. The pathophysiological analysis of EAE is useful for understanding MS. MS-related genes have been proposed by establishing and screening the disease-related genome analysis (genome-wide association studies, GWAS) database . The results suggest that specific major histocompatibility complex (MHC) class II genes are associated with a significantly high risk for the onset of MS. Moreover, although somewhat less important than the MHC, a group of genes related to differentiation and activation of helper T cells also showed a significant relationship with MS. Thus, it is believed that this disease of the CNS is a T cell-mediated disease.
3.1.1. Pathogenic T Cells: A Paradigm Shift from Th1 to Th17
Since Th1 cells strengthen cellular immunity and are present in chronic CNS inflammation , they and IFN-γ produced by them were thought to be important pathogenic factors in MS and EAE. IL-12 is a cytokine composed of p40 and p35 . Since mice lacking p40 show resistance to EAE , the idea that Th1 cells are necessary for self-pathology in neuroinflammation has been supported. However, it is also known that mice lacking p35 and mice lacking the β chain of the IL-12 receptor as well as mice lacking IFN-γ and mice lacking the IFN-γ receptor show strong symptoms of EAE compared to wild-type mice [48–53]. Thus, the identification of helper T cells as the causative factor remained unclear. IL-23 is a cytokine composed of p19 and IL-12p40. Studies using mice lacking p19 shed light on the role of helper T cells in EAE [13, 54]. Incomplete induction of IL-17 producing helper T cells (Th17) was observed in mice lacking p19, without inhibition of Th1 cell differentiation. This mutation failed to induce EAE in mice, due to the lack of Th17 cells. EAE resistance inp40-deficient mice suggested that IL-23, but not IL-12, was necessary for the induction of neuropathogenic T cells. As a result, it is now believed that helper T cells that produce IL-17 are the cause of inflammatory autoimmune diseases such as EAE and MS.
3.1.2. Cytokines Promoting Th17 Cell Development
After the discovery of the IL-23-Th17 axis, the properties of helper T cells were analyzed in detail. Th17 cells express RAR related orphan receptor γt (ROR γt) (encoded by Rorc), a master transcription factor . IL-17, IL-22, and granulocyte-macrophage colony-stimulating factor (GM-CSF), effector cytokines produced by these cells, strongly contribute to tissue inflammation [13, 56–58]. The Th17 differentiation process was also gradually clarified and divided into two stages, a priming stage and a maturation stage.
Mice lacking p19 display resistance to autoimmune diseases and a reduction in Th17 cells, so the importance of IL-23 as a differentiation factor is established. However, IL-23 cannot induce naïve T cells into mature Th17 cells. Additionally, naïve T cells do not express IL-23R. These results suggested that the priming stage of Th17 cell differentiation was regulated by other factors. Multiple groups showed that, in mice, the induction of Th17 cells is possible through simultaneous stimulation with transforming growth factor (TGF) β and IL-6 [59–61]. In the presence of IL-6 at the priming stage, a naïve T cell is stimulated by cognate antigen to differentiate into an effector cell then ROR γt, IL-17, and IL-23R are expressed, and the direction toward a Th17 cell is decided. IL-6 also induces the expression of IL-1R. IL-1 β, an inflammatory cytokine, promotes the expression of ROR γt through IRF4 pathway . Therefore, mice lacking IL-1R cannot sufficiently induce Th17 cells and do not contract EAE . Moreover, IL-1 β stimulation activates mammalian target of rapamycin (mTOR), promoting clonal expansion in an inflammatory environment . TGF β, similarly to IL-6, is also a necessary factor for the early differentiation of Th17 cells, and this cytokine induces the expression of the master transcription factor, Foxp3, that is needed for the differentiation of regulatory T cells (Treg). Thus, it was unclear whether TGF β contributed to the differentiation into Th17 cells, since Th17 and Treg cells have different properties. Since IL-6 cannot induce Th17 cells on its own, it must occur together with TGF β. The contribution of TGF β was investigated. It was found that TGF β, working together with IL-6, induced the expression of both Foxp3 and RORγt . The coexisting IL-6 suppresses Foxp3 expression by activating STAT3, thereby blocking Treg cell differentiation. However, based on recent research, it has been shown that it is possible to sufficiently induce Th17 cells with IL-6, IL-1β, and IL-23, and it became clear that TGFβ is not required . Th17 cells that have been induced by TGFβ and IL-6 gradually decrease their IL-17 production until there are only unstable Th17 cells [67, 68]. It was shown by three independent research groups that IL-21 is necessary for continuous IL-17 production [67–69]. IL-21 is produced by Th17 cells while they are undergoing IL-6 stimulation-dependent differentiation, inducing the production of IL-17 and the expression of IL-23 receptors by autocrine action. IL-21 also contributes to the suppression of Foxp3 expression that is induced by TGF β, thereby promoting the differentiation of Th17 cells. This suppression of Foxp3 expression is also observed in mice lacking IL-6. Thus, IL-21 and IL-6 regulate Foxp3 expression by independent mechanisms. Recent studies reported that Th17 cells induced mainly by IL-6 and TGF β are effective at sites of extracellular parasitic bacteria and mucosa immunity but do not appear to cause autoimmune diseases accompanied by chronic inflammation. This shows that autoimmune diseases present Th17 cells that underwent a maturation process in order to acquire high pathogenicity.
Helper T cells that induce major tissue damage are closely related to severe autoimmune diseases. Thus, the types of factors necessary for the maturation stages after the initial priming processes were investigated. IL-23, said to be necessary for Th17 cell induction, and its contribution to the production of inflammatory cytokines that are found in autoimmune diseases such as EAE (MS) and CIA (RA) garnered the attention again. Studies using mice lacking IL-23 indicated that helper T cells, whose IL-23 signals are blocked, undergo an early differentiation process of Th17 cells producing RORγt and IL-17 . This process depends on TGFβ and IL-6, not on IL-23. On the other hand, Th17 cells induced in a manner independent of IL-23 are not capable of sufficient clonal expansion, thus the pathogenicity of Th17 cells is weak, resulting in mild to no tissue damage. Self-reactive helper T cells are suppressed by immunosuppressive cells such as Treg cells. Recent studies clarified that, after IL-23 stimulation, Th17 cells avoid immunosuppressive cells [71, 72]. IL-27 is a suppression mediator. Stimulation by IL-27 activates the transcription factor STAT1. STAT1 activation inhibits the activity of STAT3, which is needed for Th17 cell differentiation . IL-23 stimulates Th17 cells to suppress the expression of the IL-27 receptor [71, 73]. Therefore, IL-23-mediated Th17 cells are resistant to IL-27. GWAS results also show that IL-23 is genetically linked to chronic inflammatory autoimmune diseases . The results of this genome analysis support the importance of IL-23.
As described above, from many analyses, TGFβ and IL-6 are necessary factors for the early stage of Th17 cell differentiation, while IL-23 plays a central role in the functional maturation and maintenance of autopathologic Th17 cells.
3.1.3. Mechanisms Underlying the Infiltration of Th17 Cells into the CNS
Blood cells in the CNS, including cells responsible for immunity as well as many blood proteins cannot pass through the blood-brain barrier (BBB) that strictly limits the flow of substances like proteins and cells from the bloodstream into the CNS. Cell migration and the transfer of the necessary proteins (nutrients) from the blood into the CNS are performed in an active way. This machinery requires energy. The structure of the BBB includes vascular endothelial cells that are strongly joined by tight junctions and various types of underlying cells such as pericytes, astrocytes, and microglia [75, 76]. The role of the BBB is to separate the CNS from the permanent changes in peripheral tissues caused by infection by external microorganisms, thereby maintaining a safe microenvironment for neurons. Pathogenic T cells must cross the BBB by some mechanisms that weaken the BBB’s defenses. In such a disease, for autoreactive helper T cells to infiltrate the CNS, they destroy the tight junctions of the BBB in an IL-17-dependent manner . Studies using whole-mount-section analysis of EAE mice showed that self-reactive helper T cells locally accumulate behind the fifth lumbar vertebra (L5) . An inflammatory cycle due to IL-17, produced by Th17 cells, and IL-6, produced by vascular endothelial cells, is formed locally at the L5 vertebra, and the vascular endothelial cells respond to this in a cyclic way to express the chemokine CCL20. As a result, Th17 cells that express the chemokine receptor CCR6 locally accumulate and pass through the tight junctions that are damaged by the inflammatory cycle . Through such processes, encephalitogenic Th17 cells pass through the BBB and arrive at the CNS, which is the target. After onset, at L5, various chemokines other than CCL20 are produced. Thus, once the inflammatory cycle has occurred, many more cells will infiltrate.
