Parameters governing exhaustion of rare T cell‐independent neutralizing IgM‐producing B cells after LCMV infection

Zellweger, Raphaël M.; Hangartner, Lars; Weber, Jacqueline; Zinkernagel, Rolf M.; Hengartner, Hans

doi:10.1002/eji.200636087

Cited by 15 publications

(18 citation statements)

References 25 publications

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“…3d and data not shown). The same inverse relation between specific extrafollicular B cell response and specific Th cell frequency was observed in the LCMV-specific system (36). Although an isotype switch can occur outside GCs (9, 37), this did not seem to happen when sufficient specific T cell help was available.…”

Section: Discussionmentioning

confidence: 65%

B Cell Activation State-Governed Formation of Germinal Centers following Viral Infection

Fink

Manjarrez‐Orduño

Schildknecht

et al. 2007

The Journal of Immunology

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Germinal centers are structures that promote humoral memory cell formation and affinity maturation, but the triggers for their development are not entirely clear. Activated extrafollicular B cells can form IgM-producing plasmablasts or enter a germinal center reaction and differentiate into memory or plasma cells, mostly of the IgG isotype. Vesicular stomatitis virus (VSV) induces both types of response, allowing events that promote each of these pathways to be studied. In this work, extrafollicular vs germinal center responses were examined at a cellular level, analyzing VSV-specific B cells in infected mice. We show that VSV-specific germinal centers are transiently formed when insufficient proportions of specific T cell help is available and that strong B cell activation in cells expressing high levels of the VSV-specific BCR promoted their differentiation into early blasts, whereas moderate stimulation of B cells or interaction with Th cells restricted extrafollicular responses and promoted germinal center formation.

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Section: Discussionmentioning

confidence: 65%

B Cell Activation State-Governed Formation of Germinal Centers following Viral Infection

Fink

Manjarrez‐Orduño

Schildknecht

et al. 2007

The Journal of Immunology

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“…The relatively inefficient response to natural Pf infection also does not appear to be due to a persistent, Pf -induced general immunosuppression as the frequency of TT-specific MBCs increased significantly in most adult females in response to a single TT booster vaccination, an increase that appeared to be maintained for years. In an experimental model of lymphocytic choriomeningitis virus (LCMV) infection, a high antigen-to-B cell ratio disrupted germinal center formation and the establishment of B cell memory [42]. It is plausible that a similar mechanism is at play during the blood stage of Pf infection when the immune system encounters high concentrations of parasite proteins.…”

Section: Discussionmentioning

confidence: 99%

The Plasmodium falciparum-Specific Human Memory B Cell Compartment Expands Gradually with Repeated Malaria Infections

et al. 2010

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Immunity to Plasmodium falciparum (Pf) malaria is only acquired after years of repeated infections and wanes rapidly without ongoing parasite exposure. Antibodies are central to malaria immunity, yet little is known about the B-cell biology that underlies the inefficient acquisition of Pf-specific humoral immunity. This year-long prospective study in Mali of 185 individuals aged 2 to 25 years shows that Pf-specific memory B-cells and antibodies are acquired gradually in a stepwise fashion over years of repeated Pf exposure. Both Pf-specific memory B cells and antibody titers increased after acute malaria and then, after six months of decreased Pf exposure, contracted to a point slightly higher than pre-infection levels. This inefficient, stepwise expansion of both the Pf-specific memory B-cell and long-lived antibody compartments depends on Pf exposure rather than age, based on the comparator response to tetanus vaccination that was efficient and stable. These observations lend new insights into the cellular basis of the delayed acquisition of malaria immunity.

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“…Non-neutralizing virus-specific IgM were recently analyzed and deemed crucial for impedance of viral persistence in LCMV infection (the prototypic Old World arenavirus), suggesting that IgM-producing cells have remained largely obscure and underappreciated in the characterization of arenaviral infections [34]. Additionally, the late appearance of neutralizing antibodies in arenaviral infections has been tied to high viral antigen-to-B cell ratios and low T cell help, which resulted in a normal IgM response but reduced the efficiency of class switching [35]. Lowering the antigen-to-B cell ratio and increasing T cell help resulted in rescuing of class switching and emergence of neutralizing IgG specificities.…”

Section: Discussionmentioning

confidence: 99%

Emerging trends in Lassa fever: redefining the role of immunoglobulin M and inflammation in diagnosing acute infection

Branco

Grove

Boisen

et al. 2011

Virol J

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BackgroundLassa fever (LF) is a devastating hemorrhagic viral disease that is endemic to West Africa and responsible for thousands of human deaths each year. Analysis of humoral immune responses (IgM and IgG) by antibody-capture ELISA (Ab-capture ELISA) and Lassa virus (LASV) viremia by antigen-capture ELISA (Ag-capture ELISA) in suspected patients admitted to the Kenema Government Hospital (KGH) Lassa Fever Ward (LFW) in Sierra Leone over the past five years is reshaping our understanding of acute LF.ResultsAnalyses in LF survivors indicated that LASV-specific IgM persists for months to years after initial infection. Furthermore, exposure to LASV appeared to be more prevalent in historically non-endemic areas of West Africa with significant percentages of reportedly healthy donors IgM and IgG positive in LASV-specific Ab-capture ELISA. We found that LF patients who were Ag positive were more likely to die than suspected cases who were only IgM positive. Analysis of metabolic and immunological parameters in Ag positive LF patients revealed a strong correlation between survival and low levels of IL-6, -8, -10, CD40L, BUN, ALP, ALT, and AST. Despite presenting to the hospital with fever and in some instances other symptoms consistent with LF, the profiles of Ag negative IgM positive individuals were similar to those of normal donors and nonfatal (NF) LF cases, suggesting that IgM status cannot necessarily be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa.ConclusionOnly LASV viremia assessed by Ag-capture immunoassay, nucleic acid detection or virus isolation should be used to diagnose acute LASV infection in West Africans. LASV-specific IgM serostatus cannot be considered a diagnostic marker of acute LF in suspected cases living in endemic areas of West Africa. By applying these criteria, we identified a dysregulated metabolic and pro-inflammatory response profile conferring a poor prognosis in acute LF. In addition to suggesting that the current diagnostic paradigm for acute LF should be reconsidered, these studies present new opportunities for therapeutic interventions based on potential prognostic markers in LF.

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Parameters governing exhaustion of rare T cell‐independent neutralizing IgM‐producing B cells after LCMV infection

Cited by 15 publications

References 25 publications

B Cell Activation State-Governed Formation of Germinal Centers following Viral Infection

B Cell Activation State-Governed Formation of Germinal Centers following Viral Infection

The Plasmodium falciparum-Specific Human Memory B Cell Compartment Expands Gradually with Repeated Malaria Infections

Emerging trends in Lassa fever: redefining the role of immunoglobulin M and inflammation in diagnosing acute infection

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