Th17 cytokines and arthritis

Th17 cells are implicated in human autoimmune diseases, such as rheumatoid arthritis (RA), although it has not been established whether this persistent destructive arthritis is driven by Th1 and/or Th17 cells. Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis as has been shown in several experimental arthritis models. Importantly, recent data from first clinical trials with anti-IL-17A antibody treatment in psoriatic arthritis patients and RA patients looks promising. This review summarizes the findings about the role of Th17 cells in arthritis and discusses the impact of the different Th17 cytokines in the pathogenesis of this disease. However, further studies are needed to unravel the interplay between IL-17A and other Th17 cytokines such as IL-17F, IL-22, and IL-21 in the pathoimmunological process of this crippling disease, in particular, whether regulating Th17 cell activity or specific combinations of Th17 cytokines will have additional value compared to neutralizing IL-17A activity alone. Moreover, tumor necrosis factor-positive Th17 cells are discussed as potential dangerous cells in driving persistent arthritis in human early RA.     

Th9 cells and IL-9 in autoimmune disorders: Pathogenesis and therapeutic potentials

Naïve CD4⁺ T cells are pleiotropically divided into various T helper (Th) cell subsets, according to their pivotal roles in the regulation of immune responses. The differentiation of Th9 cells, an interleukin (IL)-9 producing subset, can be impacted by specific environmental cues, co-stimulation with transforming growth factor β (TGF-β) and IL-4, and other regulatory factors. Although IL-9 has been recognized as a classical Th2-related cytokine, recent studies have indicated that IL-9-producing cells contribute to a group of autoimmune disorders including systemic lupus erythematosus (SLE), multiple sclerosis (MS), inflammatory bowel diseases (IBD), rheumatoid arthritis (RA) and psoriasis. Studies of Th9 cells in autoimmune diseases, although in their infancy, are expected to be of growing interest in the study of potential mechanisms of cytokine regulatory pathways and autoimmune pathogenesis. Several in vitro and in vivo pre-clinical trials have been conducted to explore potential therapeutic strategies by targeting the IL-9 pathway. Specifically, anti-IL-9 monoclonal antibodies (mAbs) and IL-9 inhibitors may potentially be used for the clinical treatment of allergic diseases, autoimmune diseases or cancers. Here, we review recent research on Th9 cells and IL-9 pertaining to cell differentiation, biological characteristics and pivotal cellular inter-relationships implicated in the development of various diseases.     

Anticytokine therapy--new approach to the treatment of autoimmune and cytokine-disturbance diseases

We pioneered the theory (Nature, 1974) that hyperproduced interferons (cytokines) can bring autoimmune diseases (AD) and neutralizing these cytokines can be therapeutic. In 1975 we first performed successful anticytokine therapy using anti-IFN-alpha antibodies in patients with rheumatoid arthritis (RA). In 1989 we proposed also treating AD including AIDS by removing TNF-alpha and IFN-alpha. Our theory has been widely confirmed: injections of IFN-alpha and -gamma can exacerbate AD, while antibodies to IFN-alpha and -gamma and TNF-alpha can be therapeutic. Anti-IFN-gamma may be a universal treatment for Th1 AD. We had good results using anti-IFN-gamma to treat RA, multiple sclerosis (MS), transplant rejection, alopecia areata, vitiligo, psoriatic arthritis, psoriasis and others. For Th1/Th2 diseases, antagonists to cortisol could prevent the Th1-Th2 shift and allow treatment as a Th1 disease. Anticytokine therapy can also be therapeutic in many neuropsychiatric diseases. Every disturbance of homeostasis may lead to cytokine disturbance. IL-10 may restore homeostasis by inhibiting the production of certain Th1 cytokines and could be used to treat some embryonic disturbances and AD including MS.     