3.1.4. The CCR7 Ligand Is Necessary for the Induction of Pathogenic Th17 Cells
The chemokines that are produced at L5, the entry site of immune cells, include CCL21. Alt et al. presented a model in which pathogenic T cells infiltrate the CNS in a manner dependent on CCR7, the receptor for CCL21. They reported that the CCL21-CCR7 signal is necessary for EAE . Since EAE does not occur in mice lacking CCL21 or in CCR7 knockout mice, this model was initially considered valid . However, when pathogenic Th17 cells are adoptively transferred into mice lacking CCL21 or into wild-type mice, both groups show similar symptoms and rates of onset. Thus, there is no direct relationship between CNS migration of TH17 cells and CCL21. It is thought that the CCR7 ligand has an indispensable role in the disease at a step other than the infiltration into the CNS. When CCR7 knockout mice and mice lacking CCL21 were studied in detail, it was found that CCL21 stimulates DCs to strongly induce IL-23 production . It was clarified that, in mice lacking CCL21, there is a reduction in IL-23 production and blocking of the induction of Th17 cells. Since the differentiation into Th2 cells was similar to that of wild-type mice, it is thought that CCL21-CCR7 stimulation is specific to a Th subset. DCs migrate into lymph nodes in a manner dependent on CCL21. This migration is dependent on ERK. However, the production of IL-23 is dependent on the Akt pathway . CCR7 ligands direct DC functions between cellular migration and IL-23 production. These DC functions are switched by this chemokine and microenvironment.
3.2. Th17 in RA and Psoriasis
As for MS and EAE, Th17 cells strongly contribute to RA. Since Th17 cells cannot be separated from RA and MS disease conditions, the role and function of IL-17 have been analyzed in detail. The important clinical issue for RA is bone and joint destruction. Since bone destruction is directly related to changes in the joint structure, treatment for prevention of joint destruction is very important. Osteoclasts are the only cells that break down the bone, and they are a specially differentiated type of macrophage. Osteoclasts differentiate from monocytes, and receptor activator of nuclear factor kappa-B ligand (RANKL) promotes this process [83, 84]. Studies focused on how helper T cells that infiltrate the joints induce osteoclastogenesis from monocytes. Helper T cells that produce IL-17 have been found in the synovial tissue of patients with RA . IL-17 stimulates the osteoblasts in the joints, inducing RANKL expression. Then, through the interaction with osteoblasts, monocytes respond to RANKL and mature into osteoclasts. After this mechanism was reported, interest in IL-17 for RA and its animal models grew [86, 87]. The identity of the helper T cells that regulate IL-17 production in the synovium remained unclear, but, after the discovery of Th17 cells as a new subset in 2006, the RANKL-dependent induction mechanism of osteoclasts via Th17 cells in RA became clear . In RA and CIA, continuing inflammation is an important disease condition, similar to bone destruction. IL-22 produced by Th17 cells certainly regulates chronic inflammation. IL-22 stimulates synovial fibroblasts to induce cell proliferation and the production of inflammatory chemokines . Studies using a mouse model also showed that IL-22 induces osteoclastogenesis . Moreover, IL-6 produced by fibroblasts responding to IL-17 derived from Th17 cells amplifies inflammation . IL-6 stimulates synovial tissue in an autocrine manner, worsening the condition by amplification cycle that releases inflammatory mediators. Thus, IL-17 maintains the inflammatory cycle via downstream cytokines. It has recently been reported that IL-17 in the synovial tissue is not derived from Th17 cells, but rather from mast cells . That does not change the importance of IL-17 for the disease condition, but the possibility remains that the role of Th17 cells in this disease will be revised.
Psoriasis is a chronic inflammatory skin disease characterized by hyperproliferation and abnormal differentiation of epidermal cells. Pronounced acanthosis and inflammatory infiltration such as of neutrophils and lymphocytes are observed in lesions. As cyclosporin, a calcineurin inhibitor, shows therapeutic effectiveness, it is thought that T cells contribute to psoriasis pathology. Recent studies clarified that Th17 cells contribute to the onset of psoriasis [92, 93]. Th17 cells that have infiltrated the skin produce not just IL-17, but also IL-22. IL-22 stimulates keratocytes in the skin, leading to the activation of STAT3, followed by the proliferation of keratinocytes and acanthosis . IL-17 and IL-22 induce keratinocytes to express CXCL1 and CXCL8, inducing further cell infiltration [94–98]. Thus, a positive psoriasis feedback loop is formed. A contribution of IL-36 to the detailed mechanism of this positive feedback loop has been suggested . IL-36 is produced by keratinocytes and stimulates resident DCs that are normally present in the skin. In response to IL-36, DCs express IL-23, which appears to increase the pathogenicity of Th17 cells . In the normal skin, an IL-36R antagonist is expressed, to compete with IL-36 stimulation . However, it is thought that, as the disease condition progresses, the suppression by the IL-36R antagonist is abrogated.
3.3. Plasticity of Pathogenic Helper T Cells
In chronic inflammation, IL-23 stimulation confers higher pathogenicity on Th17 cells, and, in this process, not just IL-17, but also IFNγ, IL-22, and GM-CSF are produced. In a recent study, based on the way functional cytokines are produced, helper T cells have been divided into multiple subsets such as Th9 cells and Th22 cells . Th1 cells and Th2 cells stably maintain their properties. In contrast, it seems that Th17 cells infiltrated into CNS lesions produce various cytokines and differentiate from Th17 cells into other subsets . Studies using an IL-17 reporter mouse indicated that, during EAE onset, cells that produced IL-17 were converted into cells that produced IFNγ . Based on this result, a model was proposed in which Th17 cells redifferentiated either into Th17/Th1 hybrid cells, or into a type of Th1 cells that stopped producing IL-17 (ex-Th17). This model may explain the presence of Th1/Th17 hybrid cells in the CNS from patients with MS. Moreover, these cells producing IFNγ, which may be ex-Th17 cells, are more pathogenic than Th17 cells. IFNγ can be produced by conventional Th1 cells and ex-Th17 cells. However, conventional Th1 cells are not exposed to IL-23 and, therefore, do not express IL-1R, while ex-Th17 cells exposed to IL-23 in the past can express IL-1R. Therefore, the expression of IL-1R helps distinguishing between IFNγ-producing ex-Th17 cells and conventional Th1 cells. Since GM-CSF is encephalitogenic, a new subset of cells has been named ThGM-CSF [56, 57]. According to this model, it is highly possible that GM-CSF-producing helper T cells acquire the ability to produce GM-CSF after Th17 cells stop producing IL-17. In fact, helper T cells that produce both IL-17 and GM-CSF have been observed . Additionally, there are cases where other subsets turn into Th17 cells. TGFβ, which is necessary for the differentiation of Th17 cells, is a cytokine that induces the differentiation of Treg cells. Komatsu et al. using a CIA mouse model showed that Foxp3-positive Treg cells in the joint synovia redifferentiated into Th17 cells (IL-17-producing ex-Treg cells) . IL-17-producing ex-Treg cells express RANKL and cause strong osteoclast differentiation compared to the normal type of Th17 cells. These monocytes interact directly with IL-17-producing ex-Treg cells, not via synovial fibroblasts.
