Human marginal zone b cells are not an activated b cell subset: strong expression of cd21 as a putative mediator for rapid b cell activation

Timens, Wim; Boes, A; Poppema, Sibrand

doi:10.1002/eji.1830191129

Cited by 80 publications

(59 citation statements)

References 29 publications

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“…Splenic MZ B cells are characterized by particular morphologic, cytochemical, and immunophenotypic features (1,4,5). In addition, they have the capacity to mount T cell-independent responses to bacterial polysaccharides (TI-2 Ags) as unequivocally demonstrated in experimental animals and also supported by indirect evidence from different physiological and pathological conditions in humans (3, 6 -11).…”

mentioning

confidence: 99%

Heterogeneity of Tonsillar Subepithelial B Lymphocytes, the Splenic Marginal Zone Equivalents

Dono

Zupo²,

Leanza

et al. 2000

The Journal of Immunology

115

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The VH4 genes expressed by both resting and in vivo-activated subepithelial (SE) B cells from human tonsils were studied. Resting SE B cells were subdivided according to the presence (IgDlow) or absence (IgM-only) of surface IgD. CD27 was abundant on activated SE B cells and low on resting IgM-only B cells. Resting IgDlow SE B cells could be subdivided into CD27low and CD27high cell fractions. Resting IgDlow SE B cells displayed VH4 genes with a substantial number of mutations (13/29 of the molecular clones were mutated), whereas 25/26 of the clones from resting IgM-only SE B cells were unmutated. Moreover, mutated VH4 genes were detected mainly within the CD27high cell fraction of the IgDlow SE B cells. Several identical unmutated VH4DJH sequences (11/32) were found in different molecular clones from resting IgM-only SE B cells, suggesting local cellular expansion. Both unmutated (14/25) and mutated (11/25) sequences were found in μ transcripts of activated SE B cells. Extensive mutation was observed in the γ transcripts of activated SE B cells. Therefore, SE B cells are heterogeneous, being comprised of B cells with mutated Ig VH4 genes, that are Ag-experienced B cells, and a subset of B cells with unmutated VH4 genes that are either virgin cells or cells driven by Ags that did not induce or select for V gene mutations.

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mentioning

confidence: 99%

Heterogeneity of Tonsillar Subepithelial B Lymphocytes, the Splenic Marginal Zone Equivalents

Dono

Zupo²,

Leanza

et al. 2000

The Journal of Immunology

115

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“…Some studies have shown the effectiveness of vaccination in inducing protective concentrations of specific antibodies (5, 10, 24, 33), while others have shown limited serological responses (15). As the initiation of the antibody response to polysaccharides seems to depend on the presence of splenic tissue, and in particular on a functional marginal-zone B-cell compartment (3,14,18,34), it may be expected that polysaccharide vaccines are of limited use in asplenic patients.The physical coupling of a polysaccharide to a carrier protein greatly improves the immunogenicity of the polysaccharide, a principle first described in 1929 (11). Conjugated polysaccharides overcome the antipolysaccharide unresponsiveness in early life (2, 8), which is thought to be due to a still immature splenic marginal-zone B-cell compartment (2).…”

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confidence: 99%

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confidence: 99%

Pneumococcal Conjugate Vaccines Overcome Splenic Dependency of Antibody Response to Pneumococcal Polysaccharides

Breukels

Zandvoort²,

Dobbelsteen

et al. 2001

Infect Immun

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Protection against infections with Streptococcus pneumoniae depends on the presence of antibodies against capsular polysaccharides that facilitate phagocytosis. Asplenic patients are at increased risk for pneumococcal infections, since both phagocytosis and the initiation of the antibody response to polysaccharides take place in the spleen. Therefore, vaccination with pneumococcal polysaccharide vaccines is recommended prior to splenectomy, which, as in the case of trauma, is not always feasible. We show that in rats, vaccination with a pneumococcal conjugate vaccine can induce good antibody responses even after splenectomy, particularly after a second dose. The spleen remains necessary for a fast, primary response to (blood-borne) polysaccharides, even when they are presented in a conjugated form. Coadministration of a conjugate vaccine with additional nonconjugated polysaccharides of other serotypes did not improve the response to the nonconjugated polysaccharides. We conclude that pneumococcal conjugate vaccines can be of value in protecting asplenic or hyposplenic patients against pneumococcal infections.Protection against infections with encapsulated bacteria such as Streptococcus pneumoniae depends on the presence of antibodies against capsular polysaccharides. These serotypespecific antibodies facilitate phagocytosis, the main mode of host defense against S. pneumoniae. The spleen is an important organ in the immune response to S. pneumoniae, since it contains both antibody-producing B cells and phagocytes (4, 26). Asplenic patients are therefore at increased risk for invasive infections with S. pneumoniae (13). Although most infections occur within the first few years after splenectomy, the risk of overwhelming postsplenectomy infections is lifelong (9, 36). Therefore, vaccination against S. pneumoniae is indicated for this group. At present, the vaccine available for this aim is the 23-valent pneumococcal polysaccharide (PPS) vaccine (1). The immunogenicity of PPS vaccine in splenectomized patients has been assessed in a number of trials. Some studies have shown the effectiveness of vaccination in inducing protective concentrations of specific antibodies (5, 10, 24, 33), while others have shown limited serological responses (15). As the initiation of the antibody response to polysaccharides seems to depend on the presence of splenic tissue, and in particular on a functional marginal-zone B-cell compartment (3,14,18,34), it may be expected that polysaccharide vaccines are of limited use in asplenic patients.The physical coupling of a polysaccharide to a carrier protein greatly improves the immunogenicity of the polysaccharide, a principle first described in 1929 (11). Conjugated polysaccharides overcome the antipolysaccharide unresponsiveness in early life (2, 8), which is thought to be due to a still immature splenic marginal-zone B-cell compartment (2). The induction of antipolysaccharide antibodies by conjugate vaccines at a young age suggests that conjugates might initiate the antipolysaccharide anti...

