Consequences of DNA repair and telomere defects on the function of the Immune System: application to CVID and immune deficiencies with dysmorphic syndromes – Immune-Rep

The immune system is a privileged organ to study the DNA damage response (DDR), as it is the site of an important genetic plasticity as part of its program of development and maturation. Many DNA modifications are indeed introduced in the genome of B and T lymphocytes during programmed molecular processes or as “accidental” DNA damages during immune responses. This high genome dynamics is obviously accompanied by very efficient DNA repair mechanisms. Mutations in some of the known DNA repair factors have dramatic consequences for the immune system with the complete arrest of B and T cell development resulting in Severe Combined Immune Deficiency (SCID) in humans. In the present proposal we wish to extend our survey of DNA repair defect consequences to other populations of patients:
• Patients with early bone marrow failure syndromes (BMFS) as they represent a new entity in which we discovered critical factors of the telomere physiology
• Patients with Common Variable Immune Deficiency (CVID) or late Onset Combined Immune Deficiency (LOCID) as we believe that in some of these cases, the presence of subtle DNA repair defects may cause the pathology.
• Patients with “genetic” syndromes as although these patients often present borderline immune functions, the real molecular etiology of these immune dysfunctions is unknown.

The objectives of this grant proposal are to increase our knowledge on the role of the various DNA repair processes in the development, the maintenance, and the function of the immune system and thus, to understand why and how dysfunctions of these DNA repair processes result in human severe conditions such as CVID, LOCID or other manifestations of immune disorders such as autoimmunity. This research proposal, which initiates with a “bed-to-bench” approach, has two main “experimental” goals:
• Identify new molecular defects resulting in immune disorders by using the newest tools of molecular and cellular biology and human genetics.
• Analyze T cell repertoire through innovative next generation sequencing protocols as an indirect mean to assess the function of the thymus in these patients.

To achieve our objectives we have set-up a consortium of three partners:
• An INSERM academic laboratory (INSERM U768, Genome Dynamics in the Immune System) specialized in the study of DNA repair. This team has identified two DNA repair factors in the past: Artemis and Cernunnos
• An AP-HP clinical unit at Necker–Enfants Malades Hospital in Paris (Unité d’Immunologie, Hématologie et Rhumatologie Pédiatriques), which has a well-established expertise in pediatric inherited immune deficiencies.
• An AP-HP clinical unit at Saint-Louis Hospital in Paris (Unité d'immunopathologie Département d'Immunologie Clinique), which has expertise in immunedeficiencies in adult (CVID and LOCID). This partner is holding the DEFI cohort of CVID patients.

Beside the basic science objectives of our project on the understanding of DNA damage responses we anticipate that it will result in direct bench-to-bed application for the immediate benefit of patients and their families. These clinical perspectives include:
• Molecular diagnosis.
• Genetic counseling and prenatal diagnosis for severe conditions.
• Development of new biomarkers for the analysis of thymocytes fitness and the capacity of cells to efficiently respond to DNA damage of various sources. The DNA repair biomarker could be of considerable use in the clinics to analyze patients before any kind of genotoxic regimen to determine if these patients are at risk to over-respond to these treatments.