4. Autoimmune Disease Treatment Targeting Th17 Cells
Based on research results using GWAS and animal models, clinical trials have begun, targeting either IL-23, which contributes to the final differentiation and function acquisition of pathogenic Th17 cells, or RORγt, which is a master transcription factor for Th17 cells, or IL-17, which is an effector cytokine [74, 106] (Figure 2). With regard to autoimmune diseases such as RA, ankylosing spondylitis, chronic inflammatory intestinal diseases, psoriasis, and MS, clinical research is progressing on humanized anti-IL-23 antibodies, humanized anti-IL-17 antibodies, and humanized IL-17R antibodies, and some extremely hopeful results have been obtained. Among these, a high improvement rate has been observed in the clinical symptoms of psoriasis compared to existing treatment methods [107–110].
Screening tests are being performed to identify small molecules regulating the functions of Th17 cells. Among molecules that contribute to the maturation and function of Th17 cells, RORγt has DNA binding sites and ligand binding regions, and therefore it is thought to be easy to focus on the targeted sites. RORγt is also different from other transcription factors in that it shows hemocyte-specific expression. Thus, side effects might be minimized in biological applications. The cardiac glycoside, digoxin, which has been used to treat heart disease, has been screened as a RORγt-specific inhibitor . Digoxin inhibits the differentiation of Th17 cells without inhibiting the differentiation into other subsets. Digoxin derivatives that are derived from this cardiac glycoside specifically inhibit the production of IL-17 in human and mouse Th17 cells. The small molecule, SR100, which is a ligand of the liver X receptor LXR, one of the endonuclear receptors expressed in the liver, specifically binds to the ligand binding domain of RORγt . As a result, there is a change in RORγt structure suppressing its interaction with a coactivator that increases its transcription activity, thereby inhibiting Th17 cell differentiation. Ursolic acid, a natural compound, selectively binds to RORγt, suppressing not only the Th17 cell differentiation process, but also the functions of Th17 cells after differentiation. Administration to EAE mice reduced limb paralysis . Although these results were obtained in an animal model, ursolic acid shows promise, and one expects such development for all compounds that similarly bind specifically to RORγt.
In this review, we discussed IL-17 and related cytokines in chronic autoimmune diseases. Since the discovery of IL-17, there have been many reports that Th17 cells are important in human and mouse chronic autoimmune diseases. While Th17 cells and IL-17 directly lead to the worsening of RA disease conditions, they are important factors that can be targeted to alleviate diseases. There is hope that molecular therapy targeting IL-23 or the master transcription factor RORγt, which are necessary for autoimmune pathology, although they are unnecessary for the differentiation process of Th17 cells, will improve symptoms at the biological level. It is also predicted that multiple approaches will expand the range of application to other diseases in the future. If the molecular therapy strategies that have succeeded with helper T cells that produce IL-17 can also be applied to other helper T cells then they may be applied to not only diseases that are due to excessive immune response such as allergies, but also to immunodeficiency recovery and cancer immunity. In this review, we provided an overview of the role of IL-17 and Th17 cells in autoimmune diseases and hope that we have stimulated the reader’s scientific sensitivity.
|CD:||Cluster of differentiation|
|CNS:||Central nervous system|
|CTLA:||Cytotoxic T-lymphocyte-associated protein|
|EAE:||Experimental autoimmune encephalomyelitis|
|G-CSF:||Granulocyte colony-stimulating factor|
|GM-CSF:||Granulocyte-macrophage colony-stimulating factor|
|GWAS:||Genome-wide association studies|
|MHC:||Major histocompatibility complex|
|mTOR:||Mammalian target of rapamycin (mechanistic target of rapamycin)|
|RANKL:||Receptor activator of nuclear factor kappa-B ligand|
The authors have no financial conflict of interests.
This work was supported in part by Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research to Taku Kuwabara (25460600) and by a grant from Takeda Science Foundation to Taku Kuwabara. The authors would like to thank Editage (https://www.editage.jp/) for English language editing.
- K. I. Happel, P. J. Dubin, M. Zheng et al., “Divergent roles of IL-23 and IL-12 in host defense against Klebsiella pneumoniae,” The Journal of Experimental Medicine, vol. 202, no. 6, pp. 761–769, 2005. View at: Publisher Site | Google Scholar
- X. L. Rudner, K. I. Happel, E. A. Young, and J. E. Shellito, “Interleukin-23 (IL-23)-IL-17 cytokine axis in murine Pneumocystis carinii infection,” Infection and Immunity, vol. 75, no. 6, pp. 3055–3061, 2007. View at: Publisher Site | Google Scholar
- W. Huang, L. Na, P. L. Fidel, and P. Schwarzenberger, “Requirement of interleukin-17A for systemic anti-Candida albicans host defense in mice,” Journal of Infectious Diseases, vol. 190, no. 3, pp. 624–631, 2004. View at: Publisher Site | Google Scholar
- P. Ye, F. H. Rodriguez, S. Kanaly et al., “Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony-stimulating factor expression, neutrophil recruitment, and host defense,” Journal of Experimental Medicine, vol. 194, no. 4, pp. 519–527, 2001. View at: Publisher Site | Google Scholar
- D. J. Cua and C. M. Tato, “Innate IL-17-producing cells: the sentinels of the immune system,” Nature Reviews Immunology, vol. 10, no. 7, pp. 479–489, 2010. View at: Publisher Site | Google Scholar
- L. A. Zúñiga, R. Jain, C. Haines, and D. J. Cua, “Th17 cell development: from the cradle to the grave,” Immunological Reviews, vol. 252, no. 1, pp. 78–88, 2013. View at: Publisher Site | Google Scholar
- B. R. Marks, H. N. Nowyhed, J. Y. Choi et al., “Thymic self-reactivity selects natural interleukin 17-producing T cells that can regulate peripheral inflammation,” Nature Immunology, vol. 10, pp. 1125–1132, 2009. View at: Google Scholar
- T. R. Mosmann, H. Cherwinski, M. W. Bond, M. A. Giedlin, and R. L. Coffman, “Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins,” The Journal of Immunology, vol. 136, pp. 2348–2357, 1986. View at: Google Scholar
- N. Schmitt and H. Ueno, “Regulation of human helper T cell subset differentiation by cytokines,” Current Opinion in Immunology, vol. 34, pp. 130–136, 2015. View at: Publisher Site | Google Scholar
- E. Rouvier, M.-F. Luciani, M.-G. Mattéi, F. Denizot, and P. Golstein, “CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene,” Journal of Immunology, vol. 150, no. 12, pp. 5445–5456, 1993. View at: Google Scholar
- S. L. Gaffen, “Recent advances in the IL-17 cytokine family,” Current Opinion in Immunology, vol. 23, no. 5, pp. 613–619, 2011. View at: Publisher Site | Google Scholar
- H. Park, Z. Li, X. O. Yang et al., “A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17,” Nature Immunology, vol. 6, no. 11, pp. 1133–1141, 2005. View at: Publisher Site | Google Scholar
