Malle L, Patel RS, Martin-Fernandez M, Stewart OJ, Philippot Q, Buta S, Richardson A, Barcessat V, Taft J, Bastard P, Samuels J, Mircher C, Rebillat AS, Maillebouis L, Vilaire-Meunier M, Tuballes K, Rosenberg BR, Trachtman R, Casanova JL, Notarangelo LD, Gnjatic S, Bush D, Bogunovic D. Autoimmunity in Down's syndrome via cytokines, CD4 T cells and CD11c+ B cells. Nature. 2023 Feb 22; PubMed.
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University of Southern California Keck School of Mediicine
Individuals with DS are more prone to infections than the general population. They also have diminished titers in response to vaccines and a predisposition to several autoimmune diseases, in particular hypothyroidism, celiac disease, Type 1 diabetes mellitus, and alopecia areata. This work by Malle et al. identifies elevated cytokines, as well as T-cell overactivation, as the likely basis for this clinical phenotype. Specifically, they report that basal IL-6 activation of T-cells promotes CD11c+ B cell clonal expansion with subsequent increases in IgG production resulting in a diverse repertoire of autoantibodies. They also found 365 unique autoantigens, including metabolic, cell signaling, immune signaling, and neuronal pathway intermediates.
Interestingly, it has been previously reported that there is autoimmunity against Aβ in persons with DS (Conti et al, 2010). One question has been whether these anti-Aβ autoantibodies may play a protective role in young persons with DS, given that, despite lifelong overproduction of Aβ peptides, fibrillar plaques are not seen until at about 40 years of age, perhaps when immunity (including autoimmunity) wanes. Whether the autoantibodies described in the Malle et al. paper play a role in AD pathogenesis in DS remains to be elucidated.
Nonetheless, this work provides a clearer understanding for the biological underpinnings of immune dysfunction, including autoimmunity, in persons with DS. It lays a path forward to potentially treat several co-occurring immune conditions in DS by targeting IL-6 signaling. Importantly, as we consider immunotherapy in persons with DS, either for Alzheimer’s disease or other co-morbidities, it will be important to account for these unique differences in immune function.
References:
Conti E, Galimberti G, Piazza F, Raggi ME, Ferrarese C. Increased soluble APPalpha, Abeta 1-42, and anti-Abeta 1-42 antibodies in plasma from down syndrome patients. Alzheimer Dis Assoc Disord. 2010 Jan-Mar;24(1):96-100. PubMed.
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