The Role of DNA Repair in Immunological Diversity: From Molecular Mechanisms to Clinical Ramifications

Abstract

An effective humoral immune response necessitates the generation of diverse and high-affinity antibodies to neutralize pathogens and their products. To generate this assorted immune repertoire, DNA damage is introduced at specific regions of the genome. Purposeful genotoxic insults are needed for the successful completion of multiple immunological diversity processes: V(D)J recombination, class-switch recombination, and somatic hypermutation. These three processes, in concert, yield a broad but highly specific immune response. This review highlights the importance of DNA repair mechanisms involved in each of these processes and the catastrophic diseases that arise from DNA repair deficiencies impacting immune system function. These DNA repair disorders underline not only the importance of maintaining genomic integrity for preventing disease but also for robust adaptive immunity.

Keywords: DNA damage; DNA repair; antibodies; immunodeficiency; immunological diversity.

Figure 1

Mechanisms of generating diversity in adaptive immunity. (A) V(D)J recombination relies upon RAG-mediated recombination for the rearrangement of immunoglobulin and T cell receptor variable (V), diversity (D), and joining (J) gene segments during lymphocyte development. Many enzymes involved in non-homologous end joining (NHEJ) and other DNA repair mechanisms are required to correct the programmed DNA double-strand breaks (DSB) that initiate gene segment rearrangement. (B) Class-switch recombination (CSR) of the immunoglobulin heavy chain locus swaps antibody isotype via recombination of different constant (C) regions. CSR requires activation-induced cytidine deaminase (AID) to initiate a DNA DSB break at the switch (S) region, which is subsequently repaired by classical and alternative NHEJ. The schematic shows a CSR event that leads to the production of IgG antibody isotype. (C) Somatic hypermutation (SHM) utilizes AID-dependent programmed mutations in the variable region of antibody gene segments to create a large number of antibodies with goal of creating greater affinity for antigen. Antibody heavy (V_H) and light (V_L) chains, as well as antigen (black circle) are illustrated. Figure created with BioRender.com.