- C. L. Langrish, Y. Chen, W. M. Blumenschein et al., “IL-23 drives a pathogenic T cell population that induces autoimmune inflammation,” The Journal of Experimental Medicine, vol. 201, no. 2, pp. 233–240, 2005. View at: Publisher Site | Google Scholar
- L. E. Harrington, R. D. Hatton, P. R. Mangan et al., “Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages,” Nature Immunology, vol. 6, no. 11, pp. 1123–1132, 2005. View at: Publisher Site | Google Scholar
- Z. Yao, W. C. Fanslow, M. F. Seldin et al., “Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor,” Immunity, vol. 3, no. 6, pp. 811–821, 1995. View at: Publisher Site | Google Scholar
- M. Ahmed and S. L. Gaffen, “IL-17 in obesity and adipogenesis,” Cytokine and Growth Factor Reviews, vol. 21, no. 6, pp. 449–453, 2010. View at: Publisher Site | Google Scholar
- D. Ron, Y. Fuchs, and D. S. Chorev, “Know thy Sef: a novel class of feedback antagonists of receptor tyrosine kinase signaling,” The International Journal of Biochemistry & Cell Biology, vol. 40, no. 10, pp. 2040–2052, 2008. View at: Publisher Site | Google Scholar
- M. Mellett, P. Atzei, A. Horgan et al., “Orphan receptor IL-17RD tunes IL-17A signalling and is required for neutrophilia,” Nature Communications, vol. 3, article no. 1119, 2012. View at: Publisher Site | Google Scholar
- V. Trajkovic, S. Stosic-Grujicic, T. Samardzic et al., “Interleukin-17 stimulates inducible nitric oxide synthase activation in rodent astrocytes,” Journal of Neuroimmunology, vol. 119, no. 2, pp. 183–191, 2001. View at: Publisher Site | Google Scholar
- J. K. Kolls and A. Lindén, “Interleukin-17 family members and inflammation,” Immunity, vol. 21, no. 4, pp. 467–476, 2004. View at: Publisher Site | Google Scholar
- D. Inoue, M. Numasaki, M. Watanabe et al., “IL-17A promotes the growth of airway epithelial cells through ERK-dependent signaling pathway,” Biochemical and Biophysical Research Communications, vol. 347, no. 4, pp. 852–858, 2006. View at: Publisher Site | Google Scholar
- D. Toy, D. Kugler, M. Wolfson et al., “Cutting edge: interleukin 17 signals through a heteromeric receptor complex,” Journal of Immunology, vol. 177, no. 1, pp. 36–39, 2006. View at: Publisher Site | Google Scholar
- M. Awane, P. G. Andres, D. J. Li, and H. C. Reinecker, “NF-kappa B-inducing kinase is a common mediator of IL-17-, TNF-alpha-, and IL-1 beta-induced chemokine promoter activation in intestinal epithelial cells,” The Journal of Immunology, vol. 162, pp. 5337–5344, 1999. View at: Google Scholar
- Y. Chen, P. Thai, Y.-H. Zhao, Y.-S. Ho, M. M. DeSouza, and R. Wu, “Stimulation of airway mucin gene expression by interleukin (IL)-17 through IL-6 paracrine/autocrine loop,” The Journal of Biological Chemistry, vol. 278, no. 19, pp. 17036–17043, 2003. View at: Publisher Site | Google Scholar
- M. J. Ruddy, G. C. Wong, X. K. Liu et al., “Functional cooperation between interleukin-17 and tumor necrosis factor-α is mediated by CCAAT/enhancer-binding protein family members,” Journal of Biological Chemistry, vol. 279, no. 4, pp. 2559–2567, 2004. View at: Publisher Site | Google Scholar
- S. Zhu and Y. Qian, “IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential,” Clinical Science, vol. 122, no. 11, pp. 487–511, 2012. View at: Publisher Site | Google Scholar
- F. Huang, C.-Y. Kao, S. Wachi, P. Thai, J. Ryu, and R. Wu, “Requirement for both JAK-mediated PI3K signaling and ACT1/TRAF6/TAK1-dependent NF-κB activation by IL-17A in enhancing cytokine expression in human airway epithelial cells,” The Journal of Immunology, vol. 179, no. 10, pp. 6504–6513, 2007. View at: Publisher Site | Google Scholar
- A. Saleh, L. Shan, A. J. Halayko, S. Kung, and A. S. Gounni, “Critical role for STAT3 in IL-17A-mediated CCL11 expression in human airway smooth muscle cells,” Journal of Immunology, vol. 182, no. 6, pp. 3357–3365, 2009. View at: Publisher Site | Google Scholar
- J. Hartupee, C. Liu, M. Novotny, D. Sun, X. Li, and T. A. Hamilton, “IL-17 signaling for mRNA stabilization does not require TNF receptor-associated factor 6,” The Journal of Immunology, vol. 182, no. 3, pp. 1660–1666, 2009. View at: Publisher Site | Google Scholar
- D. Sun, M. Novotny, K. Bulek, C. Liu, X. Li, and T. Hamilton, “Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF),” Nature Immunology, vol. 12, no. 9, pp. 853–860, 2011. View at: Publisher Site | Google Scholar
- A. Leonardi, A. Chariot, E. Claudio, K. Cunningham, and U. Siebenlist, “CIKS, a connection to IκB kinase and stress-activated protein kinase,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 19, pp. 10494–10499, 2000. View at: Publisher Site | Google Scholar
- X. Li, M. Commane, H. Nie et al., “Act1, an NF-κB-activating protein,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 19, pp. 10489–10493, 2000. View at: Publisher Site | Google Scholar
- H. C. Seon, H. Park, and C. Dong, “Act1 adaptor protein is an immediate and essential signaling component of interleukin-17 receptor,” Journal of Biological Chemistry, vol. 281, no. 47, pp. 35603–35607, 2006. View at: Publisher Site | Google Scholar
- Y. Qian, C. Liu, J. Hartupee et al., “The adaptor Act1 is required for interleukin 17pendent signaling associated with autoimmune and inflammatory disease,” Nature Immunology, vol. 8, no. 3, pp. 247–256, 2007. View at: Publisher Site | Google Scholar
- C. Liu, W. Qian, Y. Qian et al., “Act1, a U-box E3 ubiquitin ligase for IL-17 signaling,” Science Signaling, vol. 2, no. 92, article no. ra63, 2009. View at: Google Scholar
- X. O. Yang, S. H. Chang, H. Park et al., “Regulation of inflammatory responses by IL-17F,” The Journal of Experimental Medicine, vol. 205, no. 5, pp. 1063–1075, 2008. View at: Publisher Site | Google Scholar
- S. L. Gaffen, “Structure and signalling in the IL-17 receptor family,” Nature Reviews Immunology, vol. 9, no. 8, pp. 556–567, 2009. View at: Publisher Site | Google Scholar
- A. W. Ho and S. L. Gaffen, “IL-17RC: a partner in IL-17 signaling and beyond,” Seminars in Immunopathology, vol. 32, no. 1, pp. 33–42, 2010. View at: Publisher Site | Google Scholar
- Y. Hu, N. Ota, I. Peng et al., “IL-17RC is required for IL-17A- and IL-17F-dependent signaling and the pathogenesis of experimental autoimmune encephalomyelitis,” The Journal of Immunology, vol. 184, no. 8, pp. 4307–4316, 2010. View at: Publisher Site | Google Scholar
- K. A. Papp, C. Leonardi, A. Menter et al., “Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis,” New England Journal of Medicine, vol. 366, no. 13, pp. 1181–1189, 2012. View at: Publisher Site | Google Scholar
- Y. Hu, F. Shen, N. K. Crellin, and W. Ouyang, “The IL-17 pathway as a major therapeutic target in autoimmune diseases,” Annals of the New York Academy of Sciences, vol. 1217, no. 1, pp. 60–76, 2011. View at: Publisher Site | Google Scholar
- H. R. Conti, F. Shen, N. Nayyar et al., “Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis,” The Journal of Experimental Medicine, vol. 206, no. 2, pp. 299–311, 2009. View at: Publisher Site | Google Scholar
- J. S. Cho, E. M. Pietras, N. C. Garcia et al., “IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice,” Journal of Clinical Investigation, vol. 120, no. 5, pp. 1762–1773, 2010. View at: Publisher Site | Google Scholar
