Somatic diversification of immunoglobulins.

Rudikoff, Stuart; Pawlita, Michael; Pumphrey, Janet G.; Heller, Mark

doi:10.1073/pnas.81.7.2162

Cited by 82 publications

(33 citation statements)

References 41 publications

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“…The common exchange in JH in position 107 suggests that somatic mutation in this B cell clone occurred in more than one step and generation, in line with the more extensive data of McKean et al (1984) and Rudikoff et al (1984). Implications of the structural data for the anti-idiotypic response and network regulation The most striking feature of the present data is the structural and genetic restriction of the isogeneic anti-idiotope response.…”

Section: -----------G-------------------------------------c ---------supporting

confidence: 76%

Molecular basis of an isogeneic anti-idiotypic response.

Sablitzky¹,

Rajewsky²

1984

The EMBO Journal

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The nucleotide sequences of the variable region genes expressed in the heavy and light chains of six isogeneic anti-idiotope antibodies recognizing idiotopes on two closely related antibodies with specificity for the hapten (4-hydroxy-3-nitrophenyl)acetyl (NP) were determined. In two independently derived anti-idiotope cell lines the same or strongly homologous VX, VH and D region genes had originally been rearranged. The two lines express long and partly homologous N sequences (presumed to be not of germ line origin) at the border of D, resulting in CDR3s of unusual length. An unusually long CDR3, partly encoded by N sequences, is also present in the heavy chain of a third anti-idiotope antibody.The VH regions of the three remaining anti-idiotope antibodies originate from a single VH gene which belongs to the same VH group as the VH genes expressed in the other antiidiotopes. Two of these antibodies, expressing similar V, D and J elements, had been isolated from the same mouse and appear to have diverged from the same B cell precursor by at least two rounds of somatic mutation. Somatic point mutations have occurred in most, if not all anti-idiotope V region sequences. In two instances somatic mutations in J increase the structural homology between anti-idiotopes. The antiidiotypic response in this system is thus genetically restricted and may depend upon the selection of non-gern line sequences, suggesting an explanation for the low frequency at which anti-idiotope antibodies are expressed in this system.

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Section: -----------G-------------------------------------c ---------supporting

confidence: 76%

Molecular basis of an isogeneic anti-idiotypic response.

Sablitzky¹,

Rajewsky²

1984

The EMBO Journal

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“…Thus, it appears that they do not undergo the massive expansion characteristic of normal GC B cells. However, we have shown previously that the resulting latently infected memory B cells have accumulated normal levels of somatic hypermutations (6/100 bp [50,51]) in their immunoglobulin genes, which would require many cell divisions to accumulate given the previously reported rate of somatic hypermutation in the GC of 1/10 3 per division (3,38,47). To investigate this contradiction, we exploited the fact that the average EBV genome copy number increases in a newly infected population as it proliferates.…”

Section: Distribution Of Ebv-infected Cells In Tonsil Gcsmentioning

confidence: 99%

Germinal Center B Cells Latently Infected with Epstein-Barr Virus Proliferate Extensively but Do Not Increase in Number

