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, Canada) according to the manufacturer's recommendations. Cells were then washed, counted, and 2 3 10 6 cells were incubated with anti-B220-BV510, anti-IgD-BV421, anti-CD23-PC7, anti-IgM a-fluorescein isothiocyanate (FITC), anti-IgM b-PE, anti-CD11beF780, and anti-CD5-APC antibodies, vol.13, p.14

, Transcript analysis Peritoneal cavity B1 B cells were sorted from 39RR-deficient mice and 129 wild-type (wt) mice using a BD FACSAria III. 7 The following antibodies were used: anti-B220-BV510, anti-CD23-PC7, anti-IgMFITC, anti-CD11b-eF780, anti-IgD-BV421, anti-CD19-PE, and antiCD5-APC. Total RNA was extracted and real-time polymerase chain reaction (PCR) was performed in duplicate by use of TaqMan and SYBR assay reagents and analyzed on an ABI Prism 7000 system (Applied Biosystems, pp.59-98

, After washing, we added 100 mL/well of anti-mouse-IgM-alkaline phosphatase (AP) (1/2000) for 1.5 hours at 37°C. After washing, we assayed AP activity using AP substrate at room temperature and measured optical density at 405 nm. Next-generation sequencing for repertoire analysis We performed repertoire sequencing analysis using the strategy described by Li et al. 16 developed for T-cell repertoire diversity and clonotype. These experiments used a new generation methodology, which combines 59RACE PCR; sequencing; and, for analysis, the international ImMunoGeneTics information system (IMGT), IMGT/HighV-QUEST Web portal, and IMGT-ONTOLOGY concepts. In brief, RNA was extracted from sorted B1 and B2 B cells. RNA (500 ng) was used for sequencing. We amplified transcripts with 59RACE PCR using a reverse primer hybridizing within the m C H1 exon, as described previously. 17 Sequencing adapter sequences was thus added by primer extension, and resulting amplicons were sequenced on a GS FLX 1 sequencing system, Glyceraldehyde3-phosphate dehydrogenase (GAPDH) was used for normalization of gene expression levels (reference Mm99999915-g1). serum albumin (BSA) in PBS buffer, pp.59-98

, Results B1 B-cell usage of a 39RR-deleted allele

, Mouse B1 and B2 B cells are distinguished on the basis of membrane cell surface markers. B1 B cells are B220 low IgM high IgD low CD23CD11b 1/low , whereas B2 B cells are B220 high IgM high IgD high CD23 1

, Mixed 129 3 C57BL/6 mice (IgH a wt /b wt ) were used as control mice. A scheme of the backcross experiments is reported in Figure 1. The complete staining strategy in flow cytometry experiments is reported in Figure 2. Flow cytometry analysis of splenic B cells with IgM allotype-specific antibodies indicated lowered (P 5 .0004, MannWhitney U test) percentages of B1 B cells expressing an a allotype in a D39RR /b wt (IgM a /IgM b ratio: 0.26) but not in a wt /b wt mice (IgM a / IgM b ratio: 1.09) (Figure 3A-B). As a positive control, we confirmed the significant disadvantage (P 5 .0004) of a D39RR-expressing mature splenic B2 B cells of IgH a D39RR /b wt mice vs b wt-expressing cells (IgM a /IgM b ratio: 1.07 vs 0.35 for a wt /b wt and a D39RR /b wt mice, respectively) (Figure 3C-D). 7 Analysis of peritoneal cavity B cells also showed a strong disadvantage (P 5 .002) of the mutated a allotype both in B1 (Figure 3E-F) and B2 B cells (Figure 3G-H) of IgH a D39RR /b wt mice. In the peritoneal cavity and in the absence of a 39RR defect, we noted a bias toward higher expression of the IgH a allele in B1 B cells (but not in B2 B cells) from a wt /b wt control mice (Figure 3E-F), adult mice, they are mainly located in the spleen and peritoneal cavity where they represent the minority and majority of B-cell subpopulations, respectively. 4 First, we investigated the impact of the expression of a 39RR-deleted allele on B1 B-cell fate

, 21 Several differences in signaling pathways between C57BL/6 and Sv/129 mice, resulting in variations of the B-cell fate, have previously been described. 22 The peritoneal B1 B-cell allelic bias might thus be linked with a differential strength of expression and/or signaling between IgM a and IgM b BCR for, B-cell maturation, including a high tonic BCR signaling, vol.4

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. Ghazzaui, Left: A representative experiment is shown. Right: Percentages of IgA + B1 B-cells in eight 3?RR-deficient mice and eight wt mice. The results are reported as the means ± SEMs. (c) IgA levels in the peritoneal cavity of pristane-treated 3?RR-deficient mice and wt mice. Same mice as in part A. ELISAs were performed as described. 7 Results are reported as the means ± s.e.m for eleven 3?RR-deficient mice and eight wt mice. (d) IgA levels in culture supernatants of IgA + B1 B-cells. Same mice as in part B. ELISAs were performed as described. 7 Results are reported as the means ± SEMs for twelve 3?RR-deficient mice and eleven wt mice. (e) q-PCR analysis of I ?-C ?, Cells were gated on B220 low IgD low CD23 ? CD11b +/low cells, vol.2, 2018.