The Th17 Pathway as a Therapeutic Target in Rheumatoid Arthritis and Other Autoimmune and Inflammatory Disorders

Production of the pro-inflammatory cytokine interleukin (IL)-17 by Th17 cells and other cells of the immune system protects the host against bacterial and fungal infections, but also promotes the development of rheumatoid arthritis (RA) and other autoimmune and inflammatory disorders. Several biologicals targeting IL-17, the IL-17 receptor, or IL-17-related pathways are being tested in clinical trials, and might ultimately lead to better treatment for patients suffering from various IL-17-mediated disorders. In this review, we provide a clear overview of current knowledge on Th17 cell regulation and the main Th17 effector cytokines in relation to IL-17-mediated conditions, as well as on recent IL-17-related drug developments. We demonstrate that targeting the Th17 pathway is a promising treatment for rheumatoid arthritis and various other autoimmune and inflammatory diseases. However, improvements in technical developments assisting in the identification of patients suffering from IL-17-driven disease are needed to enable the application of tailor-made, personalized medicine.     

New Insights into the Management of Patients with Autoimmune Diseases or Inflammatory Disorders During Pregnancy

The treatment of autoimmune diseases remains a serious problem. Current therapies can lead to adverse effects in patients. One of the most vulnerable patient groups is pregnant women. It has been reported that different autoimmune diseases have a certain trend during pregnancy and after delivery which could be explained by maternal immune responses. Better management of pregnant women with autoimmune diseases or inflammatory disorders could be achieved by linking such alterations in immune responses and governed immune responses in different autoimmune disorders while considering various reports of autoimmune conditions during pregnancy. This study considers changing the T helper cells (Th1) and Th2 balance and suggests some new approaches for the better management of autoimmune diseases in pregnant women based on immune responses. Additionally, the possible role of Th17, alterations in some selected autoimmune diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), psoriasis, systemic lupus erythematosus (SLE), atopic dermatitis (AD), asthma and pemphigus during pregnancy, and possible associated mechanisms are discussed.     

IL-17 producing T cells in mouse models of multiple sclerosis and rheumatoid arthritis

Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA) are amongst the most common autoimmune diseases in the northern hemisphere. There is mounting evidence that in both afflictions, not only environmental and genetic factors influence disease, but cellular components such as autoreactive T cells also contribute to pathology. Animal models are key in the study and subsequent therapeutic development for human autoimmune diseases. As patient material is often difficult to obtain and in some cases--as in MS, where the central nervous system (CNS) is concerned--even not accessible, animal models provide a multifaceted tool to explore disease-underlying mechanisms. The pro-inflammatory T cell cytokine IL-17 has recently moved to center stage due to its crucial role in autoimmune diseases including MS and RA. A plethora of studies in animal models has sustained the relevance of this cytokine pathway for the development of autoimmunity and shed light on its cellular sources and patho-mechanisms. This review addresses the role of IL-17 producing T lymphocytes, in particular CD4(+) and γδ T cells, in three commonly used mouse models for MS and RA, namely experimental autoimmune encephalomyelitis (EAE), collagen-induced arthritis (CIA), and antigen-induced arthritis (AIA). Comparing and combining knowledge gained from different animal models will broaden our understanding of the IL-17 biology and facilitate the translation to the human diseases.     

