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The immune system declines with aging, leading to an increased susceptibility to infections and higher incidence and progression of autoimmune phenomena and neoplasia. Down syndrome prematurely shows clinical manifestations that are normally seen with aging. This review provides a concise overview of abnormalities in the adaptive immune system of Down syndrome in comparison to normal and precocious (Progeria syndromes) aging. Clinical signs and immunological changes are reviewed. We challenge the hypothesis that the immunological abnormalities in Down syndrome should be interpreted as precocious immunosenescence.