scholarly journals Death by a B Cell Superantigen

2003 ◽  
Vol 197 (9) ◽  
pp. 1125-1139 ◽  
Author(s):  
Carl S. Goodyear ◽  
Gregg J. Silverman
Keyword(s):  
B Cells ◽  
B Cell ◽  
Protein A ◽  
Death Receptor ◽  
Variable Region ◽  
Microbial Pathogens ◽  
Host Immune System ◽  
Antigen Receptors ◽  
Sequence Of Events

Amongst the many ploys used by microbial pathogens to interfere with host immune responses is the production of proteins with the properties of superantigens. These properties enable superantigens to interact with conserved variable region framework subdomains of the antigen receptors of lymphocytes rather than the complementarity determining region involved in the binding of conventional antigens. To understand how a B cell superantigen affects the host immune system, we infused protein A of Staphylococcus aureus (SpA) and followed the fate of peripheral B cells expressing B cell receptors (BCRs) with VH regions capable of binding SpA. Within hours, a sequence of events was initiated in SpA-binding splenic B cells, with rapid down-regulation of BCRs and coreceptors, CD19 and CD21, the induction of an activation phenotype, and limited rounds of proliferation. Apoptosis followed through a process heralded by the dissipation of mitochondrial membrane potential, the induction of the caspase pathway, and DNA fragmentation. After exposure, B cell apoptotic bodies were deposited in the spleen, lymph nodes, and Peyer's patches. Although in vivo apoptosis did not require the Fas death receptor, B cells were protected by interleukin (IL)-4 or CD40L, or overexpression of Bcl-2. These studies define a pathway for BCR-mediated programmed cell death that is VH region targeted by a superantigen.

scholarly journals Diversity of Functionally Distinct Clonal Sets of Human Conventional Memory B Cells That Bind Staphylococcal Protein A

2021 ◽  
Vol 12 ◽  
Author(s):  
Emily E. Radke ◽  
Zhi Li ◽  
David N. Hernandez ◽  
Hanane El Bannoudi ◽  
Sergei L. Kosakovsky Pond ◽  
...  
Keyword(s):  
Immune System ◽  
B Cells ◽  
B Cell ◽  
Binding Site ◽  
Protein A ◽  
Memory B Cells ◽  
Host Immune System ◽  
Staphylococcal Protein A ◽  
Staphylococcal Protein ◽  
Circulating Antibodies

Staphylococcus aureus, a common cause of serious and often fatal infections, is well-armed with secreted factors that disarm host immune defenses. Highly expressed in vivo during infection, Staphylococcal protein A (SpA) is reported to also contribute to nasal colonization that can be a prelude to invasive infection. Co-evolution with the host immune system has provided SpA with an Fc-antibody binding site, and a Fab-binding site responsible for non-immune superantigen interactions via germline-encoded surfaces expressed on many human BCRs. We wondered whether the recurrent exposures to S. aureus commonly experienced by adults, result in the accumulation of memory B-cell responses to other determinants on SpA. We therefore isolated SpA-specific class-switched memory B cells, and characterized their encoding VH : VL antibody genes. In SpA-reactive memory B cells, we confirmed a striking bias in usage for VH genes, which retain the surface that mediates the SpA-superantigen interaction. We postulate these interactions reflect co-evolution of the host immune system and SpA, which during infection results in immune recruitment of an extraordinarily high prevalence of B cells in the repertoire that subverts the augmentation of protective defenses. Herein, we provide the first evidence that human memory responses are supplemented by B-cell clones, and circulating-antibodies, that bind to SpA determinants independent of the non-immune Fc- and Fab-binding sites. In parallel, we demonstrate that healthy individuals, and patients recovering from S. aureus infection, both have circulating antibodies with these conventional binding specificities. These findings rationalize the potential utility of incorporating specially engineered SpA proteins into a protective vaccine.

scholarly journals Enhanced B Cell Expansion, Survival, and Humoral Responses by Targeting Death Receptor 6

2002 ◽  
Vol 197 (1) ◽  
pp. 51-62 ◽  
Author(s):  
Clint S. Schmidt ◽  
Jinqi Liu ◽  
Tonghai Zhang ◽  
Ho Yeong Song ◽  
George Sandusky ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Expansion ◽  
Death Receptor ◽  
Immunoglobulin M ◽  
Type I ◽  
Factor C

Targeted disruption of death receptor (DR)6 results in enhanced CD4+ T cell expansion and T helper cell type 2 differentiation after stimulation. Similar to T cells, DR6 is expressed on resting B cells but is down-regulated upon activation. We examined DR6−/− B cell responses both in vitro and in vivo. In vitro, DR6−/− B cells undergo increased proliferation in response to anti–immunoglobulin M, anti-CD40, and lipopolysaccharide. This hyperproliferative response was due, at least in part, to both increased cell division and reduced cell apoptosis when compared with wild-type B cells. Consistent with these observations, increased nuclear levels and activity of nuclear factor κB transcription factor, c-Rel, and elevated Bcl-xl expression were observed in DR6−/− B cells upon stimulation. In addition, DR6−/− B cells exhibited higher surface levels of CD86 upon activation and were more effective as antigen-presenting cells in an allogeneic T cell proliferation response. DR6−/− mice exhibited enhanced germinal center formation and increased titers of immunoglobulins to T-dependent as well as T-independent type I and II antigens. This is the first demonstration of a regulatory role of DR6 in the activation and function of B cells.

