Premature replacement of μ with α immunoglobulin chains impairs lymphopoiesis and mucosal homing but promotes plasma cell maturation

Duchez, Sophie; Amin, Rada; Cogné, Nadine; Delpy, Laurent; Sirac, Christophe; Pascal, Virginie; Corthésy, Blaise; Cogné, Michel

doi:10.1073/pnas.0912393107

Cited by 57 publications

(64 citation statements)

References 33 publications

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“…Instead, peritoneal cavity B-1 B cells were largely missing. These results are in accordance with, and extend, previous data (24) indicating that IgA can replace IgM to drive early B-cell development and instruct peripheral B-cell maturation. Whereas V H gene use may influence the FO versus MZ B-cell fate (27), our data reveal that BCR extrinsic factors critically contribute to this decision.…”

Section: Discussionsupporting

confidence: 82%

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Antibody repertoire diversification through VH gene replacement in mice cloned from an IgA plasma cell

Kumar

Bach

Mainoldi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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In mammals, VDJ recombination is responsible for the establishment of a highly diversified preimmune antibody repertoire. Acquisition of a functional Ig heavy (H) chain variable (V) gene rearrangement is thought to prevent further recombination at the IgH locus. Here, we describe V H Q52 NT ; Vκgr32 NT Ig monoclonal mice reprogrammed from the nucleus of an intestinal IgA + plasma cell. In V H Q52 NT mice, IgA replaced IgM to drive early B-cell development and peripheral B-cell maturation. In V H Q52 NT animals, over 20% of mature B cells disrupted the single productive, nonautoimmune IgH rearrangement through VH replacement and exchanged it with a highly diversified pool of IgH specificities. VH replacement occurred in early pro-B cells, was independent of pre-B-cell receptor signaling, and involved predominantly one adjacent V H germ-line gene. VH replacement was also identified in 5% of peripheral B cells of mice inheriting a different productive V H rearrangement expressed in the form of an IgM H chain. In summary, editing of a productive IgH rearrangement through VH replacement can account for up to 20% of the IgH repertoire expressed by mature B cells. A functional immune system relies on the ability of B-lymphocytes to recognize foreign antigens in a highly specific fashion through the Ig receptor (also called B-cell receptor, or BCR). Each BCR consists of two identical Ig heavy (H) and light (L) chains, which are expressed on the surface of the B cell together with an Igα/Igβ heterodimer to form a signaling unit. In most vertebrates, the ability of the immune system to generate a highly diversified repertoire of antibody specificities relies on the stochastic assembly of variable (V), diversity (D), and joining (J) gene segments that encode for the antigen-binding domain of IgH and IgL chains of the BCR. This process, called V(D)J recombination, is mediated by the ordered recruitment at Ig loci of the RAG-1/2 endonucleases, followed by nonhomologous endjoining factors that catalyze the joining of the cleaved DNA segments (1). The latter processes are often accompanied by trimming and insertion of n-nucleotides at junctional ends. All together these mechanisms contribute to generate a highly diversified pool of Ig specificities.Ig receptor editing provides B cells with the opportunity to exchange BCR specificity through secondary VDJ recombination. Whereas IgL chain editing was shown to play a central role in the neutralization of autoimmune BCR specificities expressed by newly generated immature B cells (2), the contribution of IgH receptor editing to antibody repertoire diversification has remained largely unappreciated. Two mechanisms promote secondary IgH rearrangements. In V H -to-J H direct joining, RAG proteins cleave at Recombination Signal Sequences (RSSs) of V H and J H elements lying, respectively, upstream and downstream of the original V H rearrangement, followed by microhomology-driven joining of the Ig gene segments. This mechanism has been mainly observed in IgH knock-in mice carrying nonpr...

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Section: Discussionsupporting

confidence: 82%

“…NT mice may result from impaired expression and/or signaling of a pre-BCR composed of an IgA H chain (24). Altered pre-BCR function may, in turn, prolong RAG-mediated recombination at the IgH locus, hence facilitating VH replacement.…”

Section: The Lower Number Of Pre-b Cells In V H Q52mentioning

confidence: 99%

Antibody repertoire diversification through VH gene replacement in mice cloned from an IgA plasma cell

Kumar

Bach

Mainoldi

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…Human IgA metabolism in this model mimics that of normal mouse IgA and notably features transport of pIgA from the internal milieu toward mucosal secretions. 15 Kidney dysfunction occurs in these mice when they additionally express the human FcaRI receptor. 16 We show that, by itself, the a1KI model mimics an initial phase of amorphous IgA deposition without inflammation following kinetics in which immune stimuli by environmental antigens modulate the IgA repertoire and structure.…”

Section: Discussionmentioning

confidence: 99%

“…15 We recently observed that IgA deposition occurs in these mice and leads to hematuria when deposits also include soluble CD89. 16 We now examined whether responses to environmental antigenic challenges induce modifications influencing initial IgA deposition and whether primary structures from different monoclonal IgA could also participate in this process.…”

mentioning

confidence: 99%

IgA Structure Variations Associate with Immune Stimulations and IgA Mesangial Deposition

