The contribution of thymic tolerance to central nervous system autoimmunity

Abstract

Autoimmune diseases of the central nervous system (CNS) are associated with high levels of morbidity and economic cost. Research efforts have previously focused on the contribution of the peripheral adaptive and innate immune systems to CNS autoimmunity. However, a failure of thymic negative selection is a necessary step in CNS-reactive T cells escaping into the periphery. Even with defective thymic or peripheral tolerance, the development of CNS inflammation is rare. The reasons underlying this are currently poorly understood. In this review, we examine evidence implicating thymic selection in the pathogenesis of CNS autoimmunity. Animal models suggest that thymic negative selection is an important factor in determining susceptibility to and severity of CNS inflammation. There are indirect clinical data that suggest thymic function is also important in human CNS autoimmune diseases. Specifically, the association between thymoma and paraneoplastic encephalitis and changes in T cell receptor excision circles in multiple sclerosis implicate thymic tolerance in these diseases. We identify potential associations between CNS autoimmunity susceptibility factors and thymic tolerance. The therapeutic manipulation of thymopoiesis has the potential to open up new treatment modalities, but a better understanding of thymic tolerance in CNS autoimmunity is required before this can be realised.

iMS2Net: A multiscale networking methodology to decipher metabolic synergy of organism

“…Specifically, development and maturation of T cells in the thymus and its microenvironment plays an important role in the generation of a suitably functioning immune system. Some reports suggest that thymic function and its tolerance are critical factors in evaluating the susceptibility to CNS inflammation ( Nunes-Alves et al., 2013 ; Alberti and Handel, 2021 ). Using iMS2Net, we discover the cooperativeness of multiorgans, such as brain-thymus, brain-Hpf, and Hpf-thymus ( Figure 4 A).…”

Sex-specific remodeling of T-cell compartment with aging: Implications for rat susceptibility to central nervous system autoimmune diseases

“…1). Considering the focus of this review, it should be pointed out that aging does not affect thymopoiesis only quantitatively, but also qualitatively by affecting (i) thymic negative selection, and thereby the output of self-reactive T cells [1,31] and (ii) the generation of regulatory forkhead box P3 (FoxP3)+ T cells (Tregs) required to suppress self-reactive T-cells in the periphery [32][33][34] (Fig. 1).…”

“…CNS antigen-specific T cells are also circulating in mice [82]. The presence of clonally expanded self-reactive T cells in the periphery is related to defects in thymic negative selection [1]. An "immaculate" negative selection would require the expression of all relevant self-antigens in the thymus in sufficient quantity at the time of TCR selection [83].…”

“…The central nervous system (CNS) autoimmune diseases are divided into CNS-specific inflammatory disorders and systemic inflammatory disorders with CNS manifestations due to a direct reaction against CNS parenchyma or CNS blood vessel wall [1]. This review focuses multiple sclerosis (MS), which globally affects approx.…”

“…This suggests that sex should be considered as a significant biological variable in estimating adverse effects of senolytic interventions on development of autoimmune diseases. The immunopathogenesis of MS and EAE encompasses activation of self-reactive T cells (that escaped negative selection in thymus) in the peripheral lymphoid organs, their migration in the CNS tissue, where (upon reactivation) together with activated blood-born innate immunity cells and microglia they cause the tissue damage and inflammation [1,3,[23][24][25]. In this review, we attempted to display and synthesize findings from our and other studies on age-related sex-specific changes in thymus and peripheral lymphoid tissue ("afferent" compartment), and cerebral/spinal cord tissue ("target" compartment) T-cell compartments of possible relevance for MS/EAE development.…”