, of five 3?RR-deficient mice and four wt mice. (f) Representative immunostaining (×200 magnitude) with antibodies against IgA in the guts of 3?RR-deficient mice (right) and wt mice (left). A representative experiment out of three mice per genotype is shown. (g) Representative immunostaining (×200 magnitude), The results are reported as the means ± s.e.m

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G. Issaoui-h*, S. A. Boyer-f, and D. ,

, IgD class switch recombination (CSR) is a rare and enigmatic event limited to few B-cell subsets in specific lymphoid tissues

, High throughput sequencing technologies now allow the acquisition of huge number of sequence, but raw data remain impossible to analyze by hand. Manually finding S?-?? junction sequences in these huge amounts of data would be like searching needles in haystacks. We recently reported a new computational tool (CSReport) for automatic analysis of CSR junctions sequenced by high-throughput sequencing [4] that we used to analyze IgD CSR more in depth. PCR for S?-?? junctions were done as previously described [2]. Junctions were studied using a touchdown PCR, IgD CSR is differently regulated than conventional IgG, IgA and IgE CSR since it is not under the control of the IgH 3? regulatory region (3?RR) super-enhancer

. Briefly, Sequenced reads were then mapped to each switch regions using BLAST algorithm. The computational tool we developed performs junction's assembly, identify junction's structure and breakpoint, and outputs results of statistical summarization of identified junctions

, From these figures, we estimate that only 5-10% of sequenced reads can be mapped to a S?-?? junction with BLAST/CSReport. This is therefore in agreement with our finding of 185,683 out of 2,522,418 reads (7%) are identified as a S?-?? junction. The number of unique junctions (i.e. clonally independent) is indeed dependent of the biological frequency of this CSR event in the studied sample. When compared to previous studies of other switch junctions [4], IgD CSR clearly appears to be an elusive and rare event only occurring in specific B-cell compartments. The positions of IgD junctions (in term of distance from S? and ??) are reported in Fig. 1A. The structural profiles of IgD junctions (blunt, micro-homology or junctions with insertion) are reported in Fig. 1B. The mutational profiles of IgD junctions are reported in Fig. 1C. The colocations of IgD junctions with WRCY/ RGYW (AID sites) and TCY/WGA (APOBEC3 sites) motifs are reported in Fig. 1D. Finally the nucleotide motifs (most frequent 8-nt motifs at breakpoint in S? and ??) are reported in Fig. 1E. Summarization of these 222 independent junctions provided descriptions of S?-?? CSR sequences at an unprecedented level. Until now only 21 had been reported after cloning and subsequent sequencing by Sanger's method [2]. In the present study the positions of IgD junctions (in term of distance from S? and ??), their structural profiles (blunt, micro-homology or junctions with insertion) and their mutational profiles are similar to those previously reported [2] reinforcing the validity of our experimental protocol for automatic analysis of CSR junctions. The distribution of breakpoints along S regions gave indications of motif targeting during the generation of double-strand breaks. If colocation of breakpoints in S? with WRCY/RGYW motifs was found as for conventional AID, As S?-?? junctions are amplified as PCR products of variable length (roughly equal to 1 kb, according to double-strand breaks' location), they are fragmented in 150-250 bp for sequencing. Therefore, many reads do not contain the junctional site (but are mapped either to S? or ??)

, If mutation frequencies in S ? for S?-?? junctions were of the order of magnitude of those for S?-S? 1 and S?-S? 3 junctions, it was not the case for mutation frequencies in the ?? acceptor regions compared to S? 1 and S? 3 [5]. These results reinforce the hypothesis that ?? is differently targeted than S? during IgD CSR. Altogether these results reinforce the concept that IgD CSR markedly differs from conventional IgG, IgA and IgE CSR [2]. It is of evidence that IgD CSR is regulated and that double-strand breaks in the ?? region are not random breaks. Since IgD CSR is restricted to specific B-cell subsets it is likely that specific microenvironments might promote activity of endonucleases yet to be identified, Clearly, a role for APOBEC3 in the targeting of the ?? region during the enigmatic IgD CSR deserves to be investigated

K. Chen, W. Xu, M. Wilson, B. He, N. W. Miller et al., Immunoglobulin D enhances immune surveillance by activating antimicrobial: proinflammatory and B cell-stimulating programs in basophils, Nat. Immunol, vol.10, pp.889-898, 2009.

P. Rouaud, A. Saintamand, F. Saad, C. Carrion, S. Lecardeur et al., Elucidation of the enigmatic IgD class-switch recombination via germline deletion of the IgH 3' regulatory region, J. Exp. Med, vol.211, pp.975-985, 2014.
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J. H. Choi, K. W. Wang, D. Zhang, X. Zhan, T. Wang et al., IgD class switching is initiated by microbiota and limited to mucosa-associated lymphoid tissue in mice, Proc. Natl. Acad. Sci. U. S. A, vol.114, pp.1196-1204, 2017.

A. Saintamand, P. Rouaud, F. Saad, G. Rios, M. Cogné et al., Elucidation of IgH 3' region regulatory role during class switch recombination via germline deletion, Nat. Commun, vol.6, p.7084, 2015.
URL : https://hal.archives-ouvertes.fr/hal-01212563

F. Boyer, H. Boutouil, I. Dalloul, Z. Dalloul, J. Cook-moreau et al., CSReport: a new computational tool designed for automatic analysis of class switch recombination junctions sequenced by high-throughput sequencing, J. Immunol, vol.198, pp.4148-4155, 2017.
URL : https://hal.archives-ouvertes.fr/hal-01567748

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, Each point in the graph is a unique junction defined by 2-bp positions (in S? and ??). B: Structural profile of S?-?? junctions. C: Mutation frequency in the donor region (S ? ) and the acceptor region (? d ) during ??CSR. D: Estimation of local density of WRCY/RGYW (green/red) motifs, TCY/WGA (green/red) motifs and breakpoint along S? and ?? regions. Colocation events are highlighted by dotted lines. E: most frequent 8-nt motifs at breakpoints in S? and ??, CSReport provides valuable S?-?? DNA break/repair information on larges data set. Structural and positional results obtained from analysis of S?-?? junctions in IgD + IgM ? sorted peritoneal B-cells (pool of 19 mice), vol.188, pp.86-88, 2017.