Somatic diversification of antibody responses

Zheng, Biao; Kelsoe, Garnett; Han, Shuhua

doi:10.1007/bf01540967

Cited by 8 publications

(5 citation statements)

References 118 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since somatic hypermutation and heavy chain isotype switching are both thought to occur in the germinal center (45)(46)(47), and since the current study analyzed IgM ϩ B cells, few mutated kappa sequences were expected. However, 24% of the productive and 7% of nonproductive VJ rearrangements were found to be mutated, suggesting that IgM ϩ memory B cells are commonly encountered in the peripheral blood.…”

Section: Discussionmentioning

confidence: 93%

“…In the germinal center the mutational machinery is thought to be activated before heavy chain isotype switching (48). Therefore, these somatically mutated B cells may represent cells at an early phase of germinal center cell maturation (45)(46)(47). It is noteworthy that IgM ϩ B cells with mutated kappa chain genes were found to comprise nearly one-fourth of peripheral IgM ϩ B cells, suggesting that B cells may exit germinal centers at this early stage of maturation frequently and persist in the circulating pool.…”

Section: Discussionmentioning

confidence: 99%

“…It is noteworthy that IgM ϩ B cells with mutated kappa chain genes were found to comprise nearly one-fourth of peripheral IgM ϩ B cells, suggesting that B cells may exit germinal centers at this early stage of maturation frequently and persist in the circulating pool. It is also noteworthy that the frequency of somatic mutations in the productive rearrangements was greater than in the nonproductive rearrangements suggesting that these B cells may have been influenced by antigen mediated selection (45)(46)(47). Evidence for antigen selection of somatically mutated VJ rearrangements suggests that B cells expressing these gene products had passed through the light zone of the germinal center, where antigen selection occurs (45)(46)(47)49), before reentering the circulation.…”

Section: Discussionmentioning

confidence: 99%

“…It is also noteworthy that the frequency of somatic mutations in the productive rearrangements was greater than in the nonproductive rearrangements suggesting that these B cells may have been influenced by antigen mediated selection (45)(46)(47). Evidence for antigen selection of somatically mutated VJ rearrangements suggests that B cells expressing these gene products had passed through the light zone of the germinal center, where antigen selection occurs (45)(46)(47)49), before reentering the circulation. The exact stage and pathway of maturation of these cells is not certain, but the data imply that antigen-selected IgM ϩ memory cells occur frequently in human peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Molecular mechanisms and selective influences that shape the kappa gene repertoire of IgM+ B cells.

Foster

Brezinschek²,

Brezinschek³

et al. 1997

J. Clin. Invest.

135

175

View full text Add to dashboard Cite

To analyze the human kappa chain repertoire and the influences that shape it, a single cell PCR technique was used that amplified V J rearrangements from genomic DNA of individual human B cells. More than 350 productive and 250 nonproductive V J rearrangements were sequenced. Nearly every functional V gene segment was used in rearrangements, although six V gene segments, A27, L2, L6, L12a, A17, and O12/O2 were used preferentially. Of these, A27, L2, L6, and L12a showed evidence of positive selection based on the variable region and not CDR3, whereas A17 was overrepresented because of a rearrangement bias based on molecular mechanisms. Utilization of J segments was also nonrandom, with J 1 and J 2 being overrepresented and J 3 and J 5 underrepresented in the nonproductive repertoire, implying a molecular basis for the bias. In B cells with two V J rearrangements, marked differences were noted in the V segments used for the initial and subsequent rearrangements, whereas J segments were used comparably. Junctional diversity was generated by n-nucleotide addition in 60% and by exonuclease trimming in 75% of the V J rearrangements analyzed. Despite this large degree of diversity, a strict CDR3 length was maintained in both productive and nonproductive rearrangements. More than 23% of the productive rearrangements, but only 7% of the nonproductive rearrangements contained somatic hypermutations. Mutations were significantly more frequent in V sequences derived from CD5Ϫ as compared with CD5

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Molecular mechanisms and selective influences that shape the kappa gene repertoire of IgM+ B cells.

