Expanded CD4+ Effector/Memory T Cell Subset in APECED Produces Predominantly Interferon Gamma

Heikkilä, Nelli; Laakso, Sini M.; Mannerström, Helga; Kekäläinen, Eliisa; Saavalainen, Päivi; Jarva, Hanna; Arstila, T. Petteri

doi:10.1007/s10875-016-0302-5

Cited by 8 publications

(7 citation statements)

References 25 publications

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“…Some aspects of the immmunophenotypic constellation seen in Down syndrome are evocative of autoimmunepolyendocrinopathy-candiasis-ectodermal-dystrophy (APECED), a disease characterised by depressed immune function and autoimmunity. APECED is caused by inactivating mutations in the autoimmune regulator (AIRE) transcription factor gene, which resides on Hsa21 [202]. Decreased AIRE protein expression results in an altered programme of downstream gene expression that compromises myeloid immune cell numbers, phenotypes and function [203].…”

Section: Chdmentioning

confidence: 99%

“…These studies establish connections between trisomy 21, reduced AIRE and loss of central tolerance. Insufficiency of AIRE may also contribute to the interferonopathy observed in Down syndrome [207], since APECED patients have expanded memory T-cell subsets that produce interferon-γ [202]. AIRE expression has been reported to be decreased in Down syndrome [105].…”

Section: Chdmentioning

confidence: 99%

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What people with Down Syndrome can teach us about cardiopulmonary disease

Colvin

Yeager

2017

Eur Respir Rev

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Down syndrome is the most common chromosomal abnormality among live-born infants. Through full or partial trisomy of chromosome 21, Down syndrome is associated with cognitive impairment, congenital malformations ( particularly cardiovascular) and dysmorphic features. Immune disturbances in Down syndrome account for an enormous disease burden ranging from quality-of-life issues (autoimmune alopecia) to more serious health issues (autoimmune thyroiditis) and life-threatening issues (leukaemia, respiratory tract infections and pulmonary hypertension). Cardiovascular and pulmonary diseases account for ∼75% of the mortality seen in persons with Down syndrome. This review summarises the cardiovascular, respiratory and immune challenges faced by individuals with Down syndrome, and the genetic underpinnings of their pathobiology. We strongly advocate increased comparative studies of cardiopulmonary disease in persons with and without Down syndrome, as we believe these will lead to new strategies to prevent and treat diseases affecting millions of people worldwide.

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Section: Chdmentioning

confidence: 99%

Section: Chdmentioning

confidence: 99%

What people with Down Syndrome can teach us about cardiopulmonary disease

Colvin

Yeager

2017

Eur Respir Rev

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“…IFN-γ induced by experimental Trypanosoma cruzi infection inhibits thymic cell proliferation and promotes thymic atrophy [36]. To examine whether Th1-type thymic recirculating T cells contribute to thymic epithelial cell senescence in aged mice in vivo, we used an immunization model with complete Freund’s adjuvant (CFA).…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2019

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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.

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“…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 …”

Section: Association Between Aire Gene Mutations With Loss Of Self‐tomentioning

confidence: 99%

“…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. 81,82 Despite the broad diversity of PTAs expressed by mTECs through PGE, patients with APECED present reactivity only against a minor fraction of self-proteins, 83 indicating that Aire may be acting beyond the selection of T cells.…”

Section: Association Between Aire Gene Mutations With Loss Of Self-tomentioning

confidence: 99%

Update on Aire and thymic negative selection

et al. 2017

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SummaryTwenty years ago, the autoimmune regulator (Aire) gene was associated with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, and was cloned and sequenced. Its importance goes beyond its abstract link with human autoimmune disease. Aire identification opened new perspectives to better understand the molecular basis of central tolerance and self-non-self distinction, the main properties of the immune system. Since 1997, a growing number of immunologists and molecular geneticists have made important discoveries about the function of Aire, which is essentially a pleiotropic gene. Aire is one of the functional markers in medullary thymic epithelial cells (mTECs), controlling their differentiation and expression of peripheral tissue antigens (PTAs), mTEC-thymocyte adhesion and the expression of microRNAs, among other functions. With Aire, the immunological tolerance became even more apparent from the molecular genetics point of view. Currently, mTECs represent the most unusual cells because they express almost the entire functional genome but still maintain their identity. Due to the enormous diversity of PTAs, this uncommon gene expression pattern was termed promiscuous gene expression, the interpretation of which is essentially immunological -i.e. it is related to self-representation in the thymus. Therefore, this knowledge is strongly linked to the negative selection of autoreactive thymocytes. In this update, we focus on the most relevant results of Aire as a transcriptional and post-transcriptional controller of PTAs in mTECs, its mechanism of action, and its influence on the negative selection of autoreactive thymocytes as the bases of the induction of central tolerance and prevention of autoimmune diseases.

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Expanded CD4+ Effector/Memory T Cell Subset in APECED Produces Predominantly Interferon Gamma

Abstract: These data reveal abnormalities in the Th population and suggest that they may in part be traced to premature activation already in the thymus.

Cited by 8 publications

References 25 publications

What people with Down Syndrome can teach us about cardiopulmonary disease

What people with Down Syndrome can teach us about cardiopulmonary disease

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

Update on Aire and thymic negative selection

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