Long-Range Control of Class Switch Recombination by Transcriptional Regulatory Elements

Dauba, Audrey; Khamlichi, Ahmed Amine

doi:10.3389/fimmu.2021.738216

Cited by 10 publications

(9 citation statements)

References 153 publications

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“…Non-IgM isotype expression requires class switch recombination (CSR) to position rearranged variable (V), diversity (D), and joining (J) gene fragments near the different constant (C) region genes, either directly (e.g., CSR from Cµ to Cγ3) or sequentially (e.g., CSR from Cµ to Cγ3 and then to Cγ2b) [ 33 , 34 ]. Processes instrumental in CSR include: (i) RNA Pol II-mediated sterile transcription across targeted switch (S) sites and C sequences; (ii) activation-induced cytidine deaminase (AID) recruitment to positions of RNA Pol II stalling and DNA looping to juxtapose promoters, enhancers, and S regions [ 35 , 36 ]; (iii) DNA breaks within S sequences; and (iv) S-S ligations to delete intervening sequences and position V-D-J near non-Cµ C fragments [ 34 , 37 , 38 ].…”

Section: Introductionmentioning

confidence: 99%

How Estrogen, Testosterone, and Sex Differences Influence Serum Immunoglobulin Isotype Patterns in Mice and Humans

Surman

Jones

Penkert

et al. 2023

Viruses

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Females often exhibit superior immune responses compared to males toward vaccines and pathogens such as influenza viruses and SARS-CoV-2. To help explain these differences, we first studied serum immunoglobulin isotype patterns in C57BL/6 male and female mice. We focused on IgG2b, an isotype that lends to virus control and that has been previously shown to be elevated in murine females compared to males. Improvements in IgG2b serum levels, and/or IgG2b ratios with other non-IgM isotypes, were observed when: (i) wildtype (WT) female mice were compared to estrogen receptor knockout mice (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all higher in WT mice), (ii) unmanipulated female mice were compared to ovariectomized mice (IgG2b/IgA was higher in unmanipulated animals), (iii) female mice were supplemented with estrogen in the context of an inflammatory insult (IgG2b and IgG2b/IgG3 were improved by estrogen supplementation), and (iv) male mice were supplemented with testosterone, a hormone that can convert to estrogen in vivo (IgG2b, IgG2b/IgG3, IgG2b/IgG1, and IgG2b/IgA were all improved by supplementation). We next examined data from three sets of previously described male and female human blood samples. In each case, there were higher IgG2 levels, and/or ratios of IgG2 with non-IgM isotypes, in human females compared to males. The effects of sex and sex hormones in the mouse and human studies were subtle, but frequent, suggesting that sex hormones represent only a fraction of the factors that influence isotype patterns. Examination of the gene loci suggested that upregulation of murine IgG2b or human IgG2 could be mediated by estrogen receptor binding to estrogen response elements and cytosine-adenine (CA) repeats upstream of respective Cγ genes. Given that murine IgG2b and human IgG2 lend to virus control, the isotype biases in females may be sufficient to improve outcomes following vaccination or infection. Future attention to sex hormone levels, and consequent immunoglobulin isotype patterns, in clinical trials are encouraged to support the optimization of vaccine and drug products for male and female hosts.

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Section: Introductionmentioning

confidence: 99%

How Estrogen, Testosterone, and Sex Differences Influence Serum Immunoglobulin Isotype Patterns in Mice and Humans

Surman

Jones

Penkert

et al. 2023

Viruses

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“…The 3′RR and functional S-regions are sufficient to recruit AID and provide CSR when placed at an artificial location in the genome at the IGK locus [ 585 ]. Defects in the IGH regulatory enhancers in mice affect recombination at the IGH locus to varying degrees and may lead to a deficiency in antibody production [ 579 , 586 , 587 , 588 ].…”

Section: Structural Variations In the MM Genomesmentioning

confidence: 99%

Genome Instability in Multiple Myeloma: Facts and Factors

Aksenova

Zhuk

Lada

et al. 2021

Cancers

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Multiple myeloma (MM) is a malignant neoplasm of terminally differentiated immunoglobulin-producing B lymphocytes called plasma cells. MM is the second most common hematologic malignancy, and it poses a heavy economic and social burden because it remains incurable and confers a profound disability to patients. Despite current progress in MM treatment, the disease invariably recurs, even after the transplantation of autologous hematopoietic stem cells (ASCT). Biological processes leading to a pathological myeloma clone and the mechanisms of further evolution of the disease are far from complete understanding. Genetically, MM is a complex disease that demonstrates a high level of heterogeneity. Myeloma genomes carry numerous genetic changes, including structural genome variations and chromosomal gains and losses, and these changes occur in combinations with point mutations affecting various cellular pathways, including genome maintenance. MM genome instability in its extreme is manifested in mutation kataegis and complex genomic rearrangements: chromothripsis, templated insertions, and chromoplexy. Chemotherapeutic agents used to treat MM add another level of complexity because many of them exacerbate genome instability. Genome abnormalities are driver events and deciphering their mechanisms will help understand the causes of MM and play a pivotal role in developing new therapies.

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“…In addition, antibodies recruit cellular effectors of immunity to eliminate pathogens and tumor cells. During development, variable regions of the immunoglobulin (Ig) locus undergo V(D)J recombination of both the heavy (IGH) and light chains (IGL) to generate 10 11 to 10 14 novel combinations of genetic material (13)(14)(15). Upon stimulation, further diversifications of Ig genes can be induced by Class Switch Recombination (CSR) and Somatic Hypermutation (SHM) (Figure 1).…”

Section: Introductionmentioning

confidence: 99%

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

Gullickson

Niedernhofer

et al. 2022

Front. Immunol.

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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.

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Long-Range Control of Class Switch Recombination by Transcriptional Regulatory Elements

Cited by 10 publications

References 153 publications

How Estrogen, Testosterone, and Sex Differences Influence Serum Immunoglobulin Isotype Patterns in Mice and Humans

How Estrogen, Testosterone, and Sex Differences Influence Serum Immunoglobulin Isotype Patterns in Mice and Humans

Genome Instability in Multiple Myeloma: Facts and Factors

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

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