Role of IL-22– and TNF-α–Producing Th22 Cells in Uveitis Patients with Behçet’s Disease

Abstract

Behçet’s disease is a systemic inflammatory disorder with recurrent episodes of oral ulceration, skin lesions, genital ulceration, and intraocular inflammation (uveitis). The intraocular inflammation is strictly associated with Th effector cells. IL-22 is a member of the IL-10 cytokine family that is involved in inflammatory processes. Recently, Th22 cells were identified as a Th cell population that produces IL-22 and TNF-α and are distinct from Th1, Th2, and Th17 cells. In this study, we established Th22-type T cell clones from ocular samples taken from Behçet’s disease patients with active uveitis. These clones produced large amounts of IL-22 and TNF-α but not the Th1 cytokine IFN-γ and the Th17 cytokine IL-17. CD4+ T cells from the peripheral blood of Behçet’s disease patients differentiated into Th22 cells in the presence of IL-6 and TNF-α in vitro. The polarized Th22 cell lines produced large amounts of IL-22, and the polarized Th1 and Th17 cells also produced IL-22. In the presence of anti–TNF-α– and anti–IL-6–blocking Abs, Behçet’s disease Th22-type T cells failed to produce IL-22. In addition, infliximab-pretreated Th22 cells and Th22-type ocular T cells produced less IL-22 and TNF-α. Moreover, IL-22–producing T cells were isolated from mice with experimental autoimmune uveitis, an animal model of Behçet’s disease, and the intraocular T cells from uveitis models produced large amounts of IL-22 in the presence of retinal Ags. Our results suggest that inflammatory cytokines IL-22 and TNF-α may play a key role in the ocular immune response in Behçet’s disease.

Yeni Tanımlanmış Bir T Hücre Alt Tipi: Th22 ve Cilt Hastalıkları

“…Behçet hastalığında aktif üveiti olan hastalarda oküler örnekler alınmış ve bu örneklerde yüksek miktarda İL-22 ve TNF-α olduğu saptanmış, ancak Th1 sitokini İFN-γ ve Th17 sitokini İL-17 normal olarak bulunmuş. Hastaların periferik kan örneklerinde ise in vitro olarak İL-6 ve TNF-α varlığında CD4 T hücrelerinin Th22 hücrelerine dönüştüğü görülmüş (17). Bu çalışmanın sonuçlarına göre, İL-22 ve TNF-α'nın Behçet hastalarında oküler immün cevapta bu sitokinlerin önemli rolü olduğu düşünülmüştür.…”

Increased differentiation of Th22 cells in Hashimoto^|^rsquo;s thyroiditis

“…The Th22 cell line primarily secretes IL-22 and TNF-α and expresses CC chemokine receptor (CCR) 4, CCR6, and CCR10. Th22 cell develops along a pathway that is distinct from that of the Th1, Th2, or Th17 differentiation pathways [17,19]. To induce Th22 differentiation, IL-6 is a major effector, while it can also be promoted by TNF-α in the presence of IL-6.…”

“…It was originally reported that Th22 cells were important in the pathogenesis of chronic inflammatory skin diseases [20,21]. Th22 cells have also been shown to contribute to numerous autoimmune diseases such as atopic dermatitis [22], Behcet's disease [19], systemic lupus erythematosus [23], rheumatoid arthritis [24], immune thrombocytopenia [25], systemic sclerosis [26], and others. Recently, it was reported that Th22 cells were elevated at the onset of GD [27] and in newly diagnosed HT patients [28].…”

“…It has been reported that Th22 cells develop along a pathway that is distinct from that of the Th1, Th2, or Th17 cells differentiation pathways [17,19]. For the present assay, freshly isolated PBMCs were cultured in the presence of anti-CD3, anti-CD28, anti-IFN-γ, and anti-IL-4 antibodies, and recombinant IL-2, IL-6, and TNF-α for Th22 cell polarization.…”

“…For the polarization of Th22 cells, PBMCs from subjects were cultured on 24-well plates pre-coated with 4 μg/mL anti-hCD3 in the presence of 1 μg/mL anti-hCD28, 10 μg/mL anti-hIFN-γ, 10 μg/mL antihIL-4, and recombinant human proteins, such as 10 ng/mL IL-2, 30 ng/mL IL-6 and 60 ng/mL TNF-α, as previous described [17,19]. After 6 days of culture, 50 ng/mL PMA, 1 μg/mL ionomycin, and 2 μL/mL…”