Sustained immune youth risks autoimmune disease in the aging host

Immune responses underlying autoimmune diseases follow the same principles that protect individuals from infection and malignancies. However, while protective immunity wanes with progressive age, the risk for autoimmune disease steadily increases; incidence rates for many autoimmune diseases peak in later life. Here, we discuss whether aging predisposes to autoimmunity, arguing that disease progression in the autoimmune vasculitis giant cell arteritis is driven by age-inappropriate sustenance of immune competence. Stem-like memory CD4⁺ T cells (T_SCM) that reside near the vasculitic lesions provide a continuous supply of pathogenic effector T cells. Antigen-presenting cells lacking inhibitory ligands further impede peripheral tolerance mechanisms. In the context of aging-associated accumulation of neoantigens, this incessant immune competence sets the stage for unopposed autoimmunity. We propose that sustained immune youthfulness can be detrimental to the aging host, while immune aging may be a beneficial adaptation to balance reactivity to self-antigens and non-self-antigens and thus protect from autoimmunity in aging.