Infection-Associated Thymic Atrophy

Abstract

The thymus is a vital organ of the immune system that plays an essential role in thymocyte development and maturation. Thymic atrophy occurs with age (physiological thymic atrophy) or as a result of viral, bacterial, parasitic or fungal infection (pathological thymic atrophy). Thymic atrophy directly results in loss of thymocytes and/or destruction of the thymic architecture, and indirectly leads to a decrease in naïve T cells and limited T cell receptor diversity. Thus, it is important to recognize the causes and mechanisms that induce thymic atrophy. In this review, we highlight current progress in infection-associated pathogenic thymic atrophy and discuss its possible mechanisms. In addition, we discuss whether extracellular vesicles/exosomes could be potential carriers of pathogenic substances to the thymus, and potential drugs for the treatment of thymic atrophy. Having acknowledged that most current research is limited to serological aspects, we look forward to the possibility of extending future work regarding the impact of neural modulation on thymic atrophy.

Keywords: atrophy; glucocorticoids; immunosenescence; infections; thymus gland.

Figure 1

The normal structure of the thymus gland and the changes that occur with atrophy. The thymus parenchyma is composed of cortex and medulla, which are separated by cortico-medullary junction (CMJ). The cortex is constructed from thymic epithelial cells (TEC) as its framework and thymocytes filling in the interspace. The medulla is composed of TECs, naïve T cells and macrophages. The process of T cell maturation begins with the transformation of double negative (DN) thymocytes to double positive (DP) thymocytes in the outer cortex of the thymus gland. DP thymocytes then undergo positive and negative selection in the inner cortex and medulla, respectively, to become self-tolerant single positive (SP) thymocytes. Finally, SP thymocytes mature and are transported to peripheral lymphoid tissues. Thymic atrophy leads to the destruction of thymus structure and abnormal maturation of thymocytes. In thymic atrophy, the medullary structure is destroyed and the CMJ is disappeared, so both positive and negative selection are interrupted. Without positive selection, premature exiting of DP thymocytes may occur. Without negative selection, the autoreactive T cells may have the opportunity to migrate out of the thymus. In addition, cortical structural disorders not only cause the depletion of a large number of DP thymocytes, but also delay the maturation of SP thymocytes, leading to the accumulation of SP thymocytes. Besides, the figure also shows the main affected sites of thymus corresponding to different pathogens.

Figure 2

Mechanisms of infection-induced thymic atrophy. This figure summarizes the three main mechanisms of infection-related thymic atrophy and lists the characteristic pathogens corresponding to each mechanism. 1) The hypothalamic-pituitary-adrenal (HPA) axis plays an important role in infection-induced thymic atrophy. Glucocorticoids can induce apoptosis of thymocytes, especially DP thymocytes. In addition, other hormones mentioned in the picture are also thought to be involved in thymic atrophy. 2) At the molecular level, the change of thymus microenvironment is one of the major changes associated with thymic atrophy, and the main cytokines involved are IL-10, IFN-γ and TNF-α. 3) Some pathogens take the thymus as the target organ and directly invade the thymus. In addition, the products of pathogens, such as toxins, soluble antigens, and exosomes, can also play an important role in thymic atrophy.