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CD4 T-Cell Dysregulation in Psoriatic Arthritis Reveals a Regulatory Role for IL-22.

ABSTRACT: Dysregulation of interleukin-22 (IL-22) has been associated with autoimmune diseases but divergent effects upon inflammation have hampered efforts to define its contribution to pathogenesis. Here, we examined the role of IL-22 in patients with psoriatic arthritis (PsA). In the peripheral blood of PsA patients, there was a decrease in IL-22⁺CD4⁺ T cells compared with healthy controls resulting in a heightened CD4⁺ IFN?⁺/IL-22⁺ ratio accompanied by diminished CCR6 expression. IL-22 expressing cells were depleted primarily from the central memory CD4 T-cell subset in PsA patients. Paradoxically IL-22 and particularly interferon-gamma (IFN?) production were elevated within a CD4⁺ T-cell subset with phenotypic markers characteristic of naïve T cells (CD3⁺CD4⁺CD27⁺CD45RA⁺CCR7⁺CD95^-IL-2R?^-) from PsA patients with the highest IFN?⁺/IL-22⁺ ratio of all the CD4 subsets. These unconventional "naïve" CD4⁺ T cells from PsA patients displayed some phenotypic and functional characteristics of memory cells including a marked proliferative response. Increased IFN? production from these unconventional "naïve" T cells from PsA patients promoted greater expression of the chemo-attractant CXCL9 by HaCaT keratinocytes compared with their healthy counterparts. Treatment with anti-TNF therapy reversed these abnormalities in this T-cell subset though did not affect the frequency of IL-22⁺ T cells overall. Furthermore, blockade of IL-22 enhanced the IFN? mediated release of CXCL-9. These results reveal CD4⁺ T-cell dysregulation in patients with PsA which can be reversed by anti-TNF and highlight the regulatory properties of IL-22 with important implications for therapeutic approaches that inhibit its production.

SUBMITTER: Ezeonyeji A

PROVIDER: S-EPMC5666299 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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CD4 T-Cell Dysregulation in Psoriatic Arthritis Reveals a Regulatory Role for IL-22.

Ezeonyeji Amara A Baldwin Helen H Vukmanovic-Stejic Milica M Ehrenstein Michael R MR

Frontiers in immunology 20171027

Dysregulation of interleukin-22 (IL-22) has been associated with autoimmune diseases but divergent effects upon inflammation have hampered efforts to define its contribution to pathogenesis. Here, we examined the role of IL-22 in patients with psoriatic arthritis (PsA). In the peripheral blood of PsA patients, there was a decrease in IL-22+CD4+ T cells compared with healthy controls resulting in a heightened CD4+ IFNγ+/IL-22+ ratio accompani ...[more]

PMID: 29163483

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Project description:ObjectiveIL-22 is elevated in patients with inflammatory arthritis and correlates with disease activity. IL-22 deficient mice have reduced incidence of arthritis. Recombinant IL-22 restrains progression of arthritis via increase in IL-10 responses when administered prior to onset of arthritis. These findings imply a possible dual role of IL-22 in inflammatory arthritis depending on the phase of arthritis. Experiments outlined here were designed to elucidate the contribution of endogenous IL-22 before and after the onset of arthritis.MethodsCollagen induced arthritis (CIA) was induced in DBA1 or IFN-γ deficient mice following immunization with collagen and complete Freund's adjuvant. Anti-IL-22 antibody or isotype control were administered prior to or after onset of arthritis and disease progression assessed by clinical scoring and histopathology. IL-22, IL-17 and IFN-γ responses were measured by ELISA and flowcytometry. Anti-collagen antibody responses were analyzed by ELISA. Expression of IL-22R1 in CD4+ cells was elucidated by flowcytometry and real time PCR.ResultsCollagen specific IL-22 responses were expanded during arthritis and IL-22 producing cells were discrete from IL-17 or IFN-γ producing cells. Neutralization of IL-22 after onset of arthritis resulted in significant increase in Th1 responses and significantly reduced severity of arthritis. CD4+ cells from arthritic mice showed increased surface expression of IL-22R1. In vitro, CD4+T cells cultured with antigen presenting cells in the presence or absence of IL-22 suppressed or induced IFN-γ, respectively. The protective effect of anti-IL-22 was reversed in IFN-γ deficient mice. Moreover, administration of anti-IL-22 prior to onset of arthritis augmented arthritis severity.ConclusionWe show for the first time that IL-22 plays a dual role: protective prior to the onset of arthritis and pathogenic after onset of arthritis. The pathogenic effect of IL-22 is dependent on suppression of IFN-γ responses. IL-17 responses remained unchanged with the administration of anti-IL22 antibody. IL-22R1 is upregulated on CD4+T cells during arthritis and regulates IFN-γ in T cells.

Project description:The aim was to study changes in immunohistochemical expression markers of synovial and skin inflammation, clinical outcomes and magnetic resonance imaging (MRI) scores with abatacept treatment in patients with psoriatic arthritis (PsA).Biological-treatment-naïve PsA patients with active disease including synovitis of a knee were enrolled in this single-centre, crossover study. Patients were randomised to receive intravenous abatacept 3 mg/kg of body weight or placebo infusion on day 1, 15 and 29; thereafter abatacept 10 mg/kg of body weight was administered every 28 days for 5 months. Clinical data were collected at each visit. Synovial biopsy of the involved knee was obtained at baseline and 2 and 6 months. MRI of the same knee and skin biopsy was performed prior to arthroscopy.Fifteen patients were recruited. Significant improvements in the joint-related measures were observed; 90% were European League Against Rheumatism criteria responders and 30% achieved psoriasis area severity index (PASI)50 at 6 months. Reduction in synovitis (P?=?0.016) and vascularity (P?=?0.039) macroscopic scores consistent with decrease in total MRI score (P?=?0.016) were noticed. Abatacept decreased the immunohistological expression of FOXP3+ cells (P?=?0.027), specifically the expression of CD4+FOXP3+ regulatory T cells (Tregs) (P?=?0.008) in the synovium over 6 months. There was no significant clinical or immunohistological change in any of the skin measures.This is the first study assessing synovial and psoriatic skin immunpathological changes following abatacept treatment in PsA. Reduction in Treg expression in the synovium but not in the psoriatic lesion suggests abnormal Treg function in PsA with differential suppressive capacity in the synovium compared to the lesional skin. The results of this study demonstrate that abatacept 10 mg/kg of body weight might be an effective treatment option for joint disease in patients with PsA.Irish Health Products Regulatory Authority.CT 900/489/1 - Abatacept (case number: 2077284, EudraCT Number: 2009-017525-19, Protocol number: 77777). Registered on 12 March 2010.

Dataset Information

CD4 T-Cell Dysregulation in Psoriatic Arthritis Reveals a Regulatory Role for IL-22.

Publications

CD4 T-Cell Dysregulation in Psoriatic Arthritis Reveals a Regulatory Role for IL-22.

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