Role of IL-17 in Psoriasis and Psoriatic Arthritis

The role of T cell subpopulations in human disease is in a transition phase due to continuous discovery of new subsets of T cell, one of which is Th17, characterized by the production of signature cytokine IL-17. In the last couple of years, many articles are coming out on the role of Th17 and its signature cytokine IL-17 in different autoimmune diseases like rheumatoid arthritis, psoriasis, psoriatic arthritis (PsA), SLE and multiple sclerosis. Psoriasis and PsA are immune-mediated diseases, affecting the skin and joints, respectively. Initially, it was thought that psoriasis and PsA were Th1-mediated diseases; however, studies in knockout animal models (IL-17 knockout mice) as well as human experimental data indicate that Th17 and its signature cytokine IL-17 have a critical role in the pathogenesis of psoriatic disease. Th17 cells have been identified from the dermal extracts of psoriatic lesions. Subsequently, our research group has substantiated this observation that Th17 cells are enriched in the papillary dermis of psoriatic plaques and in freshly isolated effector T lymphocytes from the synovial fluid of PsA patients, and we have reported that the majority of these CD4?+?IL-17+ T cells are of memory phenotype (CD4RO⁺CD45RA^?CD11a⁺). Recent reports also suggest that the synovial tissue in psoriatic arthritis is enriched with IL-17R, and its most well recognized receptor IL-17RA is functionally active in psoriatic arthritis. In this review article, we have discussed the role of IL-17 in psoriatic disease and have narrated about the novel IL17/IL-17R antibodies currently in preparation for its therapeutic uses in autoimmune diseases.     

Both Th1- and Th2-derived cytokines in serum are elevated in Graves' ophthalmopathy

Increased serum cytokine levels have been reported in patients with autoimmune thyroid disease, but less is known about their levels in patients with Graves' ophthalmopathy (GO). It is not known whether GO is a cell-mediated or humoral autoimmune disease. We investigated whether serum cytokines are elevated in GO patients and whether the cytokines were Th1- or Th2-derived. In addition, elevated cytokines might reflect the activity of GO, and thus we investigated whether cytokine levels could predict the clinical response to orbital radiotherapy. We studied 62 consecutive patients with moderately severe untreated GO and 62 healthy controls, matched for sex, age and smoking habits. Serum concentrations of IL-1RA, sIL-2R, IL-6, sIL-6R, tumour necrosis factor-alpha (TNF-alpha) RI and II and sCD30 were measured using highly sensitive ELISAs, in the patients before and 3 and 6 months after radiotherapy. All patients were euthyroid, with anti-thyroid drugs, before and during the entire study period. All baseline cytokine and cytokine receptor levels were significantly elevated in GO patients compared with healthy controls, except for IL-1RA. The levels did not correlate with parameters of the thyroid disease, nor with the duration, activity or severity of GO. However, backward logistic regression analysis showed that IL-6, sCD30 and TNFalphaRI were able to predict a beneficial response to orbital radiotherapy. We therefore conclude that both Th1- and Th2-derived cytokines are elevated in GO patients compared with its controls. IL-6, sCD30 and TNFalphaRI had some value for predicting therapeutic outcome to orbital irradiation, and may thus reflect active eye disease.     

Decreased CD200R expression on monocyte-derived macrophages correlates with Th17/Treg imbalance and disease activity in rheumatoid arthritis patients

Objectives

CD200 is expressed on various cell types, including T cells, while the CD200 receptor (CD200R) is expressed on myeloid cells such as monocytes-derived macrophages (MDMs). The CD200–CD200R interaction has been shown to play an important role in the prevention of autoimmune disease. Thus, we hypothesized that CD200/CD200R1 is involved in the pathogenesis of rheumatoid arthritis (RA).

Methods

In total, 35 RA patients and 17 healthy controls (HCs) were enrolled in this study. CD200/CD200R1 expression and Th17/Treg were examined by flow cytometry. Serum levels of interleukin (IL)-2, interferon-γ (IFN-γ), IL-4 and IL-10 were detected by ELISA. Disease activity was evaluated according to the C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR) and 28-joint disease activity score (DAS28) scores.

Results

Compared with HCs, RA patients exhibited a significantly decreased level of CD200R1 on MDMs. CD200R1 expression correlated negatively with DAS28, ESR, and CRP levels. This abnormal expression was associated with Th17/Treg imbalance in the active RA patients. However, expression of CD200R1 was not correlated with Th1 (IL-2, IFN-γ) or Th2 (IL-4, IL-10) cytokine responses.

