CE17 - Recherche translationnelle en santé

primary Antibody ImmunoDeficiencies: genetics and pathophysiological mechanism – AID

primary Antibody ImmunoDeficiencies: genetics and pathophysiological mechanisms

Primary antibody deficiencies (PADs) constitute a heterogeneous group of primary immune deficiencies diagnosed in childhood or in adulthood, which remain not well understood. Our project is based on the hypothesis that most B cell immunodeficiencies, e.g. hypogammaglobulinemia, have underlying genetic defects although the latter may be more complex leading to non-Mendelian inheritance pattern.

To decipher novel pathophysiological mechanisms for primary antibody deficiencies

This project intends to study the molecular, genetic and pathophysiological mechanisms leading to primary antibody deficiencies (PADs). A detailed understanding of the precise molecular pathophysiological mechanism is essential to develop novel knowledge-based treatment strategies. Genetic delineation of PADs enables precise diagnosis, genetic counseling and phenotype/genotype correlation in addition to better treatment and follow-up, and thus improves the quality of life of chronically affected patients and their families. Whenever possible every patient with a PAD should receive a genetic diagnosis. The aim of our consortium of scientists and clinicians is to decipher novel pathophysiological mechanisms for inborn error of immunity with B cell immunodeficiency/primary antibody deficiency (PAD), to establish new diagnosis biomarker and to identify new therapeutic targets. This objective will be achieved by combining clinical, immunological, histopathological, (biased and unbiased) genetic data analysis with in-depth characterization of patients’ cells, and generation of cellular models.

Methods of the project include state of the art immuno-phenotypic characterization; genetic analysis (whole exome sequencing and next generation panel-sequencing). Furthermore, for selected identified genetic variants with of uncertain significance functional studies, e.g. ectopic expression of «mutant« and «wild-type« protein and subsequent analysis of cellular process, will be performed to investigate the causal role of the identified variants.

Genetic and/or phenotypic analysis was performed for all patients included into the study. Several possible disease-associated variants (with uncertain significance) were identified and functional evaluation were performed for selected genes. Examples for the results already obtained are: (i) the dentification of a familial case of autosomal dominant AID deficiency (unravelling a primary immunodeficiency after 50 years); (ii) the identification of a novel splice-site mutation in PIK3R1 causing APDS2 and (iii) the identification of a patient presenting with FNIP1 deficiency. In addition, the characterization of several other genetic variants of uncertain significance is ongoing.

The study decipher and characterizes novel genetic causes for primary antibody deficiency. As such it improves our knowledge about the genetic causes and pathophysiological mechanism underlying hypogammaglobulinemia.

1. Fadlallah J, Chentout L, Boisson B, Pouliet A, Masson C, Morin F, Durandy A, Casanova JL, Oksenhendler E, Kracker S. From Dysgammaglobulinemia to Autosomal-Dominant Activation-Induced Cytidine Deaminase Deficiency: Unraveling an Inherited Immunodeficiency after 50 Years. J Pediatr. 2020 Aug;223:207-211.e1. doi: 10.1016/j.jpeds.2020.03.024. Epub 2020 May 15.PMID: 32423680
2. Thouenon R, Moreno-Corona N, Poggi L, Durandy A, Kracker S. Activated PI3Kinase Delta Syndrome-A Multifaceted Disease. Front Pediatr. 2021 Jun 25;9:652405. doi: 10.3389/fped.2021.652405. eCollection 2021. PMID: 34249806 ; Review.
3. Moreno-Corona N, Chentout L, Poggi L, Thouenon R, Masson C, Parisot M, Mouel LL, Picard C, André I, Cavazzana M, Perrin L, Durandy A, Azarnoush S, Kracker S. Two Monogenetic Disorders, Activated PI3-Kinase-d Syndrome 2 and Smith-Magenis Syndrome, in One Patient: Case Report and a Literature Review of Neurodevelopmental Impact in Primary Immunodeficiencies Associated With Disturbed PI3K Signaling.Front Pediatr. 2021 Jun 24;9:688022. doi: 10.3389/fped.2021.688022. eCollection 2021.PMID: 34249818

The pathophysiological mechanisms for most primary antibody deficiencies (PADs) are not well understood in contrast to those underlying other primary immunodeficiencies.
Lymphoproliferation, chronic diarrhea, autoimmune cytopenia and increased incidence of lymphomas are the main clinical complications associated to PADs. Our project is based on the hypothesis that most PADs have underlying genetic defects. For pediatric cases of PADs we assume that they are more frequently related to monogenic causes. PADs diagnosed in adulthood have also likely underlying genetic defects, however, the late disease onset and diagnosis in these patients could be explained due to further genetic modifying, epigenetic and environmental factors.
The genetic delineation of PADs is essential to enable precise diagnosis, better treatment and follow-up und thus improve the quality of life of chronically affected patients and their families. By combining clinical, immunological, histopathological, functional and genetic data analysis, we aim to establish new diagnosis biomarkers, identify new therapeutic targets and decipher novel pathophysiological mechanisms for PADs.
Exploration of PAD pathogenesis and validation of genetic defects will be performed by in-depth characterization of patients' cells and generation of in vitro cellular models.
This project will contribute to a better understanding of the fundamental mechanisms underlying human antibody mediated immune responses and will improve the diagnosis and care of PAD patients.

Project coordinator


The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.


Anatomie et Cytologie Pathologiques
Département d’Immunologie Clinique
Immunologie, hématologie et rhumatologie pédiatriques
Centre d'Etudes des Déficits Immunitaires

Help of the ANR 469,908 euros
Beginning and duration of the scientific project: November 2019 - 48 Months

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