- S. Sawcer, G. Hellenthal, M. Pirinen et al., “Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis,” Nature, vol. 476, no. 7359, pp. 214–219, 2011. View at: Publisher Site | Google Scholar
- H. Hammarberg, O. Lidman, C. Lundberg et al., “Neuroprotection by encephalomyelitis: rescue of mechanically injured neurons and neurotrophin production by CNS-infiltrating T and natural killer cells,” Journal of Neuroscience, vol. 20, no. 14, pp. 5283–5291, 2000. View at: Google Scholar
- C. A. Hunter, “New IL-12-family members: IL-23 and IL-27, cytokines with divergent functions,” Nature Reviews Immunology, vol. 5, no. 7, pp. 521–531, 2005. View at: Publisher Site | Google Scholar
- B. M. Segal, B. K. Dwyer, and E. M. Shevach, “An interleukin (IL)-10/IL-12 immunoregulatory circuit controls susceptibility to autoimmune disease,” Journal of Experimental Medicine, vol. 187, no. 4, pp. 537–546, 1998. View at: Publisher Site | Google Scholar
- G.-X. Zhang, B. Gran, S. Yu et al., “Induction of experimental autoimmune encephalomyelitis in IL-12 receptor-β2-deficient mice: IL-12 responsiveness is not required in the pathogenesis of inflammatory demyelination in the central nervous system,” Journal of Immunology, vol. 170, no. 4, pp. 2153–2160, 2003. View at: Publisher Site | Google Scholar
- B. Gran, G.-X. Zhang, S. Yu et al., “IL-12p35-deficient mice are susceptible to experimental autoimmune encephalomyelitis: evidence for redundancy in the IL-12 system in the induction of central nervous system autoimmune demyelination,” The Journal of Immunology, vol. 169, no. 12, pp. 7104–7110, 2002. View at: Publisher Site | Google Scholar
- C.-Q. Chu, S. Wittmer, and D. K. Dalton, “Failure to suppress the expansion of the activated CD4 T cell population in interferon γ-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis,” The Journal of Experimental Medicine, vol. 192, no. 1, pp. 123–128, 2000. View at: Publisher Site | Google Scholar
- D. O. Willenborg, S. Fordham, C. C. A. Bernard, W. B. Cowden, and I. A. Ramshaw, “IFN-γ plays a critical down-regulatory role in the induction and effector phase of myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis,” Journal of Immunology, vol. 157, no. 8, pp. 3223–3227, 1996. View at: Google Scholar
- M. Krakowski and T. Owens, “Interferon-γ confers resistance to experimental allergic encephalomyelitis,” European Journal of Immunology, vol. 26, no. 7, pp. 1641–1646, 1996. View at: Publisher Site | Google Scholar
- I. A. Ferber, S. Brocke, C. Taylor-Edwards et al., “Mice with a disrupted IFN-γ gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE),” Journal of Immunology, vol. 156, no. 1, pp. 5–7, 1996. View at: Google Scholar
- D. J. Cua, J. Sherlock, Y. Chen et al., “Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain,” Nature, vol. 421, no. 6924, pp. 744–748, 2003. View at: Publisher Site | Google Scholar
- I. I. Ivanov, B. S. McKenzie, L. Zhou et al., “The Orphan Nuclear Receptor RORγt Directs the Differentiation Program of Proinflammatory IL-17+ T Helper Cells,” Cell, vol. 126, no. 6, pp. 1121–1133, 2006. View at: Publisher Site | Google Scholar
- M. El-Behi, B. Ciric, H. Dai et al., “The encephalitogenicity of T H 17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF,” Nature Immunology, vol. 12, no. 6, pp. 568–575, 2011. View at: Publisher Site | Google Scholar
- L. Codarri, G. Gyülvészi, V. Tosevski et al., “RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation,” Nature Immunology, vol. 12, no. 6, pp. 560–567, 2011. View at: Publisher Site | Google Scholar
- Y. Zheng, D. M. Danilenko, P. Valdez et al., “Interleukin-22, a TH17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis,” Nature, vol. 445, no. 7128, pp. 648–651, 2007. View at: Publisher Site | Google Scholar
- M. Veldhoen, R. J. Hocking, C. J. Atkins, R. M. Locksley, and B. Stockinger, “TGFβ in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells,” Immunity, vol. 24, no. 2, pp. 179–189, 2006. View at: Publisher Site | Google Scholar
- P. R. Mangan, L. E. Harrington, D. B. O'Quinn et al., “Transforming growth factor-β induces development of the T H17 lineage,” Nature, vol. 441, no. 7090, pp. 231–234, 2006. View at: Publisher Site | Google Scholar
- E. Bettelli, Y. Carrier, W. Gao et al., “Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells,” Nature, vol. 441, no. 7090, pp. 235–238, 2006. View at: Publisher Site | Google Scholar
- Y. Chung, S. H. Chang, G. J. Martinez et al., “Critical regulation of early Th17 cell differentiation by interleukin-1 signaling,” Immunity, vol. 30, no. 4, pp. 576–587, 2009. View at: Publisher Site | Google Scholar
- C. Sutton, C. Brereton, B. Keogh, K. H. G. Mills, and E. C. Lavelle, “A crucial role for interleukin (IL)-1 in the induction of IL-17-producing T cells that mediate autoimmune encephalomyelitis,” Journal of Experimental Medicine, vol. 203, no. 7, pp. 1685–1691, 2006. View at: Publisher Site | Google Scholar
- M. F. Gulen, Z. Kang, K. Bulek et al., “The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation,” Immunity, vol. 32, no. 1, pp. 54–66, 2010. View at: Publisher Site | Google Scholar
- K. Ichiyama, H. Yoshida, Y. Wakabayashi et al., “Foxp3 inhibits RORγt-mediated IL-17A mRNA transcription through direct interaction with RORγt,” The Journal of Biological Chemistry, vol. 283, no. 25, pp. 17003–17008, 2008. View at: Publisher Site | Google Scholar
- K. Ghoreschi, A. Laurence, X.-P. Yang et al., “Generation of pathogenic TH 17 cells in the absence of TGF-β 2 signalling,” Nature, vol. 467, no. 7318, pp. 967–971, 2010. View at: Publisher Site | Google Scholar
- R. Nurieva, X. O. Yang, G. Martinez et al., “Essential autocrine regulation by IL-21 in the generation of inflammatory T cells,” Nature, vol. 448, no. 7152, pp. 480–483, 2007. View at: Publisher Site | Google Scholar
- T. Korn, E. Bettelli, W. Gao et al., “IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells,” Nature, vol. 448, pp. 484–487, 2007. View at: Google Scholar
- L. Zhou, I. I. Ivanov, R. Spolski et al., “IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways,” Nature Immunology, vol. 8, no. 9, pp. 967–974, 2007. View at: Publisher Site | Google Scholar
- M. J. McGeachy, Y. Chen, C. M. Tato et al., “The interleukin 23 receptor is essential for the terminal differentiation of interleukin 17-producing effector T helper cells in vivo,” Nature Immunology, vol. 10, no. 3, pp. 314–324, 2009. View at: Publisher Site | Google Scholar
- C. Diveu, M. J. McGeachy, K. Boniface et al., “IL-27 blocks RORc expression to inhibit lineage commitment of Th17 cells,” Journal of Immunology, vol. 182, no. 9, pp. 5748–5756, 2009. View at: Publisher Site | Google Scholar
- A. Laurence, C. M. Tato, T. S. Davidson et al., “Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation,” Immunity, vol. 26, no. 3, pp. 371–381, 2007. View at: Publisher Site | Google Scholar
- M. El-behi, B. Ciric, S. Yu, G.-X. Zhang, D. C. Fitzgerald, and A. Rostami, “Differential effect of IL-27 on developing versus committed Th17 cells,” Journal of Immunology, vol. 183, no. 8, pp. 4957–4967, 2009. View at: Publisher Site | Google Scholar
- R. H. Duerr, K. D. Taylor, S. R. Brant et al., “A genome-wide association study identifies IL23R as an inflammatory bowel disease gene,” Science, vol. 314, no. 5804, pp. 1461–1463, 2006. View at: Publisher Site | Google Scholar