Conclusion

In this study, we demonstrate a significant correlation between CD200R1⁺ cells and disease severity in RA patients, thus indicating the relevance of the CD200/CD200R1 signaling pathway's potential involvement in the pathogenesis of RA.     

Autoimmune diseases and rehabilitation

This review gives an overview of the rehabilitation of autoimmune diseases. After general remarks on rehabilitation, the effects of acute and chronic exercises on inflammatory markers are summarized. Most of the available literature deals with rheumatoid arthritis (RA) and multiple sclerosis (MS), and therefore, rehabilitation of these diseases is described in more detail. Exercise is the main component in the rehabilitation of patients with RA and aims at increasing physical capacity, muscle strength, aerobic endurance, cardiovascular fitness and functional abilities, and helps to prevent secondary deconditioning due to reduced activity levels. Since MS causes a wide range of symptoms, the rehabilitation of these patients requires a multidisciplinary approach and encompasses physiotherapy, exercise therapy, hippotherapy, cognitive rehabilitation, psychological therapy, strategies to improve fatigue and coping programs. The ultimate goal of rehabilitation is to enable patients with chronic conditions to reach and maintain their optimal physical, sensory, intellectual, psychological and social functional levels, and to attain independence and self-determination as far as possible.     

Th22, but not Th17 Might be a Good Index to Predict the Tissue Involvement of Systemic Lupus Erythematosus

Purpose

T-helper (Th) cells abnormalities are considered to be associated with the pathogenesis of Systemic lupus erythematosus (SLE). Recently, The Th22 cells have been identified and implicated in the pathogenesis of autoimmune diseases such as Rheumatoid arthritis (RA), although therir role in Systemic lupus erythematosus (SLE) remains unclear. The present study intends to investigate their roles in SLE.

Methods

Clinical data were collected in 65 SLE patients and 30 healthy controls. The patients were divided into active and inactive groups. CD4⁺IFN-γ^?IL-17^?IL-22⁺Tcells (Th22 cells),CD4⁺ IFN-γ^?IL-22^?IL-17⁺T cells (Th17 cells),and CD4⁺ IFN-γ⁺ (Th1 cells) were assayed by flow cytometry. Serum interleukin-22 (IL-22) and IL-17 levels were measured by enzyme-linked immunosorbent assay.

Results

The main observation focused on increased Th22 cells in patients with sole lupus skin disease and decreased Th22 cells in patients with sole lupus nephritis. Likewise, concentrations of serum IL-22 were increased in patients with sole lupus skin disease, and decreased in patients with sole lupus nephritis. Additionally, there was a positive correlation between the percentage of Th22 cells and IL-22 production. The percentage of Th17 cells or concentration of serum IL-17 correlated positively with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

Conclusion

Th22 seems to be a more significant index to predict the tissue involvement of SLE than Th17, although Th17 may play a role in the activity of SLE.     

Multi-drug resistance in the treatments of autoimmune diseases]

Although corticosteroids and immunosuppressants are widely used for the treatments of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), we often experience patients who are resistant to these treatments. P-glycoprotein (P-gp) of membrane transporters, a product of the multiple drug resistance (MDR)-1 gene, plays a pivotal role in the acquisition of drug resistance. However, the relevance of MDR-1 and P-gp to resting and activated lymphocyte, major targets of the treatments in autoimmune diseases, remains unclear. We found that peripheral lymphocytes in patients with SLE and RA express P-gp on the surface and its expression is highly correlated with disease activity. P-gp on lymphocytes is induced by activation with cytokines such as IL-2, IL-4 and TNF-alpha, resulting in active efflux of corticosteroids from cytoplasm of lymphocytes, which mechanisms could lead to drug-resistance and high disease activity. However, the addition of P-gp antagonists such as ciclosporin A and inhibitors of P-gp synthesis successfully reduce efflux of corticosteroids from lymphocytes in vitro and these results imply that P-gp antagonists and P-gp synthesis inhibitors could work in order to overcome drug-resistance in vivo. Therefore, we propose that measurement of P-gp on lymphocytes is useful marker to indicate drug resistance and requirement of antagonists and/or intensive treatments to overcome drug resistance in active SLE and RA patients.     

