Human Models of Inherited Immunoglobulin Class Switch Recombination and Somatic Hypermutation Defects (Hyper-IgM Syndromes)

Durandy, Anne; Revy, Patrick; Fischer, Alain

doi:10.1016/s0065-2776(04)82007-8

Cited by 38 publications

(41 citation statements)

References 218 publications

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“…Deleterious mutations in the AID gene were recognized as the molecular cause for the HIGM2 deficiency, which together with the analysis of the AID -/-mice, provided a major contribution in our understanding of CSR [65]. In addition, these studies established the mechanistic link between CSR and SHM by demonstrating that AID indeed initiates both events.…”

Section: Higm: Csr and Shm Defectsmentioning

confidence: 96%

“…Finally, several cases of HIGM syndrome are not ascribed to mutations in either one of the abovementioned factors. For some of these patients (HIGM5), the absence of DNA-dsb detection at IgH loci in activated B cells argues for a defect at the onset of CSR, possibly involving an AID cofactor [65]. Perhaps more interestingly for the purpose of this reflection a last group of patients (HIGM4) is characterized by a CSR defect downstream of the AID generated DNA-dsb [67].…”

Section: Ung Deficiency and Morementioning

confidence: 99%

“…As for the survey of RS-SCID patients, much valuable information on the physiology of CSR and SHM was gained through the in-depth analysis of human patients suffering inherited Ig CSR and SHM deficiencies, also known as hyper-IgM (HIGM) syndromes [65]. The common features of this syndrome include normal or high serum IgM levels, but little or none of the switched isotypes (IgG, IgA, IgE).…”

Section: Human Hyper-igm Syndromesmentioning

confidence: 99%

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DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

et al. 2007

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B and T lymphocytes are exposed to various genotoxic stresses during their life, which originate from programmed molecular mechanisms during their development and maturation or are secondary to cellular metabolism during acute phases of cell proliferation and activation during immune responses. How lymphocytes handle these multiple genomic assault has become a focus of interest over the years, perhaps beginning with the identification of the murine scid model in the early 80s when it was recognized that DNA repair deficiencies had profound consequences on the immune system. In this respect, the immune system represents an ideal model to study DNA damage responses (DDR) and the survey of immune deficiency conditions in humans or the development of specific animal models provided many major contributions in our understanding of the various biochemical pathways at play during DDR in general. Although the role of DNA repair in the early phases of B and T cell development has been analyzed thoroughly, the role of these functions in various aspects of the mature immune system (homeostasis, immunological memory, ageing) is less well understood. Lastly, the analysis of DNA repair in the immune system has provided many insights in the more general understanding of cancer. IntroductionAll living organisms are exposed to endogenous and environmental genotoxic stresses causing DNA injuries. Among these lesions, DNA double-strand breaks (DNAdsb) are considered as the most harmful. Unrepaired DNA damage can lead to mutation, cancer, or cell death. Several cellular responses are triggered, in what is called the DNA damage response (DDR), to handle DNA lesions (Fig. 1). The purpose of this review is not to go in the depth of the various biochemical pathways that constitute the DDR, as this aspect has been covered elsewhere [1], but rather to discuss, in an historical way, how the immune system depends on these pathways on one hand, and how studies of the immune system have been instrumental in the better understanding of some of these pathways, in particular the non-homologous end joining (NHEJ) pathway. Indeed, the immune system is the place of many genotoxic stresses that happen at various time points during the development and maturation of lymphocytes (Fig. 2). These DNA We discuss here the links that exist between the immune system and the DDR with the standpoint of the lymphocyte lifespan, from birth to ageing, and discuss the consequences of DNA repair defects on the integrity of the immune system. Development of the immune system V(D)J recombinationB and T lymphocytes respond to foreign pathogens through specialized antigenic receptors, the BCR and TCR, respectively. The required diversity of these receptors is ensured by the V(D)J recombination process (Fig. 3), which assembles previously scattered variable (V), diversity (D), and joining (J) encoding gene segments through a specialized somatic DNA rearrangement mechanism [2]. The reaction is initiated by the lymphoid-specific factors Rag1 and Rag2, which specifically...

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Section: Higm: Csr and Shm Defectsmentioning

confidence: 96%

Section: Ung Deficiency and Morementioning

confidence: 99%

Section: Human Hyper-igm Syndromesmentioning

confidence: 99%

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DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

et al. 2007

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“…Other conditions include the hyper-IgM syndrome that can be caused by mutations in at least 6 different genes (20) and SCID, known to be caused by mutations in at least 10 different genes (15,21). The most striking example of this will likely be the syndrome of common variable immunodeficiency that promises to have many different molecular causes, including mutations in genes that encode SAP (11), inducible costimulator (ICOS) (22), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) (23), and the CD40 ligand (20).…”

Section: Other Genes With Phenotypic Variabilitymentioning

confidence: 99%

Variable phenotypic expression of mutations in genes of the immune system

Buckley

2005

Journal of Clinical Investigation

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“…SCID can be caused by at least 14 different genes [11] and more ever Omenn syndrome can be caused by different hypomorphic mutations in SCID causing genes [12]. In addition Hyper IgM syndrome can be caused by mutation in 6 different genes [13]. These variable phenotypic and molecular characterizations of PIDs pose a significant challenge to the approach and the diagnosis mostly related to lack of knowledge, appropriate immunological and molecular assays or the need to screen for several genes.…”

Section: Introductionmentioning

confidence: 99%

Variable Phenotypic Presentation of Primary Immunodeficiency Diseases: A Challenge for Diagnosis

Al‐Mousa¹

2012

J Blood Lymph

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Human Models of Inherited Immunoglobulin Class Switch Recombination and Somatic Hypermutation Defects (Hyper-IgM Syndromes)

Cited by 38 publications

References 218 publications

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

DNA repair and the immune system: From V(D)J recombination to aging lymphocytes

Variable phenotypic expression of mutations in genes of the immune system

Variable Phenotypic Presentation of Primary Immunodeficiency Diseases: A Challenge for Diagnosis

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