- E. Steed, M. S. Balda, and K. Matter, “Dynamics and functions of tight junctions,” Trends in Cell Biology, vol. 20, no. 3, pp. 142–149, 2010. View at: Publisher Site | Google Scholar
- N. J. Abbott, L. Rönnb์k, and E. Hansson, “Astrocyte-endothelial interactions at the blood-brain barrier,” Nature Reviews Neuroscience, vol. 7, no. 1, pp. 41–53, 2006. View at: Publisher Site | Google Scholar
- H. Kebir, K. Kreymborg, I. Ifergan et al., “Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation,” Nature Medicine, vol. 13, no. 10, pp. 1173–1175, 2007. View at: Publisher Site | Google Scholar
- Y. Arima, M. Harada, D. Kamimura et al., “Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier,” Cell, vol. 148, no. 3, pp. 447–457, 2012. View at: Publisher Site | Google Scholar
- H. Ogura, M. Murakami, Y. Okuyama et al., “Interleukin-17 promotes autoimmunity by triggering a positive-feedback loop via interleukin-6 induction,” Immunity, vol. 29, no. 4, pp. 628–636, 2008. View at: Publisher Site | Google Scholar
- C. Alt, M. Laschinger, and B. Engelhardt, “Functional expression of the lymphoid chemokines CCL19 (ELC) and CCL 21 (SLC) at the blood-brain barrier suggests their involvement in G-protein-dependent lymphocyte recruitment into the central nervous system during experimental autoimmune encephalomyelitis,” European Journal of Immunology, vol. 32, no. 8, pp. 2133–2144, 2002. View at: Publisher Site | Google Scholar
- T. Kuwabara, F. Ishikawa, T. Yasuda et al., “CCR 7 ligands are required for development of experimental autoimmune encephalomyelitis through generating IL-23-dependent Th17 cells,” Journal of Immunology, vol. 183, no. 4, pp. 2513–2521, 2009. View at: Publisher Site | Google Scholar
- T. Kuwabara, Y. Tanaka, F. Ishikawa, M. Kondo, H. Sekiya, and T. Kakiuchi, “CCR7 ligands up-regulate IL-23 through pi3-kinase and NF-κB pathway in dendritic cells,” Journal of Leukocyte Biology, vol. 92, no. 2, pp. 309–318, 2012. View at: Publisher Site | Google Scholar
- Y.-Y. Kung, U. Felge, I. Sarosi et al., “Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand,” Nature, vol. 402, no. 6759, pp. 304–309, 1999. View at: Publisher Site | Google Scholar
- N. J. Horwood, V. Kartsogiannis, J. M. W. Quinn, E. Romas, T. J. Martin, and M. T. Gillespie, “Activated T lymphocytes support osteoclast formation in vitro,” Biochemical and Biophysical Research Communications, vol. 265, no. 1, pp. 144–150, 1999. View at: Publisher Site | Google Scholar
- S. Kotake, N. Udagawa, N. Takahashi et al., “IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis,” Journal of Clinical Investigation, vol. 103, no. 9, pp. 1345–1352, 1999. View at: Publisher Site | Google Scholar
- S. Sarkar, L. A. Tesmer, V. Hindnavis, J. L. Endres, and D. A. Fox, “Interleukin-17 as a molecular target in immune-mediated arthritis: immunoregulatory properties of genetically modified murine dendritic cells that secrete interleukin-4,” Arthritis and Rheumatism, vol. 56, no. 1, pp. 89–100, 2007. View at: Publisher Site | Google Scholar
- S. Nakae, S. Saijo, R. Horai, K. Sudo, S. Mori, and Y. Iwakura, “IL-17 production from activated T cells is required for the spontaneous development of destructive arthritis in mice deficient in IL-1 receptor antagonist,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 10, pp. 5986–5990, 2003. View at: Publisher Site | Google Scholar
- K. Sato, A. Suematsu, K. Okamoto et al., “Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction,” Journal of Experimental Medicine, vol. 203, no. 12, pp. 2673–2682, 2006. View at: Publisher Site | Google Scholar
- E. M. Colin, P. S. Asmawidjaja, J. P. van Hamburg et al., “1,25-Dihydroxyvitamin D3 modulates Th17 polarization and interleukin-22 expression by memory T cells from patients with early rheumatoid arthritis,” Arthritis and Rheumatism, vol. 62, no. 1, pp. 132–142, 2010. View at: Publisher Site | Google Scholar
- L. Geboes, L. Dumoutier, H. Kelchtermans et al., “Proinflammatory role of the Th17 cytokine interleukin-22 in collagen-induced arthritis in C57BL/6 mice,” Arthritis and Rheumatism, vol. 60, no. 2, pp. 390–395, 2009. View at: Publisher Site | Google Scholar
- A. J. Hueber, D. L. Asquith, A. M. Miller et al., “Cutting edge: mast cells express IL-17A in rheumatoid arthritis synovium,” Journal of Immunology, vol. 184, no. 7, pp. 3336–3340, 2010. View at: Publisher Site | Google Scholar
- A. Di Cesare, P. Di Meglio, and F. O. Nestle, “The IL-23/Th17 axis in the immunopathogenesis of psoriasis,” Journal of Investigative Dermatology, vol. 129, no. 6, pp. 1339–1350, 2009. View at: Publisher Site | Google Scholar
- Y. Iwakura and H. Ishigame, “The IL-23/IL-17 axis in inflammation,” The Journal of Clinical Investigation, vol. 116, no. 5, pp. 1218–1222, 2006. View at: Publisher Site | Google Scholar
- K. Boniface, F.-X. Bernard, M. Garcia, A. L. Gurney, J.-C. Lecron, and F. Morel, “IL-22 inhibits epidermal differentiation and induces proinflammatory gene expression and migration of human keratinocytes,” Journal of Immunology, vol. 174, no. 6, pp. 3695–3702, 2005. View at: Publisher Site | Google Scholar
- K. Guilloteau, I. Paris, N. Pedretti et al., “Skin inflammation induced by the synergistic action of IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α recapitulates some features of psoriasis,” Journal of Immunology, vol. 184, no. 9, pp. 5263–5270, 2010. View at: Publisher Site | Google Scholar
- K. Wolk, H. S. Haugen, W. Xu et al., “IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not,” Journal of Molecular Medicine, vol. 87, no. 5, pp. 523–536, 2009. View at: Publisher Site | Google Scholar
- K. E. Nograles, L. C. Zaba, E. Guttman-Yassky et al., “Th17 cytokines interleukin (IL)-17 and IL-22 modulate distinct inflammatory and keratinocyte-response pathways,” British Journal of Dermatology, vol. 159, no. 5, pp. 1092–1102, 2008. View at: Publisher Site | Google Scholar
- S. M. Sa, P. A. Valdez, J. Wu et al., “The effects of IL-20 subfamily cytokines on reconstituted human epidermis suggest potential roles in cutaneous innate defense and pathogenic adaptive immunity in psoriasis,” The Journal of Immunology, vol. 178, pp. 2229–2240, 2007. View at: Google Scholar
- Y. Carrier, H.-L. Ma, H. E. Ramon et al., “Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis,” Journal of Investigative Dermatology, vol. 131, no. 12, pp. 2428–2437, 2011. View at: Publisher Site | Google Scholar
- S. Vigne, G. Palmer, C. Lamacchia et al., “IL-36R ligands are potent regulators of dendritic and T cells,” Blood, vol. 118, no. 22, pp. 5813–5823, 2011. View at: Publisher Site | Google Scholar
- H. Blumberg, H. Dinh, E. S. Trueblood et al., “Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation,” Journal of Experimental Medicine, vol. 204, no. 11, pp. 2603–2614, 2007. View at: Publisher Site | Google Scholar
- R. Basu, R. D. Hatton, and C. T. Weaver, “The Th17 family: flexibility follows function,” Immunological Reviews, vol. 252, no. 1, pp. 89–103, 2013. View at: Publisher Site | Google Scholar
- K. Hirota, J. H. Duarte, M. Veldhoen et al., “Fate mapping of IL-17-producing T cells in inflammatory responses,” Nature Immunology, vol. 12, no. 3, pp. 255–263, 2011. View at: Publisher Site | Google Scholar
