High-Affinity B Cell Receptor Ligation by Cognate Antigen Induces Cytokine-Independent Isotype Switching

Turner, Marian L.; Corcoran, Lynn M.; Brink, Robert; Hodgkin, Philip D.

doi:10.4049/jimmunol.0903437

Cited by 17 publications

(16 citation statements)

References 53 publications

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“…By contrast, the non-canonical NF-κB pathway in these B cells was normal and would have mediated – perhaps in a compensatory manner – germline Iγ1-Sγ1-Cγ1 transcription. Consistent with this notion, this transcription process is critically regulated by the κB sites in the Iγ1 promoter and the 3′ locus control region (71, 72), and can be induced by BCR crosslinking (13, 73). The normal non-canonical NF-κB pathway would also support homeostasis of Igh +/ C γ 1-cre Rab7 fl/fl B cells.…”

Section: Discussionmentioning

confidence: 64%

B Cell Rab7 Mediates Induction of Activation-Induced Cytidine Deaminase Expression and Class-Switching in T-Dependent and T-Independent Antibody Responses

Pone

Lam

Lou

et al. 2015

The Journal of Immunology

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Class switch DNA recombination (CSR) is central to the maturation of the antibody response, as it diversifies antibody effector functions. Like somatic hypermutation, CSR requires AID, whose expression is restricted to B cells, as induced by CD40 engagement or dual TLR-BCR engagement (primary CSR-inducing stimuli). By constructing conditional knockout Igh+/Cγ1-creRab7fl/fl mice, we identified a B cell-intrinsic role for Rab7, a small GTPase involved in intracellular membrane functions, in mediating AID induction and CSR. Igh+/Cγ1-creRab7fl/fl mice displayed normal B and T cell development, and were deficient in Rab7 only in B cells undergoing IghCγ1-cre Iγ1-Sγ1-Cγ1-cre transcription, as induced – like Igh germline Iγ1-Sγ1-Cγ1 and Iε-Sε-Cε transcription – by IL-4 in conjunction with a primary CSR-inducing stimulus. These mice could not mount T-independent or T-dependent class-switched IgG1 or IgE responses, while maintaining normal IgM levels. Igh+/Cγ1-creRab7fl/fl B cells showed, in vivo and in vitro, normal proliferation and survival, normal Blimp-1 expression and plasma cell differentiation, as well as intact activation of the non-canonical NF-κB, p38 kinase and ERK1/2 kinase pathways. They, however, were defective in AID expression and CSR in vivo and in vitro, as induced by CD40 engagement or dual TLR1/2-, TLR4-, TLR7- or TLR9-BCR engagement. In Igh+/Cγ1-creRab7fl/fl B cells, CSR was rescued by enforced AID expression. These findings, together with our demonstration that Rab7 mediated canonical NF-κB activation, as critical to AID induction, outline a novel role of Rab7 in signaling pathways that lead to AID expression and CSR, likely by promoting assembly of signaling complexes along intracellular membranes.

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Section: Discussionmentioning

confidence: 64%

B Cell Rab7 Mediates Induction of Activation-Induced Cytidine Deaminase Expression and Class-Switching in T-Dependent and T-Independent Antibody Responses

Pone

Lam

Lou

et al. 2015

The Journal of Immunology

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“…The cytokine profile of WAS patients shows an impairment in the production of Th1 cytokines [7] that could explain their reduced switching to IgG2 subclass. Moreover, the isotype-switching outcome is also influenced by two additional factors: cell division [55] and antibody affinity to antigens [56]. The defective proliferation of memory and natural effector B cells and the reduced affinity maturation found in WAS might contribute to these alterations in class switching.…”

Section: Discussionmentioning

confidence: 99%

Wiskott–Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans

Castiello

Bosticardo

Pala

et al. 2014

Journal of Autoimmunity

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Wiskott–Aldrich Syndrome protein (WASp) regulates the cytoskeleton in hematopoietic cells and mutations in its gene cause the Wiskott–Aldrich Syndrome (WAS), a primary immunodeficiency with microthrombocytopenia, eczema and a higher susceptibility to develop tumors. Autoimmune manifestations, frequently observed in WAS patients, are associated with an increased risk of mortality and still represent an unsolved aspect of the disease. B cells play a crucial role both in immune competence and self-tolerance and defects in their development and function result in immunodeficiency and/or autoimmunity. We performed a phenotypical and molecular analysis of central and peripheral B-cell compartments in WAS pediatric patients. We found a decreased proportion of immature B cells in the bone marrow correlating with an increased presence of transitional B cells in the periphery. These results could be explained by the defective migratory response of WAS B cells to SDF-1α, essential for the retention of immature B cells in the BM. In the periphery, we observed an unusual expansion of CD21low B-cell population and increased plasma BAFF levels that may contribute to the high susceptibility to develop autoimmune manifestations in WAS patients. WAS memory B cells were characterized by a reduced in vivo proliferation, decreased somatic hypermutation and preferential usage of IGHV4-34, an immunoglobulin gene commonly found in autoreactive B cells.In conclusion, our findings demonstrate that WASp-deficiency perturbs B-cell homeostasis thus adding a new layer of immune dysregulation concurring to the increased susceptibility to develop autoimmunity in WAS patients.

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“…Furthermore, a report has shown that one species CpG-ODN can directly stimulate mice B cells to switch isotype independence on Th1 or Th2 cytokines, 38 moreover, BCR ligation represents a novel pathway for Ag-induced IgG switch, that does not require additional cytokine signals. 39 It would be a hypothesis to explain why Th1 cytokines do not influence IgG antibody switching.…”

Section: Discussionmentioning

confidence: 99%

Cholera toxin B subunit acts as a potent systemic adjuvant for HIV-1 DNA vaccination intramuscularly in mice

Hou

Liu

Hsi

et al. 2014

Human Vaccines & Immunotherapeutics

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High-Affinity B Cell Receptor Ligation by Cognate Antigen Induces Cytokine-Independent Isotype Switching

Cited by 17 publications

References 53 publications

B Cell Rab7 Mediates Induction of Activation-Induced Cytidine Deaminase Expression and Class-Switching in T-Dependent and T-Independent Antibody Responses

B Cell Rab7 Mediates Induction of Activation-Induced Cytidine Deaminase Expression and Class-Switching in T-Dependent and T-Independent Antibody Responses

Wiskott–Aldrich Syndrome protein deficiency perturbs the homeostasis of B-cell compartment in humans

Cholera toxin B subunit acts as a potent systemic adjuvant for HIV-1 DNA vaccination intramuscularly in mice

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