Plasma cell toll‐like receptor (TLR) expression differs from that of B cells, and plasma cell TLR triggering enhances immunoglobulin production

Dorner, Marcus; Brandt, Simone; Tinguely, Marianne; Zucol, Franziska; Bourquin, Jean‐Pierre; Zauner, Ludwig; Berger, Christoph; Bernasconi, Michele; Speck, Roberto F.; Nadal, David

doi:10.1111/j.1365-2567.2009.03143.x

Cited by 98 publications

(108 citation statements)

References 22 publications

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“…While naive and memory B cells have been reported to be negative for TLR5 expression (69,70), flagellin was recently found to promote the generation and/or survival of short-lived plasma cells, and data suggest that TLR5 expression on these cells contributes to this effect (42). In addition, activated B cells were found to upregulate the expression of TLR5 (42).…”

Section: Discussionmentioning

confidence: 90%

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates

Kim

Holbrook

Hayward

et al. 2015

J Virol

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Influenza virus can cause life-threatening infections in neonates and young infants. Although vaccination is a major countermeasure against influenza, current vaccines are not approved for use in infants less than 6 months of age, in part due to the weak immune response following vaccination. Thus, there is a strong need to develop new vaccines with improved efficacy for this vulnerable population. To address this issue, we established a neonatal African green monkey (AGM) nonhuman primate model that could be used to identify effective influenza vaccine approaches for use in young infants. We assessed the ability of flagellin, a Toll-like receptor 5 (TLR5) agonist, to serve as an effective adjuvant in this at-risk population. Four-to 6-day-old AGMs were primed and boosted with inactivated PR8 influenza virus (IPR8) adjuvanted with either wild-type flagellin or inactive flagellin with a mutation at position 229 (m229), the latter of which is incapable of signaling through TLR5. Increased IgG responses were observed following a boost, as well as at early times after challenge, in infants vaccinated with flagellin-adjuvanted IPR8. Inclusion of flagellin during vaccination also resulted in a significantly increased number of influenza virus-specific T cells following challenge compared to the number in infants vaccinated with the m229 adjuvant. Finally, following challenge infants vaccinated with IPR8 plus flagellin exhibited a reduced pathology in the lungs compared to that in infants that received IPR8 plus m229. This study provides the first evidence of flagellin-mediated enhancement of vaccine responses in nonhuman primate neonates. Influenza virus remains one of the leading causes of morbidity and mortality worldwide. Infants less than 6 months of age are particularly vulnerable to development of severe disease following infection (1). Diseases associated with influenza virus infection in children include otitis media, pneumonia, myositis, and croup. While oseltamivir (Tamiflu), one of the two FDA-approved antiinfluenza drugs, can be used in infants aged 2 weeks and older, concerns exist due to the potential for adverse effects, drug resistance, and limited effectiveness in young infants (2).Currently, there are three approved approaches for vaccination against influenza in the United States: intramuscular (i.m.) administration of inactivated influenza virus, intramuscular administration of recombinant hemagglutinin (HA) proteins, and intranasal administration of a live attenuated influenza virus (LAIV). The first is approved for use in individuals aged 6 months and older, the second for use in individuals aged 18 to 49 years, and the last for use in healthy individuals aged 2 to 49 years. Thus, none are approved for use in the vulnerable neonate population. While the lack of approval for the use of these vaccines in the very young may reflect some safety concerns, a principal factor is the poor immune responses elicited in human neonates (3,4).Previous studies, while limited, have shown that an initia...

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Section: Discussionmentioning

confidence: 90%

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates

Kim

Holbrook

Hayward

et al. 2015

J Virol

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“…MPL is a Toll-like receptor 4 (TLR4) agonist derived from Salmonella enterica serovar Minnesota, and it induces strong Th1 and IL-12 responses (16). Tonsillar memory and naïve B cells do not express TLR4; however, PC do (14). Their expansion seen here may be due in part to the TLR4-containing adjuvant.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of Memory B-Cell Populations in Blood, Lymph Nodes, and Bone Marrow during Antiretroviral Therapy and Envelope Boosting in Simian Immunodeficiency Virus SIVmac251-Infected Rhesus Macaques

