Immunodominance of the <i>VH1–46</i> Antibody Gene Segment in the Primary Repertoire of Human Rotavirus-Specific B Cells Is Reduced in the Memory Compartment through Somatic Mutation of Nondominant Clones

Tian, Chengming; Luskin, Grace K.; Dischert, Kevin M.; Higginbotham, James N.; Shepherd, Bryan E.; Crowe, James E.

doi:10.4049/jimmunol.180.5.3279

Cited by 47 publications

(59 citation statements)

References 33 publications

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“…Although there is no direct evidence of such a mechanism, several recent studies indicate the presence of repertoire-based regulatory mechanisms in circulating B-cell subsets. Despite the tendency of pathogen-specific antibody responses to exhibit biased germline gene repertoires, [16][17][18] the frequency of gene family use in naïve and memory subsets is remarkably consistent across individuals. 9,11 Further, alteration of this gene family homeostasis in the circulating B-cell repertoire is associated with disease states.…”

Section: Resultsmentioning

confidence: 98%

High-throughput antibody sequencing reveals genetic evidence of global regulation of the naïve and memory repertoires that extends across individuals

et al. 2012

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Vast diversity in the antibody repertoire is a key component of the adaptive immune response. This diversity is generated centrally through the assembly of variable, diversity and joining gene segments, and peripherally by somatic hypermutation and class-switch recombination. The peripheral diversification process is thought to only occur in response to antigenic stimulus, producing antigenselected memory B cells. Surprisingly, analyses of the variable, diversity and joining gene segments have revealed that the naïve and memory subsets are composed of similar proportions of these elements. Lacking, however, is a more detailed study, analyzing the repertoires of naïve and memory subsets at the level of the complete V(D)J recombinant. This report presents a thorough examination of V(D)J recombinants in the human peripheral blood repertoire, revealing surprisingly large repertoire differences between circulating B-cell subsets and providing genetic evidence for global control of repertoire diversity in naïve and memory circulating B-cell subsets.

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Section: Resultsmentioning

confidence: 98%

High-throughput antibody sequencing reveals genetic evidence of global regulation of the naïve and memory repertoires that extends across individuals

et al. 2012

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“…Previous studies by us and others have called attention to the high frequency and persistence of RV IgM ϩ mBc in children and adults (53,64). Despite their prominence, both the origin of these cells and their relevance to RV immunity have been unclear.…”

Section: Discussionmentioning

confidence: 99%

“…To characterize the phenotype of mBc that express RV surface Ig, we and others have used an FCA (29,51,64,73). The principle of this assay consists of the specific binding of fluorescent RV recombinant virus-like particles (VLPs) that express on their surface the immunodominant RV structural protein VP6 and inside contain green fluorescent protein (GFP) linked to the amino terminus of VP2 (11).…”

mentioning

confidence: 99%

Human Rotavirus-Specific IgM Memory B Cells Have Differential Cloning Efficiencies and Switch Capacities and Play a Role in Antiviral ImmunityIn Vivo

Narváez

Feng

Vásquez

et al. 2012

J Virol

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Protective immunity to rotavirus (RV) is primarily mediated by antibodies produced by RV-specific memory B cells (RV-mBc).Of note, most of these cells express IgM, but the function of this subset is poorly understood. Here, using limiting dilution assays of highly sort-purified human IgM ؉ mBc, we found that 62% and 21% of total (non-antigen-specific) IgM ؉ and RV-IgM ؉ mBc, respectively, switched in vitro to IgG production after polyclonal stimulation. Moreover, in these assays, the median cloning efficiencies of total IgM ؉ (17%) and RV-IgM ؉ (7%) mBc were lower than those of the corresponding switched (IgG ؉ IgA ؉ ) total (34%) and RV-mBc (17%), leading to an underestimate of their actual frequency. In order to evaluate the in vivo role of IgM ؉ RV-mBc in antiviral immunity, NOD/Shi-scid interleukin-2 receptor-deficient (IL-2R␥null ) immunodeficient mice were adoptively transferred highly purified human IgM ؉ mBc and infected with virulent murine rotavirus. These mice developed high titers of serum human RV-IgM and IgG and had significantly lower levels than control mice of both antigenemia and viremia. Finally, we determined that human RV-IgM ؉ mBc are phenotypically diverse and significantly enriched in the IgM hi IgD low subset. Thus, RV-IgM ؉ mBc are heterogeneous, occur more frequently than estimated by traditional limiting dilution analysis, have the capacity to switch Ig class in vitro as well as in vivo, and can mediate systemic antiviral immunity.

