Immune aging and autoimmunity

Abstract

Age is an important risk for autoimmunity, and many autoimmune diseases preferentially occur in the second half of adulthood when immune competence has declined and thymic T cell generation has ceased. Many tolerance checkpoints have to fail for an autoimmune disease to develop, and several of those are susceptible to the immune aging process. Homeostatic T cell proliferation which is mainly responsible for T cell replenishment during adulthood can lead to the selection of T cells with increased affinity to self- or neoantigens and enhanced growth and survival properties. These cells can acquire a memory-like phenotype, in particular under lymphopenic conditions. Accumulation of end-differentiated effector T cells, either specific for self-antigen or for latent viruses, have a low activation threshold due to the expression of signaling and regulatory molecules and generate an inflammatory environment with their ability to be cytotoxic and to produce excessive amounts of cytokines and thereby inducing or amplifying autoimmune responses.

Fig. 1

Homeostatic proliferation as a risk factor for autoimmunity. Homeostatic proliferation is the major means of T cell replenishment in the adult when thymic production declines. Peripheral selection and T cell activation and differentiation induced by this turnover can generate a repertoire that is more difficult to control by peripheral tolerance mechanisms

Fig. 2

End-differentiated CD45RA⁺CD28⁻ T effector memory cells in autoimmune inflammation. One of the most striking phenotypes of immune aging is the accumulation of terminally differentiated CD45RA effector memory T cells at the expense of naive and central memory T cells. Such cells contribute to tissue inflammation through antigen-specific as well as antigen-independent mechanisms