Oruc¹,

Oblet²,

Boumédiène³

et al. 2016

JASN

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IgA1 mesangial deposition is the hallmark of IgA nephropathy and Henoch-Schönlein purpura, the onset of which often follows infections. Deposited IgA has been reported as polymeric, J chain associated, and often, hypogalactosylated but with no information concerning the influence of the IgA repertoire or the link between immune stimuli and IgA structure. We explored these issues in the a1KI mouse model, which produces polyclonal human IgA1 prone to mesangial deposition. Compared with mice challenged by a conventional environment, mice in a specific pathogen-free environment had less IgA deposition. However, serum IgA of specific pathogen-free mice showed more galactosylation and much lower polymerization. Notably, wild-type, a1KI, and even J chain-deficient mice showed increased polymeric serum IgA on exposure to pathogens. Strict germfree conditions delayed but did not completely prevent deposition; mice housed in these conditions had very low serum IgA levels and produced essentially monomeric IgA. Finally, comparing monoclonal IgA1 that had different variable regions and mesangial deposition patterns indicated that, independently of glycosylation and polymerization, deposition might also depend on IgA carrying specific variable domains. Together with IgA quantities and constant region post-translational modifications, repertoire changes during immune responses might, thus, modulate IgA propensity to deposition. These IgA features are not associated with circulating immune complexes and C3 deposition and are more pertinent to an initial IgA deposition step preceding overt clinical symptoms in patients.

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“…The absence of IgM expression in A150/A150 mice, together with previous findings that B cells expressing class-switched isotypes were poor competitors of IgM-expressing B cells in heterozygotes (28,29), led us to investigate the effect of the mutation on IgM expression. In the A150 model, this unfolds into three lines of inquiry: the effect of the mutation on IgM expression from the mutant allele, potential allelic inclusion, and allelic exclusion.…”

Section: Resultsmentioning

confidence: 99%

Complete cis Exclusion upon Duplication of the Eμ Enhancer at the Immunoglobulin Heavy Chain Locus

Puget

Leduc

Oruc

et al. 2015

Molecular and Cellular Biology

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dDeveloping lymphocytes somatically diversify their antigen-receptor loci through V(D)J recombination. The process is associated with allelic exclusion, which results in monoallelic expression of an antigen receptor locus. Various cis-regulatory elements control V(D)J recombination in a developmentally regulated manner, but their role in allelic exclusion is still unclear. At the immunoglobulin heavy chain locus (IgH), the E enhancer plays a critical role in V(D)J recombination. We generated a mouse line with a replacement mutation in the constant region of the locus that duplicates the E enhancer and allows premature expression of the ␥3 heavy chain. Strikingly, IgM expression was completely and specifically excluded in cis from the mutant allele. This cis exclusion recapitulated the main features of allelic exclusion, including differential exclusion of variable genes. Notably, sense and antisense transcription within the distal variable domain and distal V H -DJ H recombination were inhibited. cis exclusion was established and stably maintained despite an active endogenous E enhancer. The data reveal the importance of the dynamic, developmental stage-dependent interplay between IgH locus enhancers and signaling in the induction and maintenance of allelic exclusion. Developing B and T lymphocytes have the capacity to somatically alter their genomes and diversify their antigen receptor loci through V(D)J recombination. This developmentally regulated process is initiated by the lymphoid-specific RAG1/2 complex, which recognizes conserved recombination signal sequences (RSSs) flanking the V, D, and J segments in the variable domain of antigen receptor (IgH, IgL, and TCR) loci (1, 2). V(D)J recombination correlates with chromatin modifications, germ line transcription of rearranging V, D, and J segments, and large-scale chromosome dynamics within nuclear compartments (3-5).The mouse IgH locus contains ϳ200 V H genes, which are subdivided into V H gene families. The most prominent are the distal V H genes, notably the large V HJ558 gene family, and the proximal V H genes. These are followed by a dozen D segments (ϳ60 kb), 4 J H segments (ϳ2 kb), and 8 constant genes (ϳ200 kb) (6, 7).In B lymphocytes, V(D)J assembly starts at the IgH locus, where D segments are first recombined to J H segments on both alleles. Although they have the potential to undergo V H -DJ H recombination on the two alleles, the vast majority of B lymphocytes are subject to allelic exclusion, i.e., a given B cell expresses only one IgH allele. A productive V(D)J rearrangement allows production of the heavy chain, which associates with surrogate light chains and signals an arrest of V H -DJ H recombination on the second IgH allele. If the first V H -DJ H rearrangement is not productive, then the second allele can undergo V H -DJ H recombination (1, 8). Nonetheless, in rare B cells, productive rearrangements can occur on both alleles (i.e., allelic inclusion), but only one heavy chain from only one allele can associate with surrogate light chains...

show abstract

Premature replacement of μ with α immunoglobulin chains impairs lymphopoiesis and mucosal homing but promotes plasma cell maturation

Cited by 57 publications

References 33 publications

Antibody repertoire diversification through VH gene replacement in mice cloned from an IgA plasma cell

Antibody repertoire diversification through VH gene replacement in mice cloned from an IgA plasma cell

IgA Structure Variations Associate with Immune Stimulations and IgA Mesangial Deposition

Complete cis Exclusion upon Duplication of the Eμ Enhancer at the Immunoglobulin Heavy Chain Locus

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