Plasma cell differentiation during the germinal center reaction

Ise, Wataru; Kurosaki, Tomohiro

doi:10.1111/imr.12751

Cited by 54 publications

(52 citation statements)

References 96 publications

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“…Our data provide transcriptional identities to PBL subpopulations and model a multistep process of PBL differentiation that starts in a subset of LZ cells displaying transcriptional changes associated with both BCR engagement and NF-κB activation. This process is consistent with the substantial body of data supporting the origin of plasma cells from GC cells expressing high affinity receptors and receiving T cell help (Ise and Kurosaki, 2019;Nutt et al, 2015). During this differentiation process, PBLs remodel their transcriptional program by down-regulating GC markers and inducing plasma cell markers.…”

Section: Discussionsupporting

confidence: 88%

Single-cell analysis of germinal-center B cells informs on lymphoma cell of origin and outcome

Holmes

Corinaldesi

Shen

et al. 2020

Journal of Experimental Medicine

141

185

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In response to T cell–dependent antigens, mature B cells are stimulated to form germinal centers (GCs), the sites of B cell affinity maturation and the cell of origin (COO) of most B cell lymphomas. To explore the dynamics of GC B cell development beyond the known dark zone and light zone compartments, we performed single-cell (sc) transcriptomic analysis on human GC B cells and identified multiple functionally linked subpopulations, including the distinct precursors of memory B cells and plasma cells. The gene expression signatures associated with these GC subpopulations were effective in providing a sc-COO for ∼80% of diffuse large B cell lymphomas (DLBCLs) and identified novel prognostic subgroups of DLBCL.

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Section: Discussionsupporting

confidence: 88%

Single-cell analysis of germinal-center B cells informs on lymphoma cell of origin and outcome

Holmes

Corinaldesi

Shen

et al. 2020

Journal of Experimental Medicine

141

185

View full text Add to dashboard Cite

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“…Changes in BCR signal strength can, however, have implications for GC B cell fate(Ochiai et al, 2013;Phan et al, 2006;Turner and Ke, 2018). Current models of GC B cell differentiation indicate that high strength of signal received in the LZ promotes PC differentiation whereas low strength of signal fosters MBC differentiation or death(Ise and Kurosaki, 2019;Shlomchik et al, 2019). Our data are generally consistent with the notion that high antigen signal strength favors PC differentiation but also reveal several additional mechanistic insights into GC biology during chronic infection.…”

supporting

confidence: 85%

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

Staupe

Vella

Manne

et al. 2019

Preprint

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Chronic viral infections disrupt B cell responses leading to impaired affinity maturation and delayed control of viremia. Previous studies have identified early pre-germinal center (GC) B cell attrition but the impact of chronic infections on B cell fate decisions in the GC remains poorly understood. To address this question, we used single-cell transcriptional profiling of virus-specific GC B cells to test the hypothesis that chronic viral infection disrupted GC B cell fate decisions leading to suboptimal humoral immunity. These studies revealed a critical GC differentiation checkpoint that is disrupted by chronic infection, specifically at the point of dark zone re-entry. During chronic viral infection, virusspecific GC B cells were shunted towards terminal plasma cell (PC) or memory B cell (MBC) fates at the expense of continued participation in the GC. Early GC exit was associated with decreased B cell mutational burden and antibody quality. Persisting antigen and inflammation independently drove facets of dysregulation, with a key role for inflammation in directing premature terminal GC B cell differentiation and GC exit. Thus, these studies define GC defects during chronic viral infection and identify a critical GC checkpoint that is short-circuited, preventing optimal maturation of humoral immunity.

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“…Our study profiled gene expression in memory B cells, which develop upon multiple rounds of vaccinations and whose predecessors, at the minimum, would have contributed to the development of long-lived plasma cells. Although plasma cells develop distinct transcriptional programs from memory B cells 62 , their lifespan is likely imprinted at the time of differentiation 12 . Long term survival of antibodies has been shown to correlate to memory B cell numbers following meningitis vaccine 63 .…”

Section: Discussionmentioning

confidence: 99%

Impact of vaccine type on HIV-1 vaccine elicited antibody durability and B cell gene signature

Palli

Seaton

Piepenbrink

et al. 2020

Sci Rep

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Efficacious HIV-1 vaccination requires elicitation of long-lived antibody responses. However, our understanding of how different vaccine types elicit durable antibody responses is lacking. To assess the impact of vaccine type on antibody responses, we measured IgG isotypes against four consensus HIV antigens from 2 weeks to 10 years post HIV-1 vaccination and used mixed effects models to estimate half-life of responses in four human clinical trials. Compared to protein-boosted regimens, half-lives of gp120-specific antibodies were longer but peak magnitudes were lower in Modified Vaccinia Ankara (MVA)-boosted regimens. Furthermore, gp120-specific B cell transcriptomics from MVA-boosted and protein-boosted vaccines revealed a distinct signature at a peak (2 weeks after last vaccination) including CD19, CD40, and FCRL2-5 activation along with increased B cell receptor signaling. Additional analysis revealed contributions of RIG-I-like receptor pathway and genes such as SMAD5 and IL-32 to antibody durability. Thus, this study provides novel insights into vaccine induced antibody durability and B-cell receptor signaling. While vaccine-elicited antibody durability has been achieved for licensed vaccines such as yellow fever, measles, smallpox, and Hepatitis B, elicitation of long-lived, functional antibody responses with candidate HIV-1 vaccine regimens remains elusive 1,2. In the case of experimental HIV vaccines, efficacy is correlated with Envelope (Env)-specific antibody responses 3,4. In particular, Env IgG3 titers that mediate antibody-dependent cellular phagocytosis (ADCP) and antibody dependent cellullar cytotoxicity (ADCC) are correlated with decreased risk of infection 5,6. However, these responses decay more than 10-fold 6-months post-vaccination, paralleling the decline in vaccine efficacy 7. Estimates of HIV-1 specific IgG half-lives range from 25-213 days, depending on the vaccine regimen and antigen (excluding gp41) 7-9. Interestingly, the Vaccine-Induced HIV Seropositivity/ Reactivity (VISP/VISR) in non-infected HIV vaccine recipients is commonly observed for vaccines with a Gag or Env component 10 , indicating that antibody responses can remain detectable for several weeks to a year postvaccination. However, positive results on diagnostic tests are qualitative in nature and thus not quantitative in

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Plasma cell differentiation during the germinal center reaction

Cited by 54 publications

References 96 publications

Single-cell analysis of germinal-center B cells informs on lymphoma cell of origin and outcome

Single-cell analysis of germinal-center B cells informs on lymphoma cell of origin and outcome

Chronic viral infection promotes early germinal center exit of B cells and impaired antibody development

Impact of vaccine type on HIV-1 vaccine elicited antibody durability and B cell gene signature

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