Novel Findings into AIRE Genetics and Functioning: Clinical Implications

Abstract

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED), formerly known as autoimmune polyendocrine syndrome type 1, is a paradigm of a monogenic autoimmune disease caused by mutations of a gene, named autoimmune regulator (AIRE). AIRE acts as a transcription regulator that promotes immunological central tolerance by inducing the ectopic thymic expression of many tissue-specific antigens. Although the syndrome is a monogenic disease, it is characterized by a wide variability of the clinical expression with no significant correlation between genotype and phenotype. Indeed, many aspects regarding the exact role of AIRE and APECED pathogenesis still remain unraveled. In the last decades, several studies in APECED and in its mouse experimental counterpart have revealed new insights on how immune system learns self-tolerance. Moreover, novel interesting findings have extended our understanding of AIRE’s function and regulation thus improving our knowledge on the pathogenesis of APECED. In this review, we will summarize recent novelties on molecular mechanisms underlying the development of APECED and their clinical implications.

Update on Aire and thymic negative selection

“…Although the role of Aire is well defined in thymocyte negative selection, its role in Treg cell differentiation and selection remains controversial . The generation of certain Treg clones is dependent on Aire expression.…”

“…Patients with APECED present in both children and adults with a significant decrease of CD4 + CD25 + Foxp3 + Treg cells, failure in thymic selection of naive T cells with defects in TCR repertoire or abnormal expression of cytokines …”

“…Although the role of Aire is well defined in thymocyte negative selection, its role in Treg cell differentiation and selection remains controversial. 49,70 The generation of certain Treg clones is dependent on Aire expression. As an example, FOXP3 + MJ23tg and RT83tg Treg cells, which are found infiltrated in the tumours of mice with oncogene-driven prostate cancer, failed to develop in the thymus and Aire À/À hosts.…”

“…Moderate-avidity T-cell receptor interactions with self-peptide and MHC class I or II complexes expressed by cortical TECs allow survival and further differentiation of thymocytes to CD4 or CD8 single-positive subsets (CD4 + CD8 À or CD4 À CD8 + ) respectively, that will leave the thymus to the peripheral lymphoid organs. Patients with APECED present in both children and adults with a significant decrease of CD4 + CD25 + Foxp3 + Treg cells, 70 failure in thymic selection of naive T cells with defects in TCR repertoire 77 or abnormal expression of cytokines. 78 In addition, B cells that differentiate within the thymus express Aire 79,80 and APECED patients present an altered B-cell phenotype and dysregulation in B-cell function with B-cell reactivity to a unique set of approximately 100 self-proteins and production of neutralizing autoantibodies against specific cytokines.…”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…[54,67,68] IKK/NF-kB regulate expression of these cytokines. [69,70] APECED patients have high titers of neutralizing autoantibodies against these cytokines, [71,72] suggesting that loss of IL-17, IL-22, and IFN-γ may contribute to increased fungal infection. On the other hand, occasional or weak autoantibodies against IL-6, IL-9, IL-12, IL-21, IL-23, IL-26, and IL-29 were found, while no autoantibodies against IL-1α/β, IL-2, IL-4, IL-8, IL-10, IL-18, TGF-β1, and TNF were found in APECED patients, [72] suggesting that the cytokines that are not neutralized may promote inflammation and tumorigenesis.…”