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

Louise Malle, Roosheel S. Patel, Marta Martin-Fernandez, O Jay Stewart, Quentin Philippot, Sofija Buta, Ashley Richardson, Vanessa Barcessat, Justin Taft, Paul Bastard, Julie Samuels, Clotilde Mircher, Anne-Sophie Rebillat, Louise Maillebouis, Marie Vilaire-Meunier, Kevin Tuballes, Brad R. Rosenberg, Rebecca Trachtman, Jean-Laurent Casanova, Luigi D. Notarangelo, Sacha Gnjatic, Douglas Bush and Dusan Bogunovic ()
Additional contact information
Louise Malle: Icahn School of Medicine at Mount Sinai
Roosheel S. Patel: Icahn School of Medicine at Mount Sinai
Marta Martin-Fernandez: Icahn School of Medicine at Mount Sinai
O Jay Stewart: Icahn School of Medicine at Mount Sinai
Quentin Philippot: Necker Branch, INSERM U1163, Necker Hospital for Sick Children
Sofija Buta: Icahn School of Medicine at Mount Sinai
Ashley Richardson: Icahn School of Medicine at Mount Sinai
Vanessa Barcessat: Icahn School of Medicine at Mount Sinai
Justin Taft: Icahn School of Medicine at Mount Sinai
Paul Bastard: Necker Branch, INSERM U1163, Necker Hospital for Sick Children
Julie Samuels: Icahn School of Medicine at Mount Sinai
Clotilde Mircher: Institut Jérôme Lejeune
Anne-Sophie Rebillat: Institut Jérôme Lejeune
Louise Maillebouis: Institut Jérôme Lejeune
Marie Vilaire-Meunier: Institut Jérôme Lejeune
Kevin Tuballes: Icahn School of Medicine at Mount Sinai
Brad R. Rosenberg: Icahn School of Medicine at Mount Sinai
Rebecca Trachtman: Icahn School of Medicine at Mount Sinai
Jean-Laurent Casanova: Necker Branch, INSERM U1163, Necker Hospital for Sick Children
Luigi D. Notarangelo: National Institutes of Health
Sacha Gnjatic: Icahn School of Medicine at Mount Sinai
Douglas Bush: Icahn School of Medicine at Mount Sinai
Dusan Bogunovic: Icahn School of Medicine at Mount Sinai

Nature, 2023, vol. 615, issue 7951, 305-314

Abstract: 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 areata1,2. 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+TbethighCD21low 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.

Date: 2023
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DOI: 10.1038/s41586-023-05736-y

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