V(D)J recombination

V(D)J recombination is the process by which B cells and T cells of the immune system rearrange their DNA segments to generate unique receptors that can collectively recognize a vast array of antigens. This mechanism is essential for the development of the adaptive immune system, allowing it to respond to a wide variety of pathogens. V(D)J recombination occurs in the primary lymphoid organs, specifically the bone marrow for B cells and the thymus for T cells.

Mechanism

V(D)J recombination involves the random assembly of variable (V), diversity (D), and joining (J) gene segments. This process is mediated by the RAG1 and RAG2 proteins, which introduce double-strand breaks at specific recombination signal sequences (RSS) adjacent to the V, D, and J segments. The broken DNA ends are then processed and ligated together by a complex of enzymes known as the non-homologous end joining (NHEJ) pathway, resulting in a diverse repertoire of antigen receptor genes.

In B cells, this recombination results in the creation of unique B cell receptors (BCRs), which are expressed on the cell surface as immunoglobulins. In T cells, V(D)J recombination generates diverse T cell receptors (TCRs), which recognize peptides presented by Major Histocompatibility Complex (MHC) molecules.

Significance

The diversity generated by V(D)J recombination is a cornerstone of the adaptive immune response. It enables the immune system to recognize and respond to an almost limitless array of antigens. However, the process must be tightly regulated to prevent the generation of receptors that react against self-antigens, which could lead to autoimmune diseases.

Regulation

V(D)J recombination is tightly controlled at multiple levels, including the accessibility of gene segments to the recombination machinery, the activity of RAG proteins, and the cell cycle stage. The process is also influenced by chromatin structure, with certain histone modifications making gene segments more accessible for recombination.

Clinical Significance

Aberrations in V(D)J recombination can lead to immunodeficiencies, where the immune system is unable to effectively respond to infections. For example, mutations in the RAG1 or RAG2 genes can result in severe combined immunodeficiency (SCID), characterized by the absence of functional B and T cells. Additionally, errors in V(D)J recombination can contribute to the development of lymphoid cancers, such as lymphomas and leukemias, by causing inappropriate activation of oncogenes or inactivation of tumor suppressor genes.

See Also

• Adaptive immune system
• B cell
• T cell
• Immunoglobulin
• T cell receptor
• Major Histocompatibility Complex

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