An immunoglobulin heavy-chain gene is formed by at least two recombinational events

Davis, Mark M.; Calame, Kathryn; Early, P.; Livant, Donna L.; Joho, Rolf H.; Weissman, Irving L.; Hood, Leroy

doi:10.1038/283733a0

Cited by 297 publications

(129 citation statements)

References 37 publications

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“…Our approaches to immunology and biology were quite complementary, and I later took a sabbatical with Lee in 1981 to learn how to work with genes myself. He had some great students and fellows at the time, e.g., Mark Davis, Mike Hunkapiller, Michael Steinmetz, Phil Early, and Stuart Kim, and we began a series of collaborations where my lab would isolate pure normal cell subsets and together we would examine the germline or rearranged status of immunoglobulin genes (73,74) and then TCR genes (75). We continue to collaborate to this day.…”

Section: The Thymus Thymic Maturation B Lymphocyte Development Hommentioning

confidence: 99%

How One Thing Led to Another

Weissman

2016

Annu. Rev. Immunol.

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I started research in high school, experimenting on immunological tolerance to transplantation antigens. This led to studies of the thymus as the site of maturation of T cells, which led to the discovery, isolation, and clinical transplantation of purified hematopoietic stem cells (HSCs). The induction of immune tolerance with HSCs has led to isolation of other tissue-specific stem cells for regenerative medicine. Our studies of circulating competing germline stem cells in colonial protochordates led us to document competing HSCs. In human acute myelogenous leukemia we showed that all preleukemic mutations occur in HSCs, and determined their order; the final mutations occur in a multipotent progenitor derived from the preleukemic HSC clone. With these, we discovered that CD47 is an upregulated gene in all human cancers and is a “don't eat me” signal; blocking it with antibodies leads to cancer cell phagocytosis. CD47 is the first known gene common to all cancers and is a target for cancer immunotherapy.

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Section: The Thymus Thymic Maturation B Lymphocyte Development Hommentioning

confidence: 99%

How One Thing Led to Another

Weissman

2016

Annu. Rev. Immunol.

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“…Because the C H region determines the Ab effector function, class switching allows the humoral immune response to adaptively respond to a variety of different infectious organisms. Class switching is mediated by DNA recombination occurring between switch (S) region sequences residing 5Ј to each C H gene, except C␦ (4,5).…”

Section: U Pon Activation By Ag or Mitogens Igmmentioning

confidence: 99%

Differential Regulation of Mouse Germline Ig γ1 and ε Promoters by IL-4 and CD40

Chunsheng

Stavnezer

2001

The Journal of Immunology

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Before Ig class switching, RNA transcription through the specific S regions undergoing recombination is induced by cytokines and other activators that induce and direct switching. The resulting germline (GL) transcripts are essential for switch recombination. To understand the differential regulation of mouse IgG1 and IgE, we compared the promoters for GL γ1 and ε transcripts. We addressed the question of why the promoter that regulates GL ε transcription is more responsive to IL-4 than the γ1 promoter and also why GL ε transcription is more dependent on IL-4 than is γ1 transcription. We found that the IL-4-responsive region of the GL ε promoter is more inducible than that of the γ1 promoter, although each promoter contains a binding site for the IL-4-inducible transcription factor Stat6, located immediately adjacent to a binding site for a basic region leucine zipper (bZip) family protein. However, the arrangement and sequences of the sites differ between the ε and γ1 promoters. The GL ε promoter binds Stat6 with a 10-fold higher affinity than does the γ1 promoter. Furthermore, the bZip elements of the two promoters bind different transcription factors, as the GL ε promoter binds and is activated by AP-1, whereas the γ1 promoter binds and is activated by activating transcription factor 2. C/EBPβ and C/EBPγ also bind the γ1 bZip element, although they inhibit rather than activate transcription. However, inhibition of promoter activity by C/EBPβ does not require the bZip element and may instead occur via inhibiting the activity of NF-κB.

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“…These cells are useful for examining specific B cell characteristics and biosynthetic patterns because large quantities of a relatively pure population of cells can be obtained. While extrapolations to normal cells must be done with great care, the use of LBL and cell lines derived from B cell malignancies has permitted the generation of a large amount of data on the biochemical properties of the different species of/~ heavy chains (10,19,20) and on the DNA sequences encoding the # chain gene (21)(22)(23). However, very little information exists at the molecular level about the mechanisms controlling the synthesis of the various types of# heavy chain molecules during differentiation.…”

mentioning

confidence: 99%

Differential regulation of membrane and secretory mu chain synthesis in human beta cell lines. Regulation of membrane mu or secreted mu.

Hendershot¹,

Levitt²

1982

The Journal of Experimental Medicine

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Regulation of membrane and secretory mu synthesis was examined in human lymphoblastoid cell lines representing various stages of differentiation. Immunoglobulin phenotype was determined by surface and cytoplasmic staining with fluorochrome-conjugated antibodies and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis of anti-mu precipitable cellular products. The thymidine analogue, 5-bromo-2'-deoxyuridine (BUdR), which inhibits differentiation-specific proteins in a variety of systems, was used to examine regulation of immunoglobulin synthesis. We found that BUdR had a differential effect on membrane (mum) and secretory (mus) type mu heavy chains. Ig production in pre-B and plasma cell-like lines, which make mus, was unaffected by BUdR. However, surface expression of IgM (mum) in B cell lines was drastically inhibited at similar doses of BUdR without diminishing total Ig or protein synthesis. Examination of labeled mu chains from control and BUdR-treated B cell lines by SDS-PAGE revealed the production of two sizes of mu (mum and mus) in control cells and only the smaller size (mus) in BUdR-treated cells. This size difference could not be attributed to alterations in glycosylation of the molecules. These data show that BUdR inhibits the production of membrane mu chains without diminishing secretory mu chain synthesis in the same cell. Our findings suggest that thymidine-rich regions of the genome are involved in the regulation of mum vs. mus during B cell differentiation.

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An immunoglobulin heavy-chain gene is formed by at least two recombinational events

Cited by 297 publications

References 37 publications

How One Thing Led to Another

How One Thing Led to Another

Differential Regulation of Mouse Germline Ig γ1 and ε Promoters by IL-4 and CD40

Differential regulation of membrane and secretory mu chain synthesis in human beta cell lines. Regulation of membrane mu or secreted mu.

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