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Although atopic dermatitis (AD) is primarily a Th2-driven disease, it shows high heterogeneity with additional variable contributions of the Th22, Th17, and Th1 pathways, depending on the subtype of the disease. Expanding knowledge and understanding of AD pathogenesis has promoted the development of numerous novel therapeutics that target cytokines and their signaling molecules, representatively, Janus kinases, involved in the underlying immune pathways, resulting in therapeutic success and failure. The first FDA approval was for the targeted biologic dupilumab. Although this proved the therapeutic relevance of targeting Th2 cytokines in moderate-to-severe forms of AD, it did not treat all patients, necessitating additional targeted therapeutics that modulate other cytokine pathways to resolve AD in all subtypes. Three more recently FDA-approved targeted therapeutics and several others that have been developed represent different targeted approaches directed to the Th2, Th22, Th17, or Th1 pathways. This review summarizes the main features and clinical outcomes of various approaches targeting cytokines and signaling molecules in these different pathways in view of both successful and failed cases, with a discussion of their therapeutic implications. In future, AD should be treated with more specific treatments reflecting the disease heterogeneity, but the current development of targeted therapeutics has faced some challenges in this context, which is also discussed. [ABSTRACT FROM AUTHOR]

T helper cell 22 are abundant in Hepatitis B Virus-related hepatocellular carcinoma tissue, and the main cytokine interleukin 22 produced by Th22 cells is closely related to the initiation and development of HCC. Understanding the role of Th22/IL-22 in the progression of HBV-related HCC will facilitate new therapeutic development. Th22 cells were isolated from peripheral blood of healthy donors and co-cultured with HBV positive HepG2.2.15 cells. IL-22 secretion and HepG2.2.15 cell proliferation and apoptosis were monitored. Expressions of p-STAT3, Cyclin D1, Bcl-2, and cleaved caspase 3 were detected by Western blot analysis. Th22 cells significantly promoted the proliferation and inhibited the apoptosis of HepG2.2.15 cells; up-regulated expression of p-STAT3, Cyclin D1 and Bcl-2, and down-regulated cleaved caspase 3 in HepG2.2.15 cells. These effects were significantly attenuated when IL-22 and STAT3 was knockdown in Th22 and HepG2.2.15 cells, respectively. Our data suggests that HBV induces host Th22 cells to overexpress IL-22, which in turn triggers over-activation of STAT3 and its downstream signaling proteins to promote HCC progression. [ABSTRACT FROM AUTHOR]

Helicobacter pylori (H. pylori) has been shown to be one of the leading causes of peptic ulcer diseases (PUDs) and gastritis. T helper-22 (Th22) cells and its most important cytokine, interleukin-22 (IL-22) are importantly active in inflammation and inflammatory tissues. Since inflammation is one of the main attributes of infection caused by H. pylori and resulting complications (gastritis and gastrointestinal ulcer), this study was designed to evaluate the Th22 cells count and the IL-22 protein expression in people suffering from PUD and gastritis. The present study was conducted on 55 patients with gastritis, 47 patients with PUD and 48 uninfected subjects. After preparation of section and extraction of protein from antral biopsies, immunohistochemistry and western blot methods were used to evaluate the Th22 cells and IL-22 protein expression level, respectively. According to findings, the Th22 cells count and the IL-22 protein expression level in the infected subjects were siginficantly more than in the uninfected subjects. It should be noted that the Th22 cells count and the IL-22 protein expression level in the infected subjects with PUD were significantly greater than those in the infected subjects with gastritis. In addition, the Th22 cells count had positive correlation with the density of H. pylori, chronic inflammation score and acute inflammatory score in the infected subjects with PUD. The Th22 cells count had positive correlation with the Th17 cells count and inverse correlation with the Treg cells count in the infected subjects with PUD and gastritis. Our data demonstrated that abnormal hyper-activation of Th22 cells as well as its correlation with the Th17 cells during infection caused by H. pylori might damage tissues through immunopathological responses. [ABSTRACT FROM AUTHOR]

Alopecia areata (AA) is a common form of non-scarring hair loss. The pathogenesis of AA is believed to involve multiple inflammatory cytokines, including possibly IL-17A. To assess the efficacy and safety of the IL-17A antagonist secukinumab in AA, we conducted a double-blinded, randomized prospective pilot study in which 11 subjects were treated with either secukinumab (n = 7) or placebo (n = 4) subcutaneously at weeks 0, 1, 2, 3, 4 and every 4 weeks thereafter until (inclusive of) week 20. The primary endpoint for the study was the percentage of patients achieving SALT50 at 24 weeks. A total of three subjects out of 11 completed the study through the primary endpoint, and therefore, we used the last observation carried forward method to analyze the missing data. At the primary endpoint or last completed observation, 0% (0/7) of the secukinumab-treated subjects achieved a 50% reduction in SALT score (SALT50), and likewise, 0% (0/4) of the placebo-treated subjects achieved SALT50. In the secukinumab group, one (14.3%) subject had some hair regrowth, one (14.3%) subject had worsening hair loss, and five (71.4%) subjects had no change in response to treatment. No adverse events attributable to the study drug were observed. The lack of a treatment response to most of our treated patients suggests that the TH17/IL-17 axis likely has no pathogenic role in AA and an alternative therapeutic approach should be considered for this disease. However, due to the low statistical power of this study, future studies may be required to corroborate these findings. [ABSTRACT FROM AUTHOR]

