V(D)J recombination
Overview
V(D)J recombination is a unique mechanism of genetic recombination that occurs in developing lymphocytes during the early stages of T and B cell maturation. It results in the highly diverse repertoire of antibodies and T cell receptors found on B cells and T cells, respectively. The process is a defining feature of the adaptive immune system and its immense capacity to recognize antigens.
Mechanism of V(D)J Recombination
The mechanism of V(D)J recombination is complex and involves several steps. The process is initiated by the lymphocyte-specific RAG complex, which binds to specific recombination signal sequences (RSS) flanking the V, D, and J gene segments. The RAG complex introduces double-strand breaks (DSBs) at the border of the RSS and the coding gene segment. This is followed by the formation of a hairpin structure at the coding ends and blunt ends at the signal sequences.
The hairpin structure is then opened and processed by the Artemis:DNA-PKcs complex, an endonuclease that introduces nicks at the apex of the hairpin, leading to the formation of palindromic P nucleotides. The coding ends are further processed by the addition of non-templated N nucleotides by terminal deoxynucleotidyl transferase (TdT).
The processed coding ends are then ligated by the non-homologous end joining (NHEJ) pathway to form a coding joint, while the signal ends are ligated to form a signal joint. The resulting recombination event leads to the expression of a unique antigen receptor, contributing to the diversity of the immune response.
Role in Immune Diversity
The V(D)J recombination process plays a crucial role in the generation of immune diversity. It allows for the combination of different V, D, and J gene segments, leading to a vast array of possible antigen receptor sequences. This diversity is further increased by the addition of P and N nucleotides during the joining process.
The process of V(D)J recombination is tightly regulated to ensure the generation of functional and diverse antigen receptor repertoires. Aberrations in this process can lead to immunodeficiency, autoimmunity, or lymphoid malignancies.
Clinical Significance
Defects in the V(D)J recombination process can lead to several immune disorders. For example, mutations in the RAG genes can result in severe combined immunodeficiency (SCID), a condition characterized by a lack of functional T and B cells. Similarly, defects in the NHEJ pathway can lead to immunodeficiency syndromes.
On the other hand, aberrant V(D)J recombination can lead to the generation of oncogenic translocations and the development of lymphoid malignancies. For example, the chromosomal translocation t(14;18) in follicular lymphoma results from an aberrant V(D)J recombination event.