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“…For example, in the murine model, B-cell-but not T-cell-deficient mice are unable to establish long-lasting protective immunity against RV reinfection (26). The interaction of RV with B cells has been shown to be peculiar in many ways: the structural viral protein VP6 binds to an important fraction of human naive B cells via surface Ig (55,58), and VP6 memory B cells (mBC) are enriched in the CD27 Ϫ IgG ϩ (58) and CD27 ϩ IgM ϩ subsets (66). VP6-specific naive B cells and, to a lesser extent, the mBC predominantly use the VH1-46 gene segment (66).…”

mentioning

confidence: 99%

“…The interaction of RV with B cells has been shown to be peculiar in many ways: the structural viral protein VP6 binds to an important fraction of human naive B cells via surface Ig (55,58), and VP6 memory B cells (mBC) are enriched in the CD27 Ϫ IgG ϩ (58) and CD27 ϩ IgM ϩ subsets (66). VP6-specific naive B cells and, to a lesser extent, the mBC predominantly use the VH1-46 gene segment (66). Moreover, a massive Tcell-independent B cell activation and humoral response can be detected in vivo after oral RV infection in mice (10).…”

mentioning

confidence: 99%

Rotavirus Differentially Infects and Polyclonally Stimulates Human B Cells Depending on Their Differentiation State and Tissue of Origin

Narváez

Franco

Ángel

et al. 2010

J Virol

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Rotaviruses (RV) are the main cause of severe gastroenteritis in infants and are responsible for the death of approximately 600,000 young children annually around the world (54 and http://www.who.int/immunization monitoring/burden/rotavirus estimates/en/). At present, two live attenuated vaccines are licensed for use in humans, and both vaccines are highly protective against severe disease in developed countries (60,69). However, these oral vaccines induce lower levels of protection in children from developing countries, suggesting that the improvement of these vaccine or the development of new RV vaccines is warranted (32). Although the RV immune response has been extensively studied in both animals and humans, the immune factors that correlate with protection for natural infection or vaccination in people remain unclear, and this is an important obstacle for the development of the next generation of RV vaccines (2, 25).B cells play a critical role in the RV immune response, and both intestinal and systemic immunoglobulins (Ig) are associated with protection (25). For example, in the murine model, B-cell-but not T-cell-deficient mice are unable to establish long-lasting protective immunity against RV reinfection (26). The interaction of RV with B cells has been shown to be peculiar in many ways: the structural viral protein VP6 binds to an important fraction of human naive B cells via surface Ig (55, 58), and VP6 memory B cells (mBC) are enriched in the CD27 Ϫ IgG ϩ (58) and CD27 ϩ IgM ϩ subsets (66). VP6-specific naive B cells and, to a lesser extent, the mBC predominantly use the VH1-46 gene segment (66). Moreover, a massive Tcell-independent B cell activation and humoral response can be detected in vivo after oral RV infection in mice (10). However, the activation of these cells is probably viral strain dependent, since simian rhesus RV (RRV), but not bovine WC3 RV, has been shown to polyclonally stimulate a total antibodysecreting cell (ASC) response in intestinal organ fragment cultures (44). Although the principal immune function of B cells has been associated with the production of Ig, recent reports show that these cells also can play an important role in modulating the immune response independently of Ig through the production of cytokines like tumor necrosis factor alpha (TNF-␣), interleukin-6 (IL-6), and IL-10 and their related potential function as antigen-presenting cells (3,18,31,67).We and others have shown that RVs undergo systemic, extraintestinal replication in both immunodeficient and wild-type mice (16,24). In addition, a significant antigenemia and viremia is seen in most acutely infected children (8, 9). In particular, we have shown the in vivo replication of homologous and heterologous RV strains in B220 ϩ cells (a marker expressed by B cells or plasmacytoid dendritic cells [pDC]) obtained from murine mesenteric lymph node (24), and recently we also demonstrated that approximately 10% of primary human circulating B cells (CBC) are targets of RV infection in vitro (49).

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Immunodominance of the VH1–46 Antibody Gene Segment in the Primary Repertoire of Human Rotavirus-Specific B Cells Is Reduced in the Memory Compartment through Somatic Mutation of Nondominant Clones

Cited by 47 publications

References 33 publications

High-throughput antibody sequencing reveals genetic evidence of global regulation of the naïve and memory repertoires that extends across individuals

High-throughput antibody sequencing reveals genetic evidence of global regulation of the naïve and memory repertoires that extends across individuals

Human Rotavirus-Specific IgM Memory B Cells Have Differential Cloning Efficiencies and Switch Capacities and Play a Role in Antiviral ImmunityIn Vivo

Rotavirus Differentially Infects and Polyclonally Stimulates Human B Cells Depending on Their Differentiation State and Tissue of Origin

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