From Characterization of Immune Repertoire to Modeling Inborn Errors in Human Adaptive Immunity

The functionality of the adaptive immunity is initially defined by the development of almost infinite number of diverse B cell receptors (BCR) on B cells and T cell receptors (TCR) on T cells, which can be defined as the immune repertoire. This immune repertoire is generated by the combinatorial rearrangements of gene segments via the V(D)J recombination process, allowing for the plasticity of the adaptive immune system to recognize any foreign antigen. Patients harboring mutations in the genes involved in the V(D)J recombination process may lead to dysregulated or even absence of the adaptive immune system, leading to Severe Combined Immuno Deficiencies (SCIDs). We studied the immune repertoire of SCID patients with mutations in various gene such as RAGs, DCRLE1C, IL7RA among others, which showed distinct characteristics of the immune repertoire, from reduced repertoire diversity to differential gene usage and altered characteristics of the BCRs and TCRs. Next we sought to generate a cellular model of human origin to induce endogenous V(D)J recombination upon introduction of patient derived mutations. Using this cellular platform, we would like to assess the direct effect of a given mutation from a patient on the VDJ recombination process and on the immune repertoire. This will allow us to demonstrate whether there is a correlation between the V(D)J recombination, mutation and severity of the disease.