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“…Marginal zone B-cells are a non-activated B-cell subset [19], but on activation, they migrate to the follicular zone where CD21 (CR2) is proteolytically cleaved and antigen transferred to follicular dendritic cells. There is, notably, no T-cell help, because i) there is no efficient processing and presentation of polysaccharides, and ii) solely CR2 mediated B-cell triggering does not upregulate co-stimulatory molecules [20].…”

Section: Microanatomic Site Of Splenic Immune Reaction Towards Polysamentioning

confidence: 99%

The role of complement in the success of vaccination with conjugated vs. unconjugated polysaccharide antigen

Salehen¹,

Stover²

2008

Vaccine

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The complement system, a well-characterised arm of the innate immune system, significantly influences the adaptive immune response via direct cell-cell interaction and maintenance of lymphoid organ architecture. Development of vaccines is a major advance in modern health care. In this review, we highlight the importance of the marginal zone in response to both, polysaccharide and conjugated vaccines, and discuss the relevance of complement herein, based on findings obtained from animal models with specific deletions of certain complement components and from vaccination reports of complement-deficient individuals. We conclude that both, intactness of the complement system and maturity of expression of its components, are relatively more important to aid in the immune response to polysaccharide vaccine than to conjugated vaccines. keywords (3): complement vaccine polysaccharide running titleComplement essential for polysaccharide vaccines 2 The importance of complement activation in adaptive immunityThe complement system is part of the innate immune defence, because it partakes in first-line, pattern-mediated recognition via its germ-line encoded serum proteins and receptors. It has evolved from a primordial fluid-phase system that "simply" tags and mediates uptake of micro-organisms by cells of early chordates. Large-scale gene duplications, exon shuffling and transposition events are the main evolutionary mechanisms that have generated a wide range of diversified molecules, which we now ascribe to innate and adaptive immune defences Importantly, after subcutaneous administration of T-independent or T-dependent antigens in mice, it is the spleen that reacts with formation of antibody forming cells before the draining lymphnodes, especially in response to T-independent antigen [32].Germinal centers are formed during an immune response elicited with a so-called Tindependent antigen. This reaction is, however, of short duration. It is possible that the absence of somatic hypermutation of the immunoglobulin V genes is due to both, the curtailed germinal center reaction -as somatic hypermutation is a relatively late event -6 and the lack of T-cell help [33]. Of note, marginal zone B-cells are incapable of participating in the process of somatic hypermutation due to the lack of expression of activation-induced cytidine deaminase, an enzyme essential for this process [34].The involvement of T-cells is not strictly excluded in the antibody response against polysaccharides, as B7 ligand dependent costimulation of B-cells (by T-cells) is needed, however, the interaction in this early response is short and T-cell receptor unspecific [35].The absence of somatic hypermutation does, however, explain the low affinity binding of anti-polysaccharide antibodies.

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Human marginal zone b cells are not an activated b cell subset: strong expression of cd21 as a putative mediator for rapid b cell activation

Cited by 80 publications

References 29 publications

Heterogeneity of Tonsillar Subepithelial B Lymphocytes, the Splenic Marginal Zone Equivalents

Heterogeneity of Tonsillar Subepithelial B Lymphocytes, the Splenic Marginal Zone Equivalents

Pneumococcal Conjugate Vaccines Overcome Splenic Dependency of Antibody Response to Pneumococcal Polysaccharides

The role of complement in the success of vaccination with conjugated vs. unconjugated polysaccharide antigen

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