- F. Ronchi, C. Basso, S. Preite et al., “Experimental priming of encephalitogenic Th1/Th17 cells requires pertussis toxin-driven IL-1β production by myeloid cells,” Nature Communications, vol. 7, article 11541, 2016. View at: Publisher Site | Google Scholar
- N. Komatsu, K. Okamoto, S. Sawa et al., “Pathogenic conversion of Foxp3 + T cells into TH17 cells in autoimmune arthritis,” Nature Medicine, vol. 20, no. 1, pp. 62–68, 2014. View at: Publisher Site | Google Scholar
- Y. Kochi, Y. Okada, A. Suzuki et al., “A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility,” Nature Genetics, vol. 42, no. 6, pp. 515–519, 2010. View at: Publisher Site | Google Scholar
- T. Kopp, E. Riedl, C. Bangert et al., “Clinical improvement in psoriasis with specific targeting of interleukin-23,” Nature, vol. 521, no. 7551, pp. 222–226, 2015. View at: Publisher Site | Google Scholar
- R. G. Langley, B. E. Elewski, M. Lebwohl et al., “Secukinumab in plaque psoriasis—results of two phase 3 trials,” The New England Journal of Medicine, vol. 371, no. 4, pp. 326–338, 2014. View at: Publisher Site | Google Scholar
- K. A. Papp, R. G. Langley, M. Lebwohl et al., “Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2),” The Lancet, vol. 371, no. 9625, pp. 1675–1684, 2008. View at: Publisher Site | Google Scholar
- C. L. Leonardi, A. B. Kimball, K. A. Papp et al., “Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1),” The Lancet, vol. 371, no. 9625, pp. 1665–1674, 2008. View at: Publisher Site | Google Scholar
- J. R. Huh, M. W. L. Leung, P. Huang et al., “Digoxin and its derivatives suppress T H 17 cell differentiation by antagonizing RORγt activity,” Nature, vol. 472, no. 7344, pp. 486–490, 2011. View at: Publisher Site | Google Scholar
- L. A. Solt, N. Kumar, P. Nuhant et al., “Suppression of TH 17 differentiation and autoimmunity by a synthetic ROR ligand,” Nature, vol. 472, no. 7344, pp. 491–494, 2011. View at: Publisher Site | Google Scholar
- T. Xu, X. Wang, B. Zhong, R. I. Nurieva, S. Ding, and C. Dong, “Ursolic acid suppresses interleukin-17 (IL-17) production by selectively antagonizing the function of RORγt protein,” Journal of Biological Chemistry, vol. 286, no. 26, pp. 22707–22710, 2011. View at: Publisher Site | Google Scholar
Copyright © 2017 Taku Kuwabara et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
13.54: Autoimmune Diseases - Biology
Prompted in part by the COVID-19 pandemic, the T.H. Chan School of Public Health at Harvard University and the Human Vaccines Project on Tuesday announced a joint effort to accelerate the development of new vaccines, diagnostics, and treatments with the help of artificial intelligence.
Called the Human Immunomics Initiative, the new project will bring together subject-matter experts in epidemiology, causal inference, immunology, and computational and systems biology in search of new, AI-assisted immunological models. According to the partner organizations, the Human Immunomics Initiative aims to take advantage of new insights in genomics, systems biology, and bioinformatics to develop insights into effective immunity in aging populations.
Those at least 60 years of age are considered to be at high risk for COVID-19 infection and mortality.
"The world's population is aging at unprecedented rates, significantly increasing the burden of noncommunicable diseases and vulnerability to infectious diseases, as evidenced by the current COVID-19 pandemic," Human Vaccines Project President and CEO Wayne Koff said in a statement. "The complexity of the human immune system has confounded efforts to prevent and control diseases in aging populations, and this collaboration will marry expansive data collection through clinical research with new technologies and cutting-edge science to catalyze new approaches to fighting major global diseases."
The partners said that the initiative will launch with a pilot phase looking at how immunity changes as people age, working with blood samples from thousands of people enrolled in epidemiological studies worldwide, and building models by combining unspecified new testing methods with AI and biological science.
Michelle Williams, dean of Harvard Chan, noted that the Human Vaccines Project has sought to change how researchers address diseases by decoding the human immunome. "The way we fight disease is broken. We launch into disease-specific battles without understanding the rules that affect our chances of success," she said.
"Successful vaccination requires four components: knowing the vaccine target, what kind of immune response you want, how to generate that response, and understanding responses in the people who you want to vaccinate," added Sarah Fortune, chair of the Department of Immunology and Infectious Diseases at Harvard Chan.
Steinman, R.M. & Mellman, I. Immunotherapy bewitched, bothered, and bewildered no more. Science 305, 197–200 (2004).
Lake, R.A. & van der Most, R.G. A better way for a cancer cell to die. N. Engl. J. Med. 354, 2503–2504 (2006).
Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer in spite of immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6, 715–727 (2006).
Zitvogel, L., Casares, N., Pequignot, M., Albert, M.L. & Kroemer, G. The immune response against dying tumor cells. Adv. Immunol. 84, 131–179 (2004).
Bellamy, C.O., Malcomson, R.D., Harrison, D.J. & Wyllie, A.H. Cell death in health and disease: the biology and regulation of apoptosis. Semin. Cancer Biol. 6, 3–16 (1995).
Thompson, C.B. Apoptosis in the pathogenesis and treatment of disease. Science 267, 1456–1462 (1995).
Igney, F.H. & Krammer, P.H. Death and anti-death: tumour resistance to apoptosis. Nat. Rev. Cancer 2, 277–288 (2002).
Steinman, R.M., Turley, S., Mellman, I. & Inaba, K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J. Exp. Med. 191, 411–416 (2000).
Liu, K. et al. Immune tolerance after delivery of dying cells to dendritic cells in situ. J. Exp. Med. 196, 1091–1097 (2002).
Kroemer, G. et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ. 12, 1463–1467 (2005).
Savill, J. & Fadok, V. Corpse clearance defines the meaning of cell death. Nature 407, 784–788 (2000).
Lauber, K., Blumenthal, S.G., Waibel, M. & Wesselborg, S. Clearance of apoptotic cells: getting rid of the corpses. Mol. Cell 14, 277–287 (2004).
Yoshida, H. et al. Phosphatidylserine-dependent engulfment by macrophages of nuclei from erythroid precursor cells. Nature 437, 754–758 (2005).
Gardai, S.J. et al. Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte. Cell 123, 321–334 (2005).
Henson, P.M. & Hume, D.A. Apoptotic cell removal in development and tissue homeostasis. Trends Immunol. 27, 244–250 (2006).
Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150 (2004).
Gaipl, U.S. et al. Inefficient clearance of dying cells and autoreactivity. Curr. Top. Microbiol. Immunol. 305, 161–176 (2006).
Vakkila, J. & Lotze, M.T. Inflammation and necrosis promote tumour growth. Nat. Rev. Immunol. 4, 641–648 (2004).
Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).
Blachere, N.E., Darnell, R.B. & Albert, M.L. Apoptotic cells deliver processed antigen to dendritic cells for cross-presentation. PLoS Biol. 3, e185 (2005).
Bedard, K., Szabo, E., Michalak, M. & Opas, M. Cellular functions of endoplasmic reticulum chaperones calreticulin, calnexin, and ERp57. Int. Rev. Cytol. 245, 91–121 (2005).