Background: Hovhannisyan et al. first showed evidence of plasticity between Treg and Th17 in the inflamed intestine of Crohn's disease (CD) patients. Our previous report suggests that the inflammatory cytokine milieu generates IL-17 Foxp3 CD4 T lymphocytes which is a crossover population converting Treg subset to Th17 in the peripheral blood of IBD patients. This is considered as an evidence of Treg/Th17 plasticity. Aim: The aim of this study was to characterize a variety of helper T cell crossover population, not limited to IL-17 Foxp3 CD4 T lymphocytes, in the lamina propria (LP) of IBD patients. Methods: Fresh colonoscopic biopsies were obtained from patients with CD ( n = 50) and ulcerative colitis (UC, n = 32) and from healthy controls (HC, n = 25). LP mononuclear cells were assessed for intracellular cytokines and transcription factors such as IFNγ, IL-13, IL-17, IL-22, T-bet, Gata-3, RORγt, and Foxp3 using multicolor flow cytometry to detect subsets of LP CD4 T lymphocytes. Results: Patients with IBD demonstrated increased crossover populations in IL-17 Foxp3, T-bet Foxp3, Gata3 Foxp3, RORγt Foxp3 populations compared to HC. There was an inverse correlation of Harvey-Bradshaw index with Gata3 Foxp3 population in CD patients, while IL-13 Foxp3 population was directly correlated with Mayo clinical scores in UC patients. Furthermore, total IL-22 expressing cells as well as Th22 and IL-22 Th1 populations were decreased in UC compared to CD and HC. Conclusion: IBD patients exhibit the increased crossover populations in LP Treg cells toward Th2 and Th17 compared to HC. The prevalence of Treg/Th2 crossover populations is associated with clinical disease score of IBD. [ABSTRACT FROM AUTHOR]

Th17, Th22 and Th9 are recently discovered effector populations that may contribute to the pathogenesis of autoimmune and inflammatory diseases. The presented study aimed to investigate the link between Th22 and Th9 subsets in type 1 diabetes, as this disease involves different subsets of CD4+ T lymphocytes. The study groups consisted of 23 patients with type 1 diabetes and 11 healthy individuals. All subjects had CD4+IL-22 Th22 and CD4+IL-9 Th9 lymphocytes investigated by flow cytometry. In addition, the plasma concentrations of IL-22 as well as IL-9 were analyzed. Our study demonstrated that Th9 and Th22 cell counts as well as their plasma cytokines were upregulated in patients with type 1 and correlated with HbA1c and CRP values. Taking these all into account, one can conclude that Th22 and Th9 lymphocyte activities may contribute to chronic, low-level inflammation that is considered an integral part of type 1 diabetes. [ABSTRACT FROM AUTHOR]

Interleukin (IL)-22, a member of the IL-10 family, is a cytokine secreted by several types of immune cells including IL-22CD4 T cells (Th22) and IL-22 expressing innate leukocytes (ILC22). Recent studies have demonstrated that IL-22 is a key component in mucosal barrier defense, tissue repair, epithelial cell survival, and proliferation. Furthermore, accumulating evidence has defined both protective and pathogenic properties of IL-22 in a number of conditions including autoimmune disease, infection, and malignancy. In this review, we summarize the expression and signaling pathway and functional characteristics of the IL-22 and IL-22 receptor axis in physiological and pathological scenarios and discuss the potential to target IL-22 signaling to treat human diseases. [ABSTRACT FROM AUTHOR]

T helper cell 22 (Th22) is a new subset of T cells clearly separate from Th17 and other known T cell subsets with distinct gene expression and function. With the CCR6 + CCR4 + CCR10 + phenotype and aryl hydrocarbon receptor as the key transcription factor, Th22 subsets produce cytokines such as IL-22, whose function depends on the activation of signal transduction and activators of transcription 3. IL-22 was up-regulated in Rheumatoid arthritis, Crohn's disease, Psoriasis, and atopic dermatitis patients whereas it was down-regulated in the serum of patients with sarcoidosis and systemic lupus erythematosus. Furthermore, it has been demonstrated that IL-22 may have promise as a potential therapeutic for chronic inflammatory diseases, and treatment with recombinant cytokine or gene therapy delivery of IL-22 may alleviate tissue destruction during inflammatory responses. In summary, Th22 cell plays an important and complicated role in inflammatory and autoimmune disease. [ABSTRACT FROM AUTHOR]