APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors

Martino, Lucia De; Capalbo, Donatella; Improda, Nicola; D’Elia, Federica; Mase, Raffaella Di; D’Assante, Roberta; D’Acunzo, Ida; Pignata, Claudio; Salerno, Mariacarolina

doi:10.3389/fimmu.2013.00331

Cited by 37 publications

(33 citation statements)

References 131 publications

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“…In human, AIRE mutations impair clonal deletion of T cells and cause the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome (40). This syndrome exhibits pleiotropic manifestations affecting many organs (41,42).…”

Section: Aire-induced Versus -Independent Tramentioning

confidence: 99%

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

St-Pierre

Trofimov

Brochu

et al. 2015

The Journal of Immunology

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Establishment of self-tolerance in the thymus depends on promiscuous expression of tissue-restricted Ags (TRA) by thymic epithelial cells (TEC). This promiscuous gene expression (pGE) is regulated in part by the autoimmune regulator (AIRE). To evaluate the commonalities and discrepancies between AIRE-dependent and -independent pGE, we analyzed the transcriptome of the three main TEC subsets in wild-type and Aire knockout mice. We found that the impact of AIRE-dependent pGE is not limited to generation of TRA. AIRE decreases, via non–cell autonomous mechanisms, the expression of genes coding for positive regulators of cell proliferation, and it thereby reduces the number of cortical TEC. In mature medullary TEC, AIRE-driven pGE upregulates non-TRA coding genes that enhance cell–cell interactions (e.g., claudins, integrins, and selectins) and are probably of prime relevance to tolerance induction. We also found that AIRE-dependent and -independent TRA present several distinctive features. In particular, relative to AIRE-induced TRA, AIRE-independent TRA are more numerous and show greater splicing complexity. Furthermore, we report that AIRE-dependent versus -independent TRA project nonredundant representations of peripheral tissues in the thymus.

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Section: Aire-induced Versus -Independent Tramentioning

confidence: 99%

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

St-Pierre

Trofimov

Brochu

et al. 2015

The Journal of Immunology

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“…[62][63][64][65] Interestingly, the classical central T-cell tolerance defect, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome ([APECED] due to a defect of the autoimmune regulator transcription factor) is not typically associated with cytopenias. 66 Furthermore, immune dysregulatory processes such as hemophagocytosis or lymphoproliferation (and subsequent splenic sequestration of blood cells) may cause secondary cytopenia in critically ill patients. The underlying pathomechanisms are pathological macrophage activation, functional natural killer (NK) cell defects, and polyclonal or oligoclonal lymphoproliferation.…”

Section: Immune Dysregulation Underlying Cytopenia In Pidmentioning

confidence: 99%

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

Seidel

2014

Blood

124

137

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Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

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“…Noteworthy, this lack is exemplified by the significant intrafamilial differences even between siblings carrying the same mutation, suggesting that disease-modifying genes, environmental factors, and immune system dynamics may play a role in modulating clinical expression of the syndrome (36, 37). …”

Section: New Insights Into Aire Mutationsmentioning

confidence: 99%

Novel Findings into AIRE Genetics and Functioning: Clinical Implications

et al. 2016

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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.

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APECED: A Paradigm of Complex Interactions between Genetic Background and Susceptibility Factors

Cited by 37 publications

References 131 publications

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

Differential Features of AIRE-Induced and AIRE-Independent Promiscuous Gene Expression in Thymic Epithelial Cells

Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment

Novel Findings into AIRE Genetics and Functioning: Clinical Implications

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