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Case Report: FOXP3 Mutation in a Patient Presenting With ALPS

ALPS and IPEX are two well-characterized inborn errors of immunity with immune dysregulation, considered as two master models of monogenic auto-immune diseases. Thus, with autoimmunity as their primary clinical manifestation, these two entities may show clinical overlap. Traditionally, immunological...

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Autores principales: Rais, Afef, Mekki, Najla, Fedhila, Faten, Alosaimi, Mohammed Faraj, Ben Khaled, Monia, Zameli, Amal, Agrebi, Nourhen, Sellami, Maryam Kallel, Geha, Raif, Ben-Mustapha, Imen, Barbouche, Mohamed-Ridha
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438314/
https://www.ncbi.nlm.nih.gov/pubmed/34531853
http://dx.doi.org/10.3389/fimmu.2021.692107
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author Rais, Afef
Mekki, Najla
Fedhila, Faten
Alosaimi, Mohammed Faraj
Ben Khaled, Monia
Zameli, Amal
Agrebi, Nourhen
Sellami, Maryam Kallel
Geha, Raif
Ben-Mustapha, Imen
Barbouche, Mohamed-Ridha
author_facet Rais, Afef
Mekki, Najla
Fedhila, Faten
Alosaimi, Mohammed Faraj
Ben Khaled, Monia
Zameli, Amal
Agrebi, Nourhen
Sellami, Maryam Kallel
Geha, Raif
Ben-Mustapha, Imen
Barbouche, Mohamed-Ridha
author_sort Rais, Afef
collection PubMed
description ALPS and IPEX are two well-characterized inborn errors of immunity with immune dysregulation, considered as two master models of monogenic auto-immune diseases. Thus, with autoimmunity as their primary clinical manifestation, these two entities may show clinical overlap. Traditionally, immunological biomarkers are used to establish an accurate differential diagnosis. Herein, we describe a patient who presented with clinical features and biomarkers fulfilling the diagnostic criteria of ALPS. Severe apoptotic defect was also shown in the patient’s cell lines and PHA-activated peripheral blood lymphocytes. Sanger sequencing of the FAS gene did not reveal any causal mutation. NGS screening revealed a novel deleterious variant located in the N terminal repressor domain of FOXP3 but no mutations in the FAS pathway-related genes. TEMRA cells (terminally differentiated effector memory cells re-expressing CD45RA) and PD1 expression were increased arguing in favor of T-cell exhaustion, which could be induced by unrestrained activation of T effector cells because of Treg deficiency. Moreover, defective FOXP3 observed in the patient could intrinsically induce increased proliferation and resistance to apoptosis in T effector cells. This observation expands the spectrum of FOXP3 deficiency and underscores the role of NGS in detecting mutations that induce overlapping phenotypes among inborn errors of immunity with immune dysregulation. In addition, these findings suggest a potential link between FOXP3 and FAS pathways.
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spelling pubmed-84383142021-09-15 Case Report: FOXP3 Mutation in a Patient Presenting With ALPS Rais, Afef Mekki, Najla Fedhila, Faten Alosaimi, Mohammed Faraj Ben Khaled, Monia Zameli, Amal Agrebi, Nourhen Sellami, Maryam Kallel Geha, Raif Ben-Mustapha, Imen Barbouche, Mohamed-Ridha Front Immunol Immunology ALPS and IPEX are two well-characterized inborn errors of immunity with immune dysregulation, considered as two master models of monogenic auto-immune diseases. Thus, with autoimmunity as their primary clinical manifestation, these two entities may show clinical overlap. Traditionally, immunological biomarkers are used to establish an accurate differential diagnosis. Herein, we describe a patient who presented with clinical features and biomarkers fulfilling the diagnostic criteria of ALPS. Severe apoptotic defect was also shown in the patient’s cell lines and PHA-activated peripheral blood lymphocytes. Sanger sequencing of the FAS gene did not reveal any causal mutation. NGS screening revealed a novel deleterious variant located in the N terminal repressor domain of FOXP3 but no mutations in the FAS pathway-related genes. TEMRA cells (terminally differentiated effector memory cells re-expressing CD45RA) and PD1 expression were increased arguing in favor of T-cell exhaustion, which could be induced by unrestrained activation of T effector cells because of Treg deficiency. Moreover, defective FOXP3 observed in the patient could intrinsically induce increased proliferation and resistance to apoptosis in T effector cells. This observation expands the spectrum of FOXP3 deficiency and underscores the role of NGS in detecting mutations that induce overlapping phenotypes among inborn errors of immunity with immune dysregulation. In addition, these findings suggest a potential link between FOXP3 and FAS pathways. Frontiers Media S.A. 2021-08-31 /pmc/articles/PMC8438314/ /pubmed/34531853 http://dx.doi.org/10.3389/fimmu.2021.692107 Text en Copyright © 2021 Rais, Mekki, Fedhila, Alosaimi, Ben Khaled, Zameli, Agrebi, Sellami, Geha, Ben-Mustapha and Barbouche https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Rais, Afef
Mekki, Najla
Fedhila, Faten
Alosaimi, Mohammed Faraj
Ben Khaled, Monia
Zameli, Amal
Agrebi, Nourhen
Sellami, Maryam Kallel
Geha, Raif
Ben-Mustapha, Imen
Barbouche, Mohamed-Ridha
Case Report: FOXP3 Mutation in a Patient Presenting With ALPS
title Case Report: FOXP3 Mutation in a Patient Presenting With ALPS
title_full Case Report: FOXP3 Mutation in a Patient Presenting With ALPS
title_fullStr Case Report: FOXP3 Mutation in a Patient Presenting With ALPS
title_full_unstemmed Case Report: FOXP3 Mutation in a Patient Presenting With ALPS
title_short Case Report: FOXP3 Mutation in a Patient Presenting With ALPS
title_sort case report: foxp3 mutation in a patient presenting with alps
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8438314/
https://www.ncbi.nlm.nih.gov/pubmed/34531853
http://dx.doi.org/10.3389/fimmu.2021.692107
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