somatic hypermutation
Summary
Somatic hypermutation is a process in activated B cells that introduces point mutations into the variable regions of immunoglobulin genes, enabling affinity maturation of antibodies. It occurs in the germinal centers of lymph nodes and is mediated by activation-induced cytidine deaminase (AID). This process is essential for producing high-affinity antibodies during a humoral immune response.
Detail
Somatic hypermutation (SHM) occurs in germinal centers of secondary lymphoid organs (lymph nodes, spleen) following antigen exposure and T follicular helper cell interaction (CD40L-CD40 signaling). Activation-induced cytidine deaminase (AID) deaminates cytosine to uracil in the variable (V) regions of immunoglobulin heavy and light chain genes, creating U:G mismatches. These mismatches are processed by base excision repair and mismatch repair pathways, introducing point mutations at a much higher rate than normal genomic mutation rates. B cells with mutations that increase antigen affinity are positively selected by follicular dendritic cells and helper T cells, undergoing clonal expansion (affinity maturation). Cells with deleterious or self-reactive mutations undergo apoptosis. This process works alongside class switch recombination (also AID-dependent) but is distinct from V(D)J recombination, which occurs earlier in B cell development in the bone marrow and is RAG1/RAG2-mediated. Clinically, deficiency in AID causes Hyper-IgM syndrome type 2, characterized by elevated IgM, absent IgG/IgA/IgE, and poor germinal center formation, leading to recurrent pyogenic infections. Understanding SHM is important for grasping B cell maturation, antibody diversity, and related immunodeficiencies on USMLE Step 1.
Sources
- Kaplan USMLE Step 1 Immunology
- First Aid for the USMLE Step 1
- Janeway's Immunobiology
- Robbins Basic Pathology
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