Elevated Th22 Cells Correlated with Th17 Cells in Patients with Rheumatoid Arthritis

Background

T-helper (Th) 22 and Th17 cells are implicated in the pathogenesis of autoimmune diseases. The roles of Th22 cells in the pathophysiology of rheumatoid arthritis (RA) remain unsettled.

Materials and Methods

CD4⁺IFN??^?IL17^?IL-22⁺ T cells (Th22 cells), CD4⁺IFN??^?IL-22^?IL17⁺ T cells (pure Th17 cells), CD4⁺IL17⁺ T cells (Th17 cells), and CD4⁺IFN??⁺ T cells (Th1 cells) in RA, osteoarthritis patients, and healthy controls were examined by flow cytometry. Plasma IL-22 and IL-17 levels were examined by enzyme-linked immunosorbent assay.

Results

Th22 cells, pure Th17 cells, Th17 cells, and interleukin-22 were significantly elevated in RA patients compared with osteoarthritis and healthy controls, but there were no significant differences regarding Th1 cells and interleukin-17. Th22 cells showed a positive correlation with interleukin-22 as well as pure Th17 cells or Th17 cells in RA patients. Additionally, the percentages of Th22 cells, pure Th17 cells as well as Th17 cells correlated positively with both C-reactive protein levels and 28-joints disease activity score.

Conclusion

Together, our results indicated a possible role of Th22 pure Th17 cells and Th17 cells in RA, and blockade of the interleukin-22 may be a reasonable therapeutic strategy for RA.     

Intracellular Th1/Th2 balance of pulmonary CD4(+) T cells in patients with active interstitial pneumonia evaluated by serum KL-6

The balance between CD4⁺ T helper (Th1) lymphocytes producing interferon-γ or Interleukin-4 (Th2) in the lungs may vary among diseases and during the progression of interstitial pneumonia (IP). Both idiopathic pulmonary fibrosis (IPF) and collagen vascular diseases (CVD) are associated with IP, but the clinical course and the response to treatment are different. Since Th1 or Th2 modulating drugs have been proven to alter the lymphocyte balance in vitro, it is important to elucidate the Th1/Th2 profile in patients with active IP. Bronchoalveolar lavage (BAL) was performed in patients who had IPF (n = 12) or CVD (n = 12) with IP, as well as in patients who had bronchoectasis and bronchopneumonia (n = 12). The CVD patients had rheumatoid arthritis (n = 6), Sjogren's syndrome (n = 2), dermatomyositis (n = 1), progressive systemic sclerosis (n = 2), and CREST syndrome (n = 1) as the underlying diseases. IP activity was evaluated by measuring serum KL-6, which is a clinically useful indicator for IP. The Th1/ Th2 balance and the CD4⁺/CD8⁺ ratio were determined for lymphocytes obtained from BAL by flow cytometric analysis. In IPF patients, the CD4⁺/CD8⁺ ratio was lower than in CVD patients. IPF patients showed Th2 dominance and CVD patients showed Th1 dominance when IP was active as evaluated by the serum KL-6 level. These data indicated that the Th1/Th2 balance of CD4⁺ T cells in the BAL differs between active IPF and CVD, even though KL-6 is elevated in both diseases. Therefore, the Th1/Th2 profile should be investigated to determine the use of Th1/Th2 modulator therapy for active IP with elevation of KL-6.     

