Clinical and Immunological Diversity of Recombination Defects

abstract

The immune system is capable to detect a large variability of pathogens and distinguish them from the body’s own healthy tissue. The immune system consists of the innate- and adaptive immune system. The adaptive immune system consists of B-and T-lymphocytes, which can recognize pathogens with an antigen-specific receptor. B-lymphocytes can adapt their responses during an infection to improve recognition of the pathogen and they generate long-term immunological memory. These antigen-specific receptors are called B-cell receptor (BR) and T-cell receptor (TR), respectively. Since the number of possible antigens is innumerable, an enormous diversity of the antigen-specific receptors is required. To achieve this, the BR and TR contain a variable domain that is unique for each individual T or B cell. This variable domain is generated by recombination of the antigen receptor genes in a process which is called V(D)J recombination. This process requires lymphoid specific proteins to generate DNA double strand breaks (DSB), but is also dependent on a common DNA repair pathway to repair the DSB. Defects in V(D)J recombination hamper the production of the antigen-specific receptors, which results in a complete or partial block in B- and T-cell differentiation, leading to a combined B- and T-cell deficiency. In this General Introduction the B and T-cell development will be described, with special focus on the generation of the antigen-specific receptor repertoire. The role of DNA repair during the V(D)J recombination process and during further maturation of the B cells will be highlighted. Subsequently, clinical and immunological aspects of V(D)J recombination and DNA repair defects resulting in immunodeficiency will be addressed. Finally, the aims of this thesis will be outlined.