Molecular characterization of germ-line immunoglobulin A transcripts produced during transforming growth factor type beta-induced isotype switching.

Lebman, Deborah A.; Nomura, D; Coffman, Robert L.; Lee, Frank D.

doi:10.1073/pnas.87.10.3962

Cited by 123 publications

(53 citation statements)

References 32 publications

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“…8). IgA class-switching in sIgM ϩ sIgA Ϫ B cells has been shown to precede the synthesis of germline C␣ mRNA transcripts (49). In contrast, it was found that intestinal and splenic sIgM ϩ sIgA Ϫ B-2 cells did not express C␣ transcript-specific mRNA (Fig.…”

Section: Discussionmentioning

confidence: 89%

IL-15 and IL-15 Receptor Selectively Regulate Differentiation of Common Mucosal Immune System-Independent B-1 Cells for IgA Responses

Hiroi

Yanagita

Ohta

et al. 2000

The Journal of Immunology

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We show in this report a new regulatory role for IL-15 and IL-15R in the development of B-1 cells and their differentiation into IgA-producing cells. Mucosal IgA levels were found to be inhibited by anti-IL-15 mAb treatment in vivo, but enhanced by administration of rIL-15, while serum IgA levels remained unaffected. Mucosal B-1 cells preferentially proliferated in response to IL-15 in vitro. When mucosal B-1 and B-2 cells were separated into surface (s)IgM+sIgA− and sIgM−sIgA+ fractions, IL-15R-specific mRNA was found to be predominant in both sIgM+sIgA− and sIgM−sIgA+ B-1 cells at a much higher level than B-2 cells. Further, incubation of these different subsets of B-1 and B-2 cells with IL-15 resulted in greater enhancement of the corresponding receptor expression by B-1 subset when compared with B-2 fraction. Interestingly, de novo isolated sIgM+sIgA− B-1, but not sIgM+sIgA− B-2, cells were already class-switched cells because the germline Cα transcript was detected and was then further enhanced by IL-15. IL-15 also supported differentiation of both sIgM+sIgA− and sIgM−sIgA+ B-1 cells into IgA-producing cells. Taken together, these findings suggest that IL-15 is a critically important cytokine for the differentiation of both sIgM+,IgA− and sIgM−sIgA+ B-1 cells expressing IL-15R into IgA-producing cells in mucosal tissues.

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Section: Discussionmentioning

confidence: 89%

IL-15 and IL-15 Receptor Selectively Regulate Differentiation of Common Mucosal Immune System-Independent B-1 Cells for IgA Responses

Hiroi

Yanagita

Ohta

et al. 2000

The Journal of Immunology

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“…In response to stimulation of mature B cells by interleukins and/or other T-cell-or macrophageproduced factors, nuclear proteins (73) would bind to the tandem repeat area of the ,u locus. In response to other interleukins and other factors, the second portion of the switch complex would form near a downstream tandem repeat (switch) region (68), perhaps after the region is made accessible due to germ line (sterile) transcription (32,36,53 (20). The IgH locus inversions and duplications that are attributed to sister chromatid exchange might also be mediated by this mechanism, since switch complexes can assemble on the C of one chromosome and on a CH on another chromosome (16).…”

Section: Discussionmentioning

confidence: 99%

Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Owens¹,

Finkelman²,

Mountz³

et al. 1991

Mol. Cell. Biol.

