The μ Switch Region Tandem Repeats Are Important, but Not Required, for Antibody Class Switch Recombination

Luby, Thomas M.; Schrader, Carol E.; Stavnezer, Janet; Selsing, Erik

doi:10.1084/jem.193.2.159

Cited by 88 publications

(79 citation statements)

References 59 publications

(70 reference statements)

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“…Expression of mIgA1 in peripheral B cells did not alter their ability to produce specific antibodies after immunization and even to undergo CSR at low levels in the absence of any Sμ repeat. This partial CSR defect was similar to that reported for the core Sμ or the complete Sμ deletions (23,24). These data confirm that neither the pentameric repeats featuring the Sμ region nor expression of μ/δ are mandatory for (CD79a as a reference transcript).…”

Section: Discussionsupporting

confidence: 74%

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

Duchez

Amin

Cogné

et al. 2010

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

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Sequentially along B cell differentiation, the different classes of membrane Ig heavy chains associate with the Igα/Igβ heterodimer within the B cell receptor (BCR). Whether each Ig class conveys specific signals adapted to the corresponding differentiation stage remains debated. We investigated the impact of the forced expression of an IgA-class receptor throughout murine B cell differentiation by knocking in the human Cα Ig gene in place of the Sμ region. Despite expression of a functional BCR, homozygous mutant mice showed a partial developmental blockade at the pro-B/pre-BI and large pre-BII cell stages, with decreased numbers of small pre-BII cells. Beyond this stage, peripheral B cell compartments of reduced size developed and allowed specific antibody responses, whereas mature cells showed constitutive activation and a strong commitment to plasma cell differentiation. Secreted IgA correctly assembled into polymers, associated with the murine J chain, and was transported into secretions. In heterozygous mutants, cells expressing the IgA allele competed poorly with those expressing IgM from the wild-type allele and were almost undetectable among peripheral B lymphocytes, notably in gut-associated lymphoid tissues. Our data indicate that the IgM BCR is more efficient in driving early B cell education and in mucosal site targeting, whereas the IgA BCR appears particularly suited to promoting activation and differentiation of effector plasma cells.

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Section: Discussionsupporting

confidence: 74%

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

Duchez

Amin

Cogné

et al. 2010

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

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“…These animals have a significant defect of isotype class switching, show asymmetrical deletions of the Cm gene in post-GC B cells and, like ABC DLBCLs, accumulate aberrant junctions within the S regions. [24][25][26] The observation that the large internal deletions within the Sm region, which are particularly frequent in IgM þ DLBCLs, cluster on the productive IGH alleles may thus provide a mechanistic explanation for the resistance of these tumors to isotype switching. We hypothesize that the loss of a large part of the Sm region may occur frequently during ABC DLBCL lymphomagenesis, during early CSR attempts.…”

Section: Discussionmentioning

confidence: 99%

The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma

et al. 2011

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Gene expression profiling has identified two major molecular subtypes of diffuse large B-cell lymphoma (DLBCL) that are histologically indistinguishable but differ in cure rates. Here, we investigated whether the isotype of the B-cell receptor (BCR) expressed by the tumoral cells correlated with the molecular subtype and survival. Gene expression analysis clustered the 53 patients included in this study into three subgroups, 17 germinal center B-cell-like (GCB) cases, 26 activated B-celllike (ABC) cases and 10 intermediate cases. The molecular subtype was correlated with the isotype, as 15/17 GCB cases expressed a secondary isotype (immunoglobulin (Ig)G or IgA), whereas 24/26 ABC cases expressed a primary isotype (IgM or IgD) (Po0.0001). There was a trend toward a worse outcome for patients with an ABC DLBCL and a shorter overall survival for patients with IgM þ tumor (P ¼ 0.21 and 0.014, respectively). Finally, fluorescence in situ hybridization (FISH) analysis revealed a striking asymmetric pattern, as the IGHM gene is conserved only on the productive IGH allele in most IgM þ tumors. Taken together, these data indicate that the isotype of the BCR is a reliable indicator for the GCB and ABC subtypes in DLBCL, and suggest that the conservation of an IgM is required for ABC DLBCL lymphomagenesis to occur.

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“…Genetargeted mutational studies have demonstrated that S regions are specialized targets for CSR. Thus, deletion of the 5Ј donor S greatly diminishes CSR (11,12), whereas deletion of S␥1, which is a 3Ј acceptor, essentially abolishes CSR to C␥1 (13). Moreover, replacement of S␥1 with a 4-kb Xenopus S region, which contains a region of AGCT repeats similar to those found in mammalian S regions, allowed substantial CSR.…”

mentioning

confidence: 94%

Influence of switch region length on immunoglobulin class switch recombination

Zarrin

Tian

Wang

et al. 2005

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

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The class and effector functions of antibodies are modulated through the process of Ig heavy chain class switch recombination (CSR). CSR occurs between switch (S) regions that lie upstream of the various Ig heavy chain constant region exons. Molecular analyses of S-region functions have been hampered by their large size and repetitive nature. To test potential relationships between S-region size and efficiency of CSR, we generated normal B lymphocytes in which the 12-kb S region flanking the C␥1 exons (S␥1) was replaced with synthetic or endogenous S regions of various lengths. Replacement of S␥1 with 1-and 2-kb synthetic sequences representing the S␥1 core repeats or a 4-kb portion of the core endogenous S␥1 region supported CSR frequencies that directly correlated with S-region length. These findings indicate that Sregion size is an important factor in determining endogenous CSR efficiency. Moreover, these results also will allow the development of a systematic system to test the function of various S-region motifs by replacing endogenous S regions with synthetic S regions controlled for size effects.IgH switch region ͉ activation-induced deaminase ͉ synthetic switch region ͉ IgG1

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The μ Switch Region Tandem Repeats Are Important, but Not Required, for Antibody Class Switch Recombination

Cited by 88 publications

References 59 publications

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

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

The isotype of the BCR as a surrogate for the GCB and ABC molecular subtypes in diffuse large B-cell lymphoma

Influence of switch region length on immunoglobulin class switch recombination

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