Demberg

Brocca-Cofano

Xiao

et al. 2012

J Virol

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c Human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection causes B-cell dysregulation and the loss of memory B cells in peripheral blood mononuclear cells (PBMC). These effects are not completely reversed by antiretroviral treatment (ART).To further elucidate B-cell changes during chronic SIV infection and treatment, we investigated memory B-cell subpopulations and plasma cells/plasmablasts (PC/PB) in blood, bone marrow, and lymph nodes of rhesus macaques during ART and upon release from ART. Macaques previously immunized with SIV recombinants and the gp120 protein were included to assess the effects of prior vaccination. ART was administered for 11 weeks, with or without gp120 boosting at week 9. Naïve and resting, activated, and tissue-like memory B cells and PC/PB were evaluated by flow cytometry. Antibody-secreting cells (ASC) and serum antibody titers were assessed. No lasting changes in B-cell memory subpopulations occurred in bone marrow and lymph nodes, but significant decreases in numbers of activated memory B cells and increases in numbers of tissue-like memory B cells persisted in PBMC. Macaque PC/PB were found to be either CD27 ؉ or CD27 ؊ and therefore were defined as CD19؉ . The numbers of these PC/PB were transiently increased in both PBMC and bone marrow following gp120 boosting of the unvaccinated and vaccinated macaque groups. Similarly, ASC numbers in PBMC and bone marrow of the two macaque groups also transiently increased following envelope boosting. Nevertheless, serum binding titers against SIVgp120 remained unchanged. Thus, even during chronic SIV infection, B cells respond to antigen, but long-term memory does not develop, perhaps due to germinal center destruction. Earlier and/or prolonged treatment to allow the generation of virus-specific long-term memory B cells should benefit ART/therapeutic vaccination regimens. Early and persistent B-cell dysfunction is a hallmark of human immunodeficiency virus (HIV) infection in humans (11,20,53) and precedes the loss of CD4 ϩ T cells, as shown in the simian immunodeficiency virus (SIV) rhesus macaque model (28). B-cell subpopulations and the expression of cluster-of-differentiation (CD) markers change during early HIV (22, 55) and SIV (28, 46, 58) infections. Patients on highly active antiretroviral therapy (HAART) who control viremia still exhibit B-cell dysregulation, e.g., activation, apoptosis, and abnormal CD marker expression, together with a skewing of B-cell populations, including the continued loss of memory populations and a lower frequency of naïve B cells (4,15,40,48). The early initiation of HAART might be crucial for the preservation of B-cell functionality (37), as HAART treatment has been shown to partially reverse some of these B-cell defects (43,57).Multiple studies have examined virus-specific immune responses in patients or nonhuman primates treated with antiretroviral treatment (ART) or undergoing therapeutic vaccination with or without ART. To mention a few, investigations with humans have included...

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“…125 In contrast, endosomal TLRs such as TLR7, a receptor for single-stranded RNA, and TLR9, a receptor for unmethylated CpGmotifs containing DNA, are highly expressed in B cells. [124][125][126] The activation of TLR7 and TLR9 by RNA and DNA initiates signaling via recruitment of the adaptor molecule MyD88 and the sequential activation of NF-κB, MAPKs, AP-1 and IRF-7, resulting in B cell proliferation and immunoglobulin production. [124][125][126] However, many vaccine adjuvants contain ligands for surface TLR, including monophosphoryl lipid A, suggesting that TLR activation on other important cells such as DC, tissue structural cells or T cells can promote robust B cell responses.…”

Section: Tlrmentioning

confidence: 99%

“…[124][125][126] The activation of TLR7 and TLR9 by RNA and DNA initiates signaling via recruitment of the adaptor molecule MyD88 and the sequential activation of NF-κB, MAPKs, AP-1 and IRF-7, resulting in B cell proliferation and immunoglobulin production. [124][125][126] However, many vaccine adjuvants contain ligands for surface TLR, including monophosphoryl lipid A, suggesting that TLR activation on other important cells such as DC, tissue structural cells or T cells can promote robust B cell responses. 124,125 Interestingly, a recent study showed that B cells respond rapidly during sepsis and play an important role in a rapid innate immune response via an interferon activation pathway downstream of TLR activation.…”

Section: Tlrmentioning

confidence: 99%

B-lymphocyte lineage cells and the respiratory system

2013

Journal of Allergy and Clinical Immunology

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Adaptive humoral immune responses in the airways are mediated by B cells and plasma cells that express highly evolved and specific receptors and produce immunoglobulins of most isotypes. In some cases, such as autoimmune diseases or inflammatory diseases caused by excessive exposure to foreign antigens, these same immune cells can cause disease by virtue of overly vigorous responses. This review discusses the generation, differentiation, signaling, activation and recruitment pathways of B cells and plasma cells, with special emphasis on unique characteristics of subsets of these cells functioning within the respiratory system. The primary sensitization events that generate B cells responsible for effector responses throughout the airways usually occur in the upper airways, in tonsils and adenoid structures that make up Waldeyer's Ring. Upon secondary exposure to antigen in the airways, antigen-processing dendritic cells migrate into secondary lymphoid organs such as lymph nodes that drain the upper and lower airways and further B cell expansion takes place at those sites. Antigen exposure in the upper or lower airways can also drive expansion of B lineage cells in the airway mucosal tissue and lead to the formation of inducible lymphoid follicles or aggregates that can mediate local immunity or disease.

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Plasma cell toll‐like receptor (TLR) expression differs from that of B cells, and plasma cell TLR triggering enhances immunoglobulin production

Cited by 98 publications

References 22 publications

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates

Inclusion of Flagellin during Vaccination against Influenza Enhances Recall Responses in Nonhuman Primate Neonates

Dynamics of Memory B-Cell Populations in Blood, Lymph Nodes, and Bone Marrow during Antiretroviral Therapy and Envelope Boosting in Simian Immunodeficiency Virus SIVmac251-Infected Rhesus Macaques

B-lymphocyte lineage cells and the respiratory system

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