Roughan

Torgbor

Thorley‐Lawson

2010

J Virol

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In this study we show that in long-term persistent infection, Epstein-Barr virus (EBV)-infected cells undergoing a germinal center (GC) reaction in the tonsils are limited to the follicles and proliferate extensively. Despite this, the absolute number of infected cells per GC remains small (average of 3 to 4 cells per germinal center; range, 1 to 9 cells), and only about 38 to 55% (average, 45%) of all GCs carry infected cells. The data fit a model where, on average, cells in the GC divide approximately three times; however, only one progeny cell survives to undergo a further three divisions. Thus, a fraction of cells undergo multiple rounds of division without increasing in numbers; i.e., they die at the same rate that they are dividing. We conclude that EBV-infected cells in the GC undergo the extensive proliferation characteristic of GC cells but that the absolute number is limited either by the immune response or by the availability of an essential survival factor. We suggest that this behavior is a relic of the mechanism by which EBV establishes persistence during acute infection. Lastly, the expression of the viral latent protein LMP1 in GC B cells, unlike in vitro, does not correlate directly with the expression of bcl-2 or bcl-6. This emphasizes our claim that observations made regarding the functions of EBV proteins in cell lines or in transgenic mice should be treated with skepticism unless verified in vivo. Epstein-Barr virus (EBV) is a human herpesvirus that establishes a lifetime persistent infection in Ͼ90% of all adults (reviewed in references 21 and 51). The virus persists in rest-ing, latently infected memory B cells that circulate in the periphery and lymph nodes (5; reviewed in references 53 and 55). In these cells the virus is quiescent, at least at the level of viral protein expression (23). This lack of viral proteins is presumably a major reason why these cells are able to persist in the face of a healthy immune response. The other property for which EBV is well known is its ability to infect resting B cells and drive them to become activated proliferating lymphoblasts through the expression of nine latent proteins and several untranslated RNAs (reviewed in reference 45). The latter include a large number of microRNAs (miRNAs) (7,12,17,44).The current model of Epstein-Barr virus persistence holds that the virus drives resting B cells to become activated lymphoblasts so that they can differentiate through a germinal center (GC) reaction to become resting memory B cells (55-57), where the virus persists. The GC is the structure in the follicles of secondary lymphoid organs where antigen-activated B cells undergo a T-cell-dependent immune response (1, 35, 37). The production and maintenance of GCs are absolutely dependent on the expression of the transcription factor bcl-6 (13, 58) and are initiated by the rapid proliferation of antigenspecific B cells. During this expansion phase, B cells divide approximately every 6 to 12 h (2, 37) so that 3 Ϯ 2 founder cells can create a GC of approximatel...

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“…Molecular analyses of murine humoral immune responses have been largely limited to responses induced by soluble proteins, polysaccharides, and hapten conjugates thereof (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) . However, in nature the mouse rarely encounters an antigenic structure in association with such chemically simple forms, but rather in association with a viral particle, bacterium, or parasite .…”

mentioning

confidence: 99%

Influence of the macromolecular form of a B cell epitope on the expression of antibody variable and constant region structure.

Fish¹,

Manser²

1987

The Journal of Experimental Medicine

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We investigated the influence of the macromolecular form of an epitope on the structure of antibody variable and constant regions expressed by the B cell population participating in an immune response to that epitope. Hybridomas were constructed from strain A/J mice undergoing either primary or secondary immune responses to p-azophenylarsonate conjugated to Brucella abortus (Ars-Bruc). We determined the sequences of the V genes expressed by hybridomas selected on the basis of expression of a single VH gene segment known to encode a large family of anti-Ars antibodies. These sequences were compared with the sequences of V genes expressed by a previously characterized panel of hybridomas isolated in the same way during the primary and secondary responses of A/J mice to Ars-KLH. The repertoire of Ars-specific V domains expressed among primary and secondary hybridomas elicited with these two forms of Ars were similar, as were the differences between primary and secondary V region somatic mutational alteration and affinity for Ars. In contrast, predominant expression of IgG2 anti-Ars antibodies was elicited in the secondary Ars-Bruc response, whereas secondary anti-Ars antibodies elicited with Ars-KLH are predominantly IgG1. Thus, differences in the macromolecular form of Ars clearly influence the isotypic profile of the anti-Ars response, but the expression, diversification, and selection of V domains elicited with this hapten are not greatly affected by such differences. Our results suggest that while isotype regulation is highly perceptive of the macromolecular form of a B cell epitope, V region regulation is primarily influenced by the molecular structure of that epitope.

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Somatic diversification of immunoglobulins.

Cited by 82 publications

References 41 publications

Molecular basis of an isogeneic anti-idiotypic response.

Molecular basis of an isogeneic anti-idiotypic response.

Germinal Center B Cells Latently Infected with Epstein-Barr Virus Proliferate Extensively but Do Not Increase in Number

Influence of the macromolecular form of a B cell epitope on the expression of antibody variable and constant region structure.

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