primary Antibody ImmunoDeficiencies: genetics and pathophysiological mechanism – AID

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.