类风湿性关节炎与自身反应性B细胞

类风湿性关节炎(Rheumatoid Arthritis,RA)是一类以人体肢端关节滑膜中炎症细胞浸润为主要表现的自身免疫性疾病,其病因至今尚未真正明确.从免疫学角度研究发现:除了免疫复合物(炎性沉淀物)在关节囊液中起着一定的作用外,其患者体内的自身抗体与RA存在着密切关联.尽管目前仍有较为明确的证据表明RA是以T细胞--特别是Th1介导为主:这是由于依赖于胶原诱导关节炎(CIA,Collagen-induced arthritis)小鼠模型研究所得的结论.然而,新近的实验研究和临床免疫干预的进展使人们重新认识到B细胞是如何受自身抗原的诱导、激活、增殖和分泌自身抗体导致了RA发病以及这些自身抗体所累及的患者临床病理变化的本质,无疑将类风湿性关节炎与自身反应性B细胞的关联性重新提到一新的重要地位.毫无疑问:患者体内自身反应性B细胞和其产生的自身抗体在RA的发病中起到关键作用.患者关节滑液中浸润着高表达IL-13受体的B细胞,它们所分泌的一系列细胞因子发挥着特殊作用.值得特别注意的是IL-13可以作用于B细胞(诱导B细胞高表达CD23,促进幼稚B细胞的增殖和分化直至这种自身反应性B细胞克隆的异常扩增),越发突显自身反应性B细胞协同自身反应性T细胞介导RA发病的重要性,同时人们将更加关注其独特的免疫病理学机制对RA的诊断、进展和疾病预后的重要意义.本文将着重综述和讨论类风湿性关节炎与自身反应性B细胞的关联性的最新进展,旨在重新评估自身反应性B细胞和其分泌的自身抗体,包括一些细胞因子特别是IL-13介导的免疫失衡在类风湿性关节炎中的重要作用.     

Production of IL-16 correlates with CD4+ Th1 inflammation and phosphorylation of axonal cytoskeleton in multiple sclerosis lesions

Background  

Multiple sclerosis (MS) is a central nervous system-specific autoimmune, demyelinating and neurodegenerative disease. Infiltration of lesions by autoaggressive, myelin-specific CD4+Th1 cells correlates with clinical manifestations of disease. The cytokine IL-16 is a CD4+ T cell-specific chemoattractant that is biased towards CD4+ Th1 cells. IL-16 precursor is constitutively expressed in lymphocytes and during CD4+ T cell activation; active caspase-3 cleaves and releases C-terminal bioactive IL-16. Previously, we used an animal model of MS to demonstrate an important role for IL-16 in regulation of autoimmune inflammation and subsequent axonal damage. This role of IL-16 in MS is largely unexplored. Here we examine the regulation of IL-16 in relation to CD4+ Th1 infiltration and inflammation-related changes of axonal cytoskeleton in MS lesions.     

Interleukin-21 in autoimmune and inflammatory skin diseases

Studies on the role of interleukins (ILs) in autoimmune and inflammatory diseases allow for the better understanding of pathologic mechanisms of disease and reshaping of treatment modalities. The development of monoclonal antibodies targeting specific ILs or IL signaling pathways (i.e., anti-IL-17/IL-23 in psoriasis or anti-IL-4/IL-13 in atopic dermatitis) is the shining example of therapeutic interventions in research. IL-21, belonging to the group of ɣc-cytokines (IL-2, IL-4, IL-7, IL-9, and IL-15), is gaining attention for its pleiotropic role in several types of immune cells as activator of various inflammatory pathways. In both health and disease, IL-21 sustains T- and B-cell activity. Together with IL-6, IL-21 helps to generate Th17 cells, promotes CXCR5 expression in T cells, and their maturation into follicular T helper cells. In B cells, IL-21 sustains their proliferation and maturation into plasma cells and promotes class switching and antigen-specific antibody production. Due to these characteristics, IL-21 is a main factor in numerous immunologic disorders, such as rheumatoid arthritis and MS. Studies in preclinical skin disease models and on human skin strongly suggest that IL-21 is crucially involved in inflammatory and autoimmune cutaneous disorders. Here, we summarize the current knowledge of IL-21 in well-known skin diseases.