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Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c⁺ B cells.

ABSTRACT: Down's syndrome (DS) presents with a constellation of cardiac, neurocognitive and growth impairments. Individuals with DS are also prone to severe infections and autoimmunity including thyroiditis, type 1 diabetes, coeliac disease and alopecia areata^1,2. Here, to investigate the mechanisms underlying autoimmune susceptibility, we mapped the soluble and cellular immune landscape of individuals with DS. We found a persistent elevation of up to 22 cytokines at steady state (at levels often exceeding those in patients with acute infection) and detected basal cellular activation: chronic IL-6 signalling in CD4 T cells and a high proportion of plasmablasts and CD11c⁺Tbet^highCD21^low B cells (Tbet is also known as TBX21). This subset is known to be autoimmune-prone and displayed even greater autoreactive features in DS including receptors with fewer non-reference nucleotides and higher IGHV4-34 utilization. In vitro, incubation of naive B cells in the plasma of individuals with DS or with IL-6-activated T cells resulted in increased plasmablast differentiation compared with control plasma or unstimulated T cells, respectively. Finally, we detected 365 auto-antibodies in the plasma of individuals with DS, which targeted the gastrointestinal tract, the pancreas, the thyroid, the central nervous system, and the immune system itself. Together, these data point to an autoimmunity-prone state in DS, in which a steady-state cytokinopathy, hyperactivated CD4 T cells and ongoing B cell activation all contribute to a breach in immune tolerance. Our findings also open therapeutic paths, as we demonstrate that T cell activation is resolved not only with broad immunosuppressants such as Jak inhibitors, but also with the more tailored approach of IL-6 inhibition.

SUBMITTER: Malle L

PROVIDER: S-EPMC9945839 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c<sup>+</sup> B cells.

Malle Louise L Patel Roosheel S RS Martin-Fernandez Marta M Stewart O Jay OJ Philippot Quentin Q Buta Sofija S Richardson Ashley A Barcessat Vanessa V Taft Justin J Bastard Paul P Samuels Julie J Mircher Clotilde C Rebillat Anne-Sophie AS Maillebouis Louise L Vilaire-Meunier Marie M Tuballes Kevin K Rosenberg Brad R BR Trachtman Rebecca R Casanova Jean-Laurent JL Notarangelo Luigi D LD Gnjatic Sacha S Bush Douglas D Bogunovic Dusan D

Nature 20230222 7951

Down's syndrome (DS) presents with a constellation of cardiac, neurocognitive and growth impairments. Individuals with DS are also prone to severe infections and autoimmunity including thyroiditis, type 1 diabetes, coeliac disease and alopecia areata<sup>1,2</sup>. Here, to investigate the mechanisms underlying autoimmune susceptibility, we mapped the soluble and cellular immune landscape of individuals with DS. We found a persistent elevation of up to 22 cytokines at steady state (at levels oft ...[more]

PMID: 36813963

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Project description:IntroductionCD4+ T cells are critically involved in the pathogenesis of Rheumatoid Arthritis; an autoimmune disorder characterized by joint inflammation and bone degeneration. In this study, we focused on the critical role of cytokines, IL-21 and IL-23 in facilitating the aberrant status of RA Th17-like cells and report their significant contribution(s) in modulating the expression of inflammatory cytokines and RANKL.MethodsBlood and synovial fluid collected from a total of 167 RA patients and 25 healthy volunteers were assessed for various inflammatory markers and RANKL expression in plasma and CD4+ T cells. Subsequent ex vivo studies examined the role of specific cytokines, IL-21 and IL-23 in mediating inflammation and RANKL upregulation by blocking their expression with neutralizing antibodies in RA CD4+ T cells and terminally differentiated human Th17 cells. Further, the role of p-Akt1 as a signalling target downstream of IL-21 and IL-23 was evinced with IL-21 and IL-23 inhibition and phospho Akt-1/2 kinase inhibitor.ResultsOur observations highlighted the augmented inflammatory cytokine levels in plasma and an aberrant CD4+ T cell phenotype expressing exaggerated inflammatory cytokines and membrane RANKL expression in RA as opposed to healthy controls. Neutralization of either IL-21 or IL-23 (p19 and p40) or both, resulted in downregulation of the cytokines, TNF-α, IFN-γ and IL-17 and RANKL expression in these cells, signifying the critical role of IL-21/23 axis in modulating inflammation and RANKL. Subsequent dissection of the signaling pathway found p-Akt1 as the key phosphoprotein downstream of both IL-21 and IL-23, capable of increasing inflammatory cytokines and RANKL production.DiscussionOur findings unequivocally identify IL-21/23 axis in RA CD4+ T cells as a key regulator dictating two critical processes i.e. exaggerated inflammation and higher RANKL expression and provide critical targets in their downstream signalling for therapeutic approaches.

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Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c⁺ B cells.

Publications

Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c<sup>+</sup> B cells.

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Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c+ B cells.

Publications

Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c<sup>+</sup> B cells.

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OmicsDI is part of the ELIXIR infrastructure

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Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c⁺ B cells.