Absence of marginal zone B cells in Pyk-2–deficient mice defines their role in the humoral response

Guinamard, Rodolphe; Okigaki, Mitsuhiko; Schlessinger, Joseph; Ravetch, Jeffrey V.

doi:10.1038/76882

Cited by 478 publications

(509 citation statements)

References 34 publications

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“…TLR4, the receptor for LPS. MZ B cells proliferate and rapidly secrete high levels of IgM and IgG3 in response to LPS stimulation 26, 28, 29. However, cell proliferation in response to LPS stimulation was not affected in aged mice, nor was the level of TLR4 expression.…”

Section: Discussionmentioning

confidence: 98%

Ageing adversely affects the migration and function of marginal zone B cells

Turner

Mabbott

2017

Immunology

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SummaryMarginal zone (MZ) B cells are positioned within the spleen to capture blood‐borne antigen and immune complexes and deliver them to follicular dendritic cells in the B‐cell follicles. We show that within the spleens of aged mice antigen capture by MZ B cells, and their ability to shuttle between the follicle and MZ, were impaired. The ability of aged MZ B cells to migrate towards the MZ chemoattractant sphingosine‐1‐phosphate was increased, suggesting that aged MZ B cells had a greater propensity to be retained within the MZ. An extrinsic impairment in aged B‐cell migration towards the MZ was demonstrated using bone marrow chimeras. The follicular shuttling of MZ B cells derived from either young or aged bone marrow was similarly reduced in aged recipient spleens, showing that ageing effects on splenic stromal cells were responsible for the impaired follicular shuttling of MZ B cells. MZ B cells rapidly mount T‐cell‐independent (TI) antibody‐responses to microbial polysaccharide antigen. In aged mice the ability to produce immunoglobulins in response to the TI type 1 antigen TNP‐LPS was impaired. These ageing‐related changes to the MZ and MZ B cells have implications for the clearance of blood‐borne pathogens. Indeed elderly people have increased susceptibility to Streptococcus pneumoniae, a TI antigen, and decreased responses to vaccination. A thorough analysis of the mechanisms that underpin the ageing‐related decline in the status of the MZ and MZ B cells will help the design of novel treatments to improve immunity in the elderly.

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Section: Discussionmentioning

confidence: 98%

Ageing adversely affects the migration and function of marginal zone B cells

Turner

Mabbott

2017

Immunology

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“…In marginal zone B cells, its engagement by blood-borne antigens opsonized with C3d is believed to provide the basis for T-independent type-2 antibody responses, in particular of IgG2a and IgG3 isotypes [22,34]. The impaired IgG3 response to NP-Ficoll in TACI-Ig×Bcl-2 dTg mice is consistent with their lack of marginal zone B cells and is comparable to that observed in the marginal zone B cell-deficient Pyk-2 -/-mice [34]. Neither Pyk-2 nor TACI-Ig×Bcl-2 mice have significantly impaired IgM responses to NP-Ficoll, and their IgG3 responses are reduced but not abolished.…”

Section: Discussionmentioning

confidence: 99%

“…Inactivation of the repressor activity of RBP-J by Notch signaling promotes marginal zone B cell formation, whereas the Notchantagonizing protein MINT prevents it [40,41]. Lack of marginal zone B cells is also observed upon deficiencies of Pyk-2, DOCK-2 and Lsc, three proteins implicated in migratory responses to chemokines [34,[42][43][44], and of the transcriptional co-activator BOB.1/OBF.1/OCA-B [45]. Interestingly, neither BOB.1/OBF.1/OCA-B, nor RBP-J or BAFF deficiencies affects the B1 B cell population [2,3,41,45].…”

Section: Discussionmentioning

confidence: 99%

The anti‐apoptotic factor Bcl‐2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

et al. 2004

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The TNF family ligand B cell-activating factor (BAFF, BLyS, TALL-1) is an essential factor for B cell development. BAFF binds to three receptors, BAFF-R, transmembrane activator and CAML interactor (TACI), and B cell maturation antigen (BCMA), but only BAFF-R is required for successful survival and maturation of splenic B cells. To test whether the effect of BAFF is due to the up-regulation of anti-apoptotic factors, TACI-Ig-transgenic mice, in which BAFF function is inhibited, were crossed with transgenic mice expressing FLICE-inhibitory protein (FLIP) or Bcl-2 in the B cell compartment. FLIP expression did not rescue B cells, while enforced Bcl-2 expression restored peripheral B cells and the ability to mount T-dependent antibody responses. However, many B cells retained immaturity markers and failed to express normal amounts of CD21. Marginal zone B cells were not restored and the Tindependent IgG3, but not IgM, response was impaired in the TACI-Ig×Bcl-2 mice. These results suggest that BAFF is required not only to inhibit apoptosis of maturating B cells, but also to promote differentiation events, in particular those leading to the generation of marginal zone B cells.

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“…This treatment results in selective depletion of MZB cells without affecting other lymphocyte populations in the spleen, and thus has an advantage over mutant mouse strains noted to lack MZB cells in the setting of other immunologic defects (22). In addition, mAb depletion of MZB cells retains normal trafficking of B. hermsii through the spleen, in contrast to the altered physiology resulting from splenectomy.…”

Section: Depletion Of Mzb Cells Leads To a Decrease In B Hermsiispecmentioning

confidence: 96%

Infection-Induced Marginal Zone B Cell Production of Borrelia hermsii-Specific Antibody Is Impaired in the Absence of CD1d

Belperron

Dailey

Bockenstedt

2005

The Journal of Immunology

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Ab that arise in the absence of T cell help are a critical host defense against infection with the spirochetes Borrelia burgdorferi and Borrelia hermsii. We have previously shown that CD1d-deficient (CD1d−/−) mice have impaired resistance to infection with B. burgdorferi. In mice, CD1d expression is highest on marginal zone B (MZB) cells, which produce Ab to blood-borne Ag. In this study we examined MZB cell activation and Ab production in mice infected with B. hermsii, which achieve high levels of bacteremia. We show by flow cytometry that MZB cells associate with B. hermsii and up-regulate the activation markers syndecan I and B7.1 within 16 h of infection. By 24 h, MZB cells secrete B. hermsii-specific IgM, coinciding with the loss of activation marker expression and the reduction in spirochete burden. In contrast, MZB cells from CD1d−/− mice remain activated for at least 96 h of infection, but produce only minimal B. hermsii-specific IgM in vivo and ex vivo; pathogen burden in the blood also remains elevated. Wild-type mice depleted of MZB cells using mAb to LFA-1 and α4β1 integrin have reduced serum levels of B. hermsii-specific IgM and increased pathogen burden, similar to B. hermsii-infected CD1d−/− mice. Passive transfer of immune mouse serum, but not naive mouse serum, into infected CD1d−/− mice leads to down-regulation of activation markers and clearance of B. hermsii from the MZB cells. These results demonstrate that blood-borne spirochetes activate MZB cells to produce pathogen-specific IgM and reveal a role for CD1d in this process.

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Absence of marginal zone B cells in Pyk-2–deficient mice defines their role in the humoral response

Cited by 478 publications

References 34 publications

Ageing adversely affects the migration and function of marginal zone B cells

Ageing adversely affects the migration and function of marginal zone B cells

The anti‐apoptotic factor Bcl‐2 can functionally substitute for the B cell survival but not for the marginal zone B cell differentiation activity of BAFF

Infection-Induced Marginal Zone B Cell Production of Borrelia hermsii-Specific Antibody Is Impaired in the Absence of CD1d

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