Foster

Brezinschek²,

Brezinschek³

et al. 1997

J. Clin. Invest.

135

175

View full text Add to dashboard Cite

show abstract

“…By immunohistological staining GCs are easily recognized by their follicular dendritic cell (FDC) networks (4). Under physiological conditions, most T cells within a GC are antigen specific and express CD4 and specific markers for activated and memory cells (5,6). Within GCs, HIV proviruses are mainly present within CD4 T lymphocytes, whereas the FDC surfaces are abundantly coated with virions in the form of immune complexes (7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

Highly restricted spread of HIV-1 and multiply infected cells within splenic germinal centers

Gratton

Cheynier

Dumaurier

et al. 2000

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

127

103

View full text Add to dashboard Cite

The tremendous dynamics of HIV infection finds expression in the tempo of sequence diversification. Genetic diversity calculations require the clearance of a majority of infected cells, the obvious predator being anti-HIV immune responses. Indeed, infiltration of germinal centers (GCs) by HIV-specific CD8 ؉ cytotoxic T lymphocytes has been described. A corollary to this description would be limited diffusion of virus within lymphoid structures. HIV efficiently infects and replicates mainly in activated CD4 ؉ T lymphoblasts. These cells are found within GCs after their activation in the adjacent periarteriolar lymphoid sheath (PALS). Here GCs and PALS have been dissected from consecutive 10-m sections through splenic tissue from three HIV-1-infected patients. Nested PCR amplification of the two first hypervariable regions of the env gene indicated that 38 -78% of sections contained HIV-infected cells. Since there are several hundred CD4 ؉ T cells per GC section, approximately 0.09 -0.64% harbor proviral DNA. Such a low frequency not only suggests that virions on the follicular dendritic cell surfaces do not readily infect adjacent T cells but also indicates highly restricted spread of HIV within GCs and the PALS. Sections were heavily infiltrated by CD8 ؉ cells, which, together with a large body of extant data, suggests that the majority of infected cells are destroyed by HIV-specific cytotoxic T lymphocytes before becoming productively infected. Finally, sequence analysis revealed that those HIV-positive cells were multiply infected, which helps explain widespread recombination despite a low overall frequency of infected cells.spleen ͉ pathogenesis ͉ viral dynamics ͉ multiple infection ͉ recombination P roductive HIV replication requires activation of resting T cells. As antigenic stimulation is the driving force, secondary lymphoid organs are the main sites for HIV replication in vivo (1, 2). CD4 T lymphocytes are the principal targets for HIV, although macrophages and dendritic cells are infected at lower frequencies (3). Splenic white pulps are sites of intense immunological activity. HIV and T cell founder effects within white pulps suggested the local recruitment of antigen-specific T cells paralleled by de novo replication of HIV (1).White pulps consist of T cell-rich areas, the periarteriolar lymphoid sheaths (PALS), and the B cell-rich follicles, including the germinal centers (GCs). T cells are stimulated in the PALS upon activation by their specific antigen presented by interdigitating dendritic cells. Together with activated B cells, they induce the formation of antigen-specific follicles. GCs are secondary follicles responsible for B cell memory formation and plasmocyte maturation. By immunohistological staining GCs are easily recognized by their follicular dendritic cell (FDC) networks (4). Under physiological conditions, most T cells within a GC are antigen specific and express CD4 and specific markers for activated and memory cells (5, 6). Within GCs, HIV proviruses are mainly present within CD4 T...

show abstract

Vaccination in the context of immunological immaturity

Arvin

Lewis

2005

The Grand Challenge for the Future

View full text Add to dashboard Cite

Somatic diversification of antibody responses

Cited by 8 publications

References 118 publications

Molecular mechanisms and selective influences that shape the kappa gene repertoire of IgM+ B cells.

Molecular mechanisms and selective influences that shape the kappa gene repertoire of IgM+ B cells.

Highly restricted spread of HIV-1 and multiply infected cells within splenic germinal centers

Vaccination in the context of immunological immaturity

Contact Info

Product

Resources

About