Ogden, C.A. et al. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells. J. Exp. Med. 194, 781–795 (2001).
Jung, S. et al. In vivo depletion of CD11c(+) dendritic cells abrogates priming of CD8(+) T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002).
Zhang, K. & Kaufman, R.J. Signaling the unfolded protein response from the endoplasmic reticulum. J. Biol. Chem. 279, 25935–25938 (2004).
Gupta, V., Ogawa, A.K., Du, X., Houk, K.N. & Armstrong, R.W. A model for binding of structurally diverse natural product inhibitors of protein phosphatases PP1 and PP2A. J. Med. Chem. 40, 3199–3206 (1997).
Boyce, M. et al. A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307, 935–939 (2005).
Gelebart, P., Opas, M. & Michalak, M. Calreticulin, a Ca 2+ -binding chaperone of the endoplasmic reticulum. Int. J. Biochem. Cell Biol. 37, 260–266 (2005).
Williams, D.B. Beyond lectins: the calnexin/calreticulin chaperone system of the endoplasmic reticulum. J. Cell Sci. 119, 615–623 (2006).
Kim, S.J., Park, K.M., Kim, N. & Yeom, Y.I. Doxorubicin prevents endoplasmic reticulum stress-induced apoptosis. Biochem. Biophys. Res. Commun. 339, 463–468 (2006).
Hsieh, C.J. et al. Enhancement of vaccinia vaccine potency by linkage of tumor antigen gene to gene encoding calreticulin. Vaccine 22, 3993–4001 (2004).
Cheng, W.F. et al. Sindbis virus replicon particles encoding calreticulin linked to a tumor antigen generate long-term tumor-specific immunity. Cancer Gene Ther. 13, 873–885 (2006).
Basu, S. & Srivastava, P.K. Calreticulin, a peptide-binding chaperone of the endoplasmic reticulum, elicits tumor- and peptide-specific immunity. J. Exp. Med. 189, 797–802 (1999).
Basu, S., Binder, R.J., Suto, R., Anderson, K.M. & Srivastava, P.K. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-kappa B pathway. Int. Immunol. 12, 1539–1546 (2000).
Zamzami, N. & Kroemer, G. Methods to measure membrane potential and permeability transition in the mitochondria during apoptosis. Methods Mol. Biol. 282, 103–116 (2004).
Culina, S., Lauvau, G., Gubler, B. & van Endert, P.M. Calreticulin promotes folding of functional human leukocyte antigen class I molecules in vitro. J. Biol. Chem. 279, 54210–54215 (2004).
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92 Results for Rheumatology near Newark, NJ
A rheumatologist specializes in diagnosing and treating arthritis and other rheumatic diseases. Rheumatic diseases are characterized by inflammation and loss of function of your joints, tendons, ligaments, bones or muscles. A rheumatologist is an internal medicine doctor specializing in the health needs of adults with rheumatic problems.
A rheumatologist typically:
Evaluates a patient&rsquos medical history and physical condition
Provides expertise in diagnosing complex diseases that tend to be vague in the early stages and change with time
Orders and interprets laboratory tests and imaging exams
Diagnoses and treats rheumatic conditions including certain autoimmune diseases, pain syndromes, arthritis, and other joint disorders
Prescribes medications and other therapies
Provides advice about appropriate levels of exercise and rest
Provides referrals to surgeons when needed
A rheumatologist may also be known as an arthritis doctor or RA doctor.
There are 92 specialists practicing Rheumatology in Newark, NJ with an overall average rating of 3.8 stars. There are 35 hospitals near Newark, NJ with affiliated Rheumatology specialists, including NYU Langone Health Tisch Hospital, Overlook Medical Center and Saint Barnabas Medical Center.
Frequently Asked Questions
How can I make a same-day appointment with a Rheumatology Specialist in Newark, NJ?
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Genetic predisposition in anti-LGI1 and anti-NMDA receptor encephalitis
Address correspondence to Dr Frank Leypoldt, Institute of Clinical Chemistry and Department of Neurology, University Hospital Schleswig-Holstein Kiel, Arnold-Heller-Straße 3, 24105 Kiel, Germany. E-mail: [email protected] Search for more papers by this author
Department of Neurology, Christian-Albrechts-University Kiel, Germany
Neuroimmunology section, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck, Germany
Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany and German Center for Neurodegenerative Diseases (DZNE) Berlin, Berlin, Germany
Department of Neurology, University Hospital Münster, Germany
Department of Neurology, University Hospital Münster, Germany
Department of Clinical Neuroimmunology, University of Munich, Germany
Department of Clinical Neuroimmunology, University of Munich, Germany
Department of Neurology, Charles University, Prague, Czech Republic
Department of Neurology, Ulm University, Germany
Institute of Neuroimmunology and Multiple Sclerosis (INIMS), University Medical Center Hamburg-Eppendorf, Germany
Department of Neurology, University Hospital Hannover, Germany
Department of Neurology, Medical Faculty, Heinrich Heine University Düsseldorf, Germany
Department of Neurology, Klinikum Osnabrück, Germany
Epilepsy Centre Bethel, Krankenhaus Mara, Bielefeld, Germany
Department of Neurology, Martha-Maria Hospital Halle, Germany
Department of Neurology, Neuroimmunological Section, University Hospital Rostock, Germany
Department of Neurology, Klinikum St. Georg, Wermsdorf, Germany
Department of Neurology, Carl-Thiem-Klinikum Cottbus, Germany
Department of Pediatric Neurology, Vestische Kinder- und Jugendklinik Datteln, University Witten/Herdecke, Germany
Department of Neurology, University of Leipzig, Germany
Department of Neurology, Asklepios Fachklinikum Teupitz, Germany
Institute of Epidemiology, Department of Neurology, Neuroimmunological Section, Christian-Albrechts-University Kiel, Germany
Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Germany
Department of Neurology, Christian-Albrechts-University Kiel, Germany
Neuroimmunology section, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck, Germany
Department of Neurology, University of Lübeck, Lübeck, Germany
Department of Neurology, Christian-Albrechts-University Kiel, Germany
Neuroimmunology section, Institute of Clinical Chemistry, University Hospital Schleswig-Holstein Kiel/Lübeck, Germany
Address correspondence to Dr Frank Leypoldt, Institute of Clinical Chemistry and Department of Neurology, University Hospital Schleswig-Holstein Kiel, Arnold-Heller-Straße 3, 24105 Kiel, Germany. E-mail: [email protected] Search for more papers by this author
We performed a genome-wide association study in 1,194 controls and 150 patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR, n = 96) or anti-leucine-rich glioma-inactivated1 (anti-LGI1, n = 54) autoimmune encephalitis. Anti-LGI1 encephalitis was highly associated with 27 single-nucleotide polymorphisms (SNPs) in the HLA-II region (leading SNP rs2858870 p = 1.22 × 10 −17 , OR = 13.66 [7.50–24.87]). Potential associations, below genome-wide significance, were found with rs72961463 close to the doublecortin-like kinase 2 gene (DCLK2) and rs62110161 in a cluster of zinc-finger genes. HLA allele imputation identified association of anti-LGI1 encephalitis with HLA-II haplotypes encompassing DRB1*07:01, DQA1*02:01 and DQB1*02:02 (p < 2.2 × 10 −16 ) and anti-NMDAR encephalitis with HLA-I allele B*07:02 (p = 0.039). No shared genetic risk factors between encephalitides were identified. Ann Neurol 201883:863–869
Additional supporting information may be found online in the Supporting Information section at the end of the article.
Supplementary Table 1: List GENERATE members and contributors
Supplementary Table 2: Summary of phenotypes and genotypes in anti-LGI1 encephalitis patients
Supplementary Table 3: Sample and marker exclusion
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.