Th1 Biased Progressive Autoimmunity in Aged Aire-Deficient Mice Accelerated Thymic Epithelial Cell Senescence

Abstract

Although autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, are frequently associated with premature aging of the thymus, a direct link is missing between autoimmunity and thymic atrophy. Here we monitored the progression of thymic involution in Aire- deficient mice, in which defective negative selection causes spontaneous and progressive development of autoimmunity. In young and middle-aged mice, Aire deficiency appeared to be protective as supported by the reduced β-gal + epithelial cells and the enhanced thymic output. However, once the autoimmune phenotype was fully developed in aged Aire- deficient mice, their thymuses underwent accelerated involution. In comparison to the age-matched wildtype littermates, old Aire- deficient mice showed lower numbers of total thymocytes and recent thymic emigrants but more β-gal + thymic epithelial cells. This phenomenon may partly be attributable to the increased number of activated Th1 cells homing to the thymus. This speculation was further supported by the enhanced thymic aging following repeated challenges with complete Freund’s adjuvant immunization. Taken together, the present study highlights a unique mechanism by which autoimmunity facilitates the senescence of thymic epithelial cells through returning Th1 cells.

Thymus and autoimmunity

“…Conversely, secondary cortical atrophy can result from the chronic re-entry of activated peripheral T-cells into the thymus in HAIDs [ 153 ]. Cortical atrophy as a facet of thymic involution during aging is thought to increase the risk of HAIDs [ 154 ].…”

Programmed Cell Deaths and Potential Crosstalk With Blood–Brain Barrier Dysfunction After Hemorrhagic Stroke

“…ICH and SAH are two categories of hemorrhagic stroke that occur in different intracerebral regions. ICH is mainly secondary to arteriolosclerosis induced by hypertension, coagulopathy, and vascular malformation rupture, whereas SAH is mainly caused by the rupture of an intracranial aneurysm (Gross et al, 2019;Zhang et al, 2019) Even with different etiologies, ICH and SAH are initially caused by vascular disruption in different intracerebral sites, which can be defined as the first phase of BBB disruption. This initial hemorrhage may result in early phases of cell death because of physical injury, brain edema, and increased intracranial pressure.…”

“…This initial hemorrhage may result in early phases of cell death because of physical injury, brain edema, and increased intracranial pressure. At this stage, the death of cells comprising the NVU may significantly contribute to the induction of secondary BBB dysfunction (Hawkins and Davis, 2005;Knowland et al, 2014;Zhang et al, 2019). Currently, a normal BBB is no longer just a physical ''barrier,'' but a dynamic and metabolic interface, based on the novel structural foundation known as the NVU (Tso and Macdonald, 2014;Zou et al, 2017).…”

“…The inflammatory and innate immune responses are among the most important factors in BBB regulation. Recently, a series of experiments on aged mice revealed severe dysregulation of immunity and an excessive inflammatory response (Freitas et al, 2019;Shen et al, 2019;Zhang et al, 2019). As hemorrhagic stroke is a disease with an increased incidence in elderly populations, we should further investigate the effect of these changes on BBB dysfunction and PCDs.…”

Infection-Associated Thymic Atrophy

“…As for the functional alteration of infection-induced thymic atrophy, double positive (DP) thymocytes are the general cluster of depletion. A recent study shows that auto-immunity facilitates the death of thymic epithelial cells through returning Th1 cells ( 174 ), which reveals that auto-immune disease and thymic atrophy may be linked in a vicious cycle, leading to the disorder of immune tolerance. Double negative (DN) thymocytes are the main apoptotic cluster although other clusters are involved as well.…”