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Plasma cells secrete immunoglobulins other than immunoglobulin M (IgM) after a deletion and recombination in which a portion of the immunoglobulin heavy-chain locus (IgH), from the 5'-flanking region of the ,u constant-region gene (C,e) to the 5'-flanking region of the secreted heavy-chain constant-region gene (CH), is deleted. The recombination step is believed to be targeted via switch regions, stretches of repetitive DNA which lie in the 5' flank of all CH genes except 8. Although serum levels of IgD are very low, particularly in the mouse, IgD-secreting plasmacytomas of BALB/c and C57BL/6 mice are known. In an earlier study of two BALB/c IgD-secreting hybridomas, we reported that both had deleted the C,, gene, and we concluded that this deletion was common in the normal generation of IgD-secreting cells. To learn how such switch recombinations occur in the absence of a switch region upstream of the Cr,1 exon, we isolated seven more BALB/c and two C57BL/6IgD-secreting hybridomas. We determined the DNA sequences of the switch recombination junctions in eight of these hybridomas as well as that of the C57BL/6 hybridoma B1-8.81 and of the BALB/c, IgD-secreting plasmacytoma TEPC 1033. All of the lines had deleted the C, gene, and three had deleted the C,,, exon in the switch recombination event. The delta switch recombination junction sequences were similar to those of published productive switch recombinations occurring 5' to other heavy-chain genes, suggesting that nonhomologous, illegitimate recombination is utilized whenever the heavy-chain switch region is involved in recombination. The switch from ,u, the 5'-most heavy-chain constantregion gene, to other heavy-chain classes is accomplished by another somatic rearrangement of the heavy-chain locus, the switch recombination. In switch recombination, a 5' breakpoint upstream of the C,, gene is joined to a 3' breakpoint upstream of another CH gene, and the intervening DNA is deleted. The switch recombination has been linked to switch regions: 2 to 5 kb of tandem repeats in which the tetramers AGCT and TGGG occur frequently (46). Switch regions are found in the 5'-flanking area of each CH gene except C6. Curiously, most switch recombinations do not have their 5' breakpoints in the switch ,u region (S,,), though the 3' breakpoints usually are in the switch region of the expressed CH gene (25). Since IgD is rare in human serum and very rare in mouse serum, it was believed that normal production of secreted * Corresponding author. Synthesis of immunoglobulin (IgIgD might not require switch recombination but might occur by alternative splicing of transcripts spanning the VH-D-JH and C -C. locus, the same mechanism utilized for membrane IgD (reviewed in reference 6). Although human B cells with intact C,, genes can synthesize small but significant amounts of mRNA for secreted 8 chain (30), this is not the case in mice (15). It is likely that secretion of large amounts of IgD requires some sort of recombination, since three cultured human cell lines and three human m...

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“…This germline transcription likely facilitates the DNA lesion-inducing activity of AID by: 1) promoting chromatin accessibility, 2) AID recruitment via RNA PolII, and 3) generation of a ssDNA target for AID (17)(18)(19). Transcription through the H chain ␣ region is initiated by B cell activation and TGF-␤ signaling (20).…”

Section: Mz B Cells Switch Preferentially To Igamentioning

confidence: 99%

Enhanced IgA Class Switching in Marginal Zone and B1 B Cells Relative to Follicular/B2 B Cells

Kaminski

Stavnezer

2006

The Journal of Immunology

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Mouse splenic marginal zone (MZ) B cells and B1 B cells enriched in the peritoneal cavity respond preferentially to T cell-independent Ags compared with follicular (FO)/B2 B cells. Despite the differential responses of B cell subsets to various stimuli, and despite the need for multiple stimuli to induce IgA class switching, the relative contribution of B cell subpopulations to IgA production is unknown. By culturing purified B cell populations, we find that MZ and peritoneal B1 cells switch more readily to IgA than do splenic FO or peritoneal B2 cells in BLyS/LPS/TGF-β. Addition of IL-4, IL-5, and anti-IgD dextran to the cultures enhances IgA switching in FO/B2 and MZ B cells to a similar frequency, but this treatment suppresses IgA class switching in B1 cells. Thus, IgA switching differs among purified B cell subsets, suggesting that individual B cell populations could contribute differentially to IgA expression in vivo, depending on available stimuli.

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Molecular characterization of germ-line immunoglobulin A transcripts produced during transforming growth factor type beta-induced isotype switching.

Cited by 123 publications

References 32 publications

IL-15 and IL-15 Receptor Selectively Regulate Differentiation of Common Mucosal Immune System-Independent B-1 Cells for IgA Responses

IL-15 and IL-15 Receptor Selectively Regulate Differentiation of Common Mucosal Immune System-Independent B-1 Cells for IgA Responses

Nonhomologous recombination at sites within the mouse JH-C delta locus accompanies C mu deletion and switch to immunoglobulin D secretion.

Enhanced IgA Class Switching in Marginal Zone and B1 B Cells Relative to Follicular/B2 B Cells

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