Class-Switch Recombination Occurs Infrequently in Germinal Centers

Roco, Jonathan A.; Mesin, Luka; Binder, Sebastian; Nefzger, Christian M.; González-Figueroa, Paula; Cañete, Pablo F.; Ellyard, Julia I.; Shen, Qian; Robert, Philippe A.; Cappello, Jean; Vohra, Harpreet; Zhang, Yang; Nowosad, Carla R.; Schiepers, Arïen; Corcoran, Lynn M.; Toellner, Kai‐Michael; Polo, José M.; Meyer‐Hermann, Michael; Victora, Gabriel D.; Vinuesa, Carola G.

doi:10.1016/j.immuni.2019.07.001

Cited by 364 publications

(363 citation statements)

References 74 publications

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“…Our results therefore indicate that the enhanced demethylation of BCR downstream targets in HIGM2 naïve B cells may be the result of the expansion of autoreactive B cell clones as a consequence of the absence of AID. Our results are also consistent with the recent observation that class-switch recombination occurs infrequently in germinal centers 75 .…”

Section: Discussionsupporting

confidence: 93%

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Català-Moll

Weichenhan

Lutsik

et al. 2019

Preprint

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Mutations in activation induced deaminase (AID) lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated cytosine deamination has been proposed as mediating active demethylation, although evidences both support and cast doubt on such a role. We here made use of HIGM2 B cells to investigate direct AID involvement in active DNA demethylation.HIGM2 naïve and memory B cells both display widespread DNA methylation defects, of which approximately 25% of these defects correspond to active events. For genes that undergo active demethylation that is impaired in HIGM2 individuals, we did not observe AID involvement but a participation of TET enzymes. DNA methylation alterations in HIGM2 naïve B cells are related to premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data supports a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.

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Section: Discussionsupporting

confidence: 93%

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Català-Moll

Weichenhan

Lutsik

et al. 2019

Preprint

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“…Central and peripheral tolerance checkpoints are known to be defective in RA patients, leading to the accumulation of naïve autoreactive B cells in the periphery (34). Activation of naïve B cells, facilitated by T cell help and/or TLR ligands, induces class switching outwith the germinal centre (35). The high frequency of IgG hypoM in RA patients stongly suggests that they have arisen from an ongoing extrafollicular response.…”

Section: Discussionmentioning

confidence: 99%

Rheumatoid arthritis patients express a skewed repertoire of polyclonal, hypomutated B-cell receptors

Cowan

Miles

Capitani

et al. 2019

Preprint

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Abbreviations BCR -B cell receptor DMARD -Disease modifying anti-rheumatic drug VH -variable portion of the heavy chain BCDT -B cell depletion therapy ACPA -anti citrullinated protein antibodies RF-rheumatoid factor NGS -next generation sequencing PBMC -peripheral blood mononuclear cells ERA -early rheumatoid arthritis ESRA -established RA CDR -complementarity determining region SHM -somatic hypermutation AID -activation-induced cytidine deaminase GC -germinal centre FR -framework region CS -class-switching Conflict of interest statementThe authors have declared that no conflict of interest exists. • Abstract ObjectivesThe success of B cell depletion therapy in rheumatoid arthritis (RA) therapy testifies to their importance in disease pathogenesis, but the precise B cells mediating this are unclear. For example, it is unknown if RA patients predominantly express a limited number of circulating clonally expanded populations of B cells with highly mutated B cell antigen receptors (BCRs) that would constitute a shared antigen driven response. MethodsTo address this, we have undertaken the largest study to date utilising next generation sequencing (NGS), to identify the full length of the peripheral blood BCR sequences from the antigen-binding heavy chain. Between 25,000 to 200,000 BCR sequences per patient were analysed from 127 newly diagnosed RA patients, 16 heathy controls, 16 RA patients with established disease and 8 paired blood and synovial samples. This was complemented with B cell subset analysis from an additional 64 RA patients and 22 healthy controls. ResultsRA patients expressed a significantly higher percentage of circulating poorly mutated polyclonal IgG +ve variable heavy (IgG-Vh) BCR sequences, both at the time of diagnosis and following treatment. These sequences resided predominantly within TNF-alpha secreting IgG +ve CD27 -ve B cells, that were expanded in RA peripheral blood and enriched in the rheumatoid synovium. Surprisingly, peripheral and synovial B cell repertoires of RA patients are quite distinct, sharing very few IgG sequences. ConclusionsThis is the first report to conclusively establish that a substantial component of the peripheral B cell repertoire in RA consists of polyclonal hypomutated IgG +ve BCRs that may play a critical role in driving an autoimmune mediated inflammation.

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“…Intriguingly, a recent study suggested that most class switching to IgG occurs at extrafollicular sites prior to GC formation in protein antigen immunizations . If the same is true for other isotypes (e.g., IgE and IgA) remains to be determined.…”

Section: Tfh Cells As Drivers Of Ige Responsesmentioning

confidence: 99%

“…15,72 Intriguingly, a recent study suggested that most class switching to IgG occurs at extrafollicular sites prior to GC formation in protein antigen immunizations. 76 If the same is true for other isotypes (e.g., IgE and IgA) remains to be determined. But an important question to be answered now is where Tfh cells and their derived cytokines regulate class switching during different types of immune insults such as infections or allergic responses.…”

Section: The New Paradigm-tfh Cells Are Required For Ige Responses Inmentioning

confidence: 99%

Regulation of IgE by T follicular helper cells

Gowthaman

Chen

Eisenbarth

2020

Journal of Leukocyte Biology

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Allergies to food and environmental antigens have steeply grown to epidemic proportions. IgE antibodies are key mediators of allergic disease, including life‐threatening anaphylaxis. There is now compelling evidence that one of the hallmarks of anaphylaxis‐inducing IgE molecules is their high affinity for allergen, and the cellular pathway to high‐affinity IgE is typically through sequential switching of IgG B cells. Further, in contrast to the previously held paradigm that a subset of CD4+ T cells called Th2 cells promotes IgE responses, recent studies suggest that T follicular helper cells are crucial for inducing anaphylactic IgE. Here we discuss recent studies that have enabled us to understand the nature, induction, and regulation of this enigmatic antibody isotype in allergic sensitization.

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Class-Switch Recombination Occurs Infrequently in Germinal Centers

Cited by 364 publications

References 74 publications

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Rheumatoid arthritis patients express a skewed repertoire of polyclonal, hypomutated B-cell receptors

Regulation of IgE by T follicular helper cells

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