Hyper-IgM Syndromes
Purpose of Review: The recent elucidation of the molecular defects leading to hyper-IgM syndromes has provided considerable insight into the complex mechanisms that govern the antibody maturation in humans.
Recent Findings: The study of a large cohort of patients revealed unexpected clinical, immunological and genetic findings, which have significant implications on the molecular basis of immunoglobulin class switch recombination and somatic hypermutation, as shown for hypomorphic mutations in the nuclear factor-ÎşB essential modulator (NEMO) gene and peculiar activation-induced cytidine deaminase defects that differently affect class switch recombination and somatic hypermutation. The description of the hyper-IgM condition due to mutations in the gene encoding uracil-N glycosylase has been essential for defining the DNA-editing activity of activation-induced cytidine deaminase. Novel findings are awaited from the study of the yet genetically undefined hyper-IgM syndromes, leading to the identification of activation-induced cytidine deaminase cofactors and proteins involved in class switch recombination-induced DNA repair. In the genetically characterized hyper-IgM syndromes, the precise identification of the molecular defect allows the evaluation of hyper-IgM complications, and thus aids assessment of prognosis and proper survey and treatment.
Summary: The important contribution made by investigation of this condition improves our understanding of the physiology of the antibody response in humans.
Maturation of the antibody repertoire results in the production of efficient antibodies of various isotypes, via a two-step process. The first step occurs in the fetal liver or in the bone marrow in an antigen and T cell-independent way. It is achieved by genomic rearrangement between variable (V), diversity (D), and joining (J) elements of the immunoglobulin heavy chain gene and between V and J elements of the immunoglobulin light chain gene, resulting in the membrane expression by mature B cells of a B cell receptor of the IgM and IgD isotypes. The second step is shaped in the secondary lymphoid organs and is driven by antigen and T cell interaction. It involves two processes: the immunoglobulin class switch recombination (CSR) leading to the production of antibodies of various isotypes and the generation of somatic hypermutations (SHMs), which results in the production of antibodies with high affinity for antigen. Another pathway for preimmune repertoire diversification used in chicken is gene conversion that introduces mutations templated by germline donor sequences.
CSR is accomplished by a DNA recombination event between two switch (S) regions, located upstream of the Cµ (Sµ) and a target Cx region of another isotype (Sx) with deletion of the intervening DNA. By means of CSR, the Cµ heavy chain of immunoglobulin is replaced by a different Cx heavy chain, thus allowing the production of immunoglobulins of various isotypes with the same antigen affinity since the V region in left unchanged. Conversely, the SHM process modifies the antigen affinity (but not the isotype) of an antibody by introducing mutations in the V region at a very high frequency (1 × 10 bases per generation). Mutations are generally missense mutations but deletions or insertions can also occur. This step is followed by the positive selection and proliferation of B cells harboring a B cell receptor with a higher affinity for antigen through a close interaction with antigen-loaded follicular dendritic cells and follicular B helper T cells.
Three successive events are required for CSR and SHM to occur: transcription of target DNA sequences, DNA cleavage and DNA repair.
Purpose of Review: The recent elucidation of the molecular defects leading to hyper-IgM syndromes has provided considerable insight into the complex mechanisms that govern the antibody maturation in humans.
Recent Findings: The study of a large cohort of patients revealed unexpected clinical, immunological and genetic findings, which have significant implications on the molecular basis of immunoglobulin class switch recombination and somatic hypermutation, as shown for hypomorphic mutations in the nuclear factor-ÎşB essential modulator (NEMO) gene and peculiar activation-induced cytidine deaminase defects that differently affect class switch recombination and somatic hypermutation. The description of the hyper-IgM condition due to mutations in the gene encoding uracil-N glycosylase has been essential for defining the DNA-editing activity of activation-induced cytidine deaminase. Novel findings are awaited from the study of the yet genetically undefined hyper-IgM syndromes, leading to the identification of activation-induced cytidine deaminase cofactors and proteins involved in class switch recombination-induced DNA repair. In the genetically characterized hyper-IgM syndromes, the precise identification of the molecular defect allows the evaluation of hyper-IgM complications, and thus aids assessment of prognosis and proper survey and treatment.
Summary: The important contribution made by investigation of this condition improves our understanding of the physiology of the antibody response in humans.
Maturation of the antibody repertoire results in the production of efficient antibodies of various isotypes, via a two-step process. The first step occurs in the fetal liver or in the bone marrow in an antigen and T cell-independent way. It is achieved by genomic rearrangement between variable (V), diversity (D), and joining (J) elements of the immunoglobulin heavy chain gene and between V and J elements of the immunoglobulin light chain gene, resulting in the membrane expression by mature B cells of a B cell receptor of the IgM and IgD isotypes. The second step is shaped in the secondary lymphoid organs and is driven by antigen and T cell interaction. It involves two processes: the immunoglobulin class switch recombination (CSR) leading to the production of antibodies of various isotypes and the generation of somatic hypermutations (SHMs), which results in the production of antibodies with high affinity for antigen. Another pathway for preimmune repertoire diversification used in chicken is gene conversion that introduces mutations templated by germline donor sequences.
CSR is accomplished by a DNA recombination event between two switch (S) regions, located upstream of the Cµ (Sµ) and a target Cx region of another isotype (Sx) with deletion of the intervening DNA. By means of CSR, the Cµ heavy chain of immunoglobulin is replaced by a different Cx heavy chain, thus allowing the production of immunoglobulins of various isotypes with the same antigen affinity since the V region in left unchanged. Conversely, the SHM process modifies the antigen affinity (but not the isotype) of an antibody by introducing mutations in the V region at a very high frequency (1 × 10 bases per generation). Mutations are generally missense mutations but deletions or insertions can also occur. This step is followed by the positive selection and proliferation of B cells harboring a B cell receptor with a higher affinity for antigen through a close interaction with antigen-loaded follicular dendritic cells and follicular B helper T cells.
Three successive events are required for CSR and SHM to occur: transcription of target DNA sequences, DNA cleavage and DNA repair.