During development and differentiation into functional plasma cells, B cells undergo two DNA recombination reactions, V(D)J and class switch recombination (CSR), and a process of extensive somatic hypermutation (SHM). The functional consequences of these three reactions result in the production of a mature immune system that is diverse, has high affinity for antigens, and exhibits a wide range of functions. Although all these reactions are beneficial to the generation of a fully functional immune system, they permanently modify the information encoded in the DNA, and any mistake could lead to immune deficiency and/or transformation. The Primary Immune Deficiency Program at Mount Sinai School of Medicine is currently treating a large population of patients with severe combined immune deficiency (SCID), combined immune deficiency (CID) and common variable immune deficiency (CVID). While there has been much progress in delineating the molecular causes of SCID, currently about 20% of all cases are still of unknown origin. In addition, the molecular defects present in patients with CID and CVID have not yet been defined. This application proposes to investigate the hypothesis that deregulation and/or mutations in factors that constitute the repair machinery of (Aim 1) V(D)J recombination and for (Aim 2) class switch recombination and somatic hypermutation represents some of the molecular defects responsible for SCID, and some patients with CID and CVID. This hypothesis will be investigated by using pre-established reporter systems. DNA sequence and biochemical activity of the repair factors will also be investigated. Results obtained from the proposed analysis will help to understand the molecular defects present in these patients and facilitate the path to finding better treatments for these life threatening diseases.
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