Thymic tolerance as a key brake on autoimmunity

Abstract

Although the thymus has long been recognized as a key organ for T cell selection, the intricate details linking these selection events to human autoimmunity have been challenging to decipher. Over the last two decades, there has been rapid progress in understanding the role of thymic tolerance mechanisms in autoimmunity through genetics. Here we review some of the recent progress in understanding key thymic tolerance processes that are critical for preventing autoimmune disease.

A tale of autoimmunity: thymoma, thymectomy, and systemic lupus erythematosus

“…Central tolerance develops via clonal detection of naïve self-reactive T lymphocytes, also known as positive selection, which takes place during the maturation of CD4/CD8 dual-positive T lymphocytes. During this process, T lymphocyte precursors with selfreactivity are positively selected in the thymic cortical and medullary epithelium via interaction with MHC complexes and undergo clonal deletion via apoptosis, whereas those with low avidity for self migrate to peripheral tissues, resulting in survival of only those T lymphocytes with low or absent affinity for self-antigens [3][4][5][6]10]. For those self-reactive lymphocytes that escape clonal deletion in the thymus initially, and mature into CD4 or CD8 positive T lymphocytes with minimal or moderate self-reactivity, the thymus and peripheral tissues have a secondary fail-safe, known as negative selection, during which auto-reactive peripheral T lymphocytes undergo apoptosis in both tissues [4].…”

“…While thymomas are rare, they remain the most common mediastinal mass in adults, comprising up to 25% of mediastinal masses [2]. In cases of thymic hyperplasia or thymomaassociated autoimmune disease (e.g., myasthenia gravis, pure red cell aplasia), thymectomy has been considered standard of care [1][2][3][4][5][6]. Thymomas are classified and staged based on the World Health Organization (WHO) class system and Masaoka stage, respectively [1,2].…”

“…The prevalence of autoimmune disorders/paraneoplastic syndromes in individuals with thymoma or thymic hyperplasia has been reported to be as high as 30%, whereas the prevalence in the general population is in the range of 7-9% [1][2][3][4][5][6]12]. The prevalence and incidence of autoimmune disease/ paraneoplastic syndromes post-thymectomy is much less characterized; however, reports have shown that it is as high as 8% [1].…”

RAG gene defects at the verge of immunodeficiency and immune dysregulation

“…This process requires a well‐organized thymic architecture that permits interaction of thymocytes with cortical and medullary thymic epithelial cells (cTECs, mTECs) and other thymic stromal cells. In particular, positively selected thymocytes migrate to the thymic medulla, where they interact with mTECs, a subset of which express the transcriptional coactivator AutoImmune Regulator (AIRE), which dives expression of tissue‐restricted antigens (TRAs). These TRAs, in association with MHC molecules, are presented by mTECs to single‐positive T cells.…”

Self and the Brain. The Immune Metaphor

“…T-lymphocytes subsequently undergo a multi-step process of selection in response to self ( 41 – 43 ). Those T lymphocytes that weakly respond to self stimulus (antigen) happen to survive, while those that do not react with self die, (positive selection), and those that react too strongly with self are most of them eliminated (negative selection) or preserved as regulatory T lymphocytes ( 44 , 45 ). Thus, the self principle governing thymopoiesis determines the future immune response.…”