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The IgH 3' regulatory region controls somatic hypermutation in germinal center B cells.

ABSTRACT: Interactions with cognate antigens recruit activated B cells into germinal centers where they undergo somatic hypermutation (SHM) in V(D)J exons for the generation of high-affinity antibodies. The contribution of IgH transcriptional enhancers in SHM is unclear. The E? enhancer upstream of C? has a marginal role, whereas the influence of the IgH 3' regulatory region (3'RR) enhancers (hs3a, hs1,2, hs3b, and hs4) is controversial. To clarify the latter issue, we analyzed mice lacking the whole 30-kb extent of the IgH 3'RR. We show that SHM in VH rearranged regions is almost totally abrogated in 3'RR-deficient mice, whereas the simultaneous Ig heavy chain transcription rate is only partially reduced. In contrast, SHM in ? light chain genes remains unaltered, acquitting for any global SHM defect in our model. Beyond class switch recombination, the IgH 3'RR is a central element that controls heavy chain accessibility to activation-induced deaminase modifications including SHM.

SUBMITTER: Rouaud P

PROVIDER: S-EPMC3727322 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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The IgH 3' regulatory region controls somatic hypermutation in germinal center B cells.

Rouaud Pauline P Vincent-Fabert Christelle C Saintamand Alexis A Fiancette Rémi R Marquet Marie M Robert Isabelle I Reina-San-Martin Bernardo B Pinaud Eric E Cogné Michel M Denizot Yves Y

The Journal of experimental medicine 20130701 8

Interactions with cognate antigens recruit activated B cells into germinal centers where they undergo somatic hypermutation (SHM) in V(D)J exons for the generation of high-affinity antibodies. The contribution of IgH transcriptional enhancers in SHM is unclear. The Eμ enhancer upstream of Cμ has a marginal role, whereas the influence of the IgH 3' regulatory region (3'RR) enhancers (hs3a, hs1,2, hs3b, and hs4) is controversial. To clarify the latter issue, we analyzed mice lacking the whole 30-k ...[more]

PMID: 23825188

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Project description:The study of human B cell response to dengue virus (DENV) infection is critical to understand serotype-specific protection and the cross-reactive sub-neutralizing response. Whereas the first is beneficial and thus represents the ultimate goal of vaccination, the latter has been implicated in the development of severe disease, which occurs in a small, albeit significant, fraction of secondary DENV infections. Both primary and secondary infections are associated with the production of poly-reactive and cross-reactive IgG antibodies.To gain insight into the effect of DENV infection on the B cell repertoire, we used VH region high-throughput cDNA sequencing of the peripheral blood IgG B cell compartment of 19 individuals during the acute phase of infection. For 11 individuals, a second sample obtained 6 months later was analyzed for comparison. Probabilities of sequencing antibody secreting cells or memory B cells were estimated using second-order Monte Carlo simulation.We found that in acute disease there is an increase in IgG B cell diversity and changes in the relative use of segments IGHV1-2, IGHV1-18, and IGHV1-69. Somewhat unexpectedly, an overall low proportion of somatic hypermutated antibody genes was observed during the acute phase plasmablasts, particularly in secondary infections and those cases with more severe disease.Our data are consistent with an innate-like antiviral recognition system mediated by B cells using defined germ-line coded B cell receptors, which could provide a rapid germinal center-independent antibody response during the early phase of infection. A model describing concurrent T-dependent and T-independent B cell responses in the context of DENV infection is proposed, which incorporates the selection of B cells using hypomutated IGHV segments and their potential role in poly/cross-reactivity. Its formal demonstration could lead to a definition of its potential implication in antibody-dependent enhancement, and may contribute to rational vaccine development efforts.

Dataset Information

The IgH 3' regulatory region controls somatic hypermutation in germinal center B cells.

Publications

The IgH 3' regulatory region controls somatic hypermutation in germinal center B cells.

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