scholarly journals A B Cell Superantigen–Induced Persistent “Hole” in the B-1 Repertoire

2000 ◽  
Vol 192 (1) ◽  
pp. 87-98 ◽  
Author(s):  
Gregg J. Silverman ◽  
Stephen P. Cary ◽  
Denise C. Dwyer ◽  
Linda Luo ◽  
Raymond Wagenknecht ◽  
...  
Keyword(s):  
Immune System ◽  
B Cell ◽  
Specific Binding ◽  
Protein A ◽  
Adaptive Immune System ◽  
Variable Region ◽  
Natural Antibodies ◽  
Bacterial Toxin ◽  
Antigen Receptors ◽  
Host Immune Responses

The bacterial toxin protein A from Staphylococcus aureus (SpA) interacts with B cell antigen receptors encoded by variable region heavy chain (VH) clan III genes via a V region framework surface that has been highly conserved during the evolution of the adaptive immune system. We have investigated the consequences of exposure to this prototypic B cell superantigen, and found that treatment of neonates or adults induces a T cell–independent deletion of a large supraclonal set of susceptible B cells that includes clan III/VH S107 family–expressing lymphocytes. In studies of different SpA forms, the magnitude of the induced deletion directly correlated with the VH-specific binding affinity/avidity. Upon cessation of SpA exposure, the representation of conventional splenic (B-2 subset) lymphocytes normalized; however, we found that the VH family–restricted deficit of peritoneal B-1 cells persisted. SpA treatment also induced a persistent loss of splenic S107-μ transcripts, with a loss of certain natural antibodies and specific tolerance to phosphorylcholine immunogens that normally recruit protective antimicrobial responses dominated by the S107-expressing B-1 clone, T15. These studies illustrate how a B cell superantigen can exploit a primordial Achilles heel in the immune system, for which B-1 cells, an important source of natural antibodies and host immune responses, have special susceptibility.

scholarly journals Acetyltransferases GCN5 and PCAF are Required for B Cell Maturation in Mice

2021 ◽  
Author(s):  
Valentyn Oksenych
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Cytidine Deaminase ◽  
Dna Recombination ◽  
Variable Region ◽  
Open Chromatin ◽  
Spleen And Lymph Nodes

B lymphocyte development includes two DNA recombination processes, the V(D)J recombination of immunoglobulin (Igh) gene variable region and class switching when the Igh constant regions are changed from IgM to IgG, IgA, or IgE. The V(D)J recombination is required for successful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. The CSR occurs outside the bone marrow when mature B cells migrate to peripheral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR depend on an “open chromatin” state that makes DNA accessible to specific enzymes, recombination activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated by complex breeding a mouse model with B cells lacking both GCN5 and PCAF. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, accumulation of pro-B cells in bone marrow, and reduced CSR levels. We concluded that both GCN5 and PCAF are required for B cell development in vivo.

scholarly journals Acetyltransferases GCN5 and PCAF are required for B cell maturation

2021 ◽  
Author(s):  
Valentyn Oksenych
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Cytidine Deaminase ◽  
Dna Recombination ◽  
Variable Region ◽  
Open Chromatin ◽  
Spleen And Lymph Nodes

B lymphocyte development includes two DNA recombination processes, the V(D)J recombina-tion of immunoglobulin (Igh) gene variable region and class switching when the Igh constant regions are changed from IgM to IgG, IgA, or IgE. The V(D)J recombination is required for suc-cessful maturation of B cells from pro-B to pre-B to immature-B and then to mature B cells in the bone marrow. The CSR occurs outside the bone marrow when mature B cells migrate to periph-eral lymphoid organs, such as spleen and lymph nodes. Both V(D)J recombination and CSR de-pend on an open chromatin state that makes DNA accessible to specific enzymes, recombina-tion activating gene (RAG), and activation-induced cytidine deaminase (AID). Acetyltransferases GCN5 and PCAF possess redundant functions acetylating histone H3 lysine 9 (H3K9). Here, we generated by complex breeding a mouse model with B cells lacking both GCN5 and PCAF. We found that double-deficient mice possess low levels of mature B cells in the bone marrow and peripheral organs, accumulation of pro-B cells in bone marrow, and reduced CSR levels. We concluded that both GCN5 and PCAF are required for B cell development in vivo.

scholarly journals Transformation-associated alterations in interactions between pre-B cells and fibronectin

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2311-2320 ◽  
Author(s):  
FM Lemoine ◽  
S Dedhar ◽  
GM Lima ◽  
CJ Eaves
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Line ◽  
Cell Lines ◽  
Stromal Cells ◽  
Stromal Cell ◽  
Cell Attachment ◽  
Attachment Site ◽  
Receptor Antibodies

Abstract Marrow stromal elements produce as yet uncharacterized soluble growth factors that can stimulate the proliferation of murine pre-B cells, although close contact between these two cell types appears to ensure a better pre-B cell response. We have now shown that freshly isolated normal pre-B cells (ie, the B220+, surface mu- fraction of adult mouse bone marrow) adhere to fibronectin (FN) via an RGD cell-attachment site, as shown in a serum-free adherence assay, and they lose this functional ability on differentiation in vivo into B cells (ie, the B220+, surface mu+ fraction). Similarly, cells from an immortalized but stromal cell-dependent and nontumorigenic murine pre-B cell line originally derived from a Whitlock-Witte culture were also found to adhere to fibronectin (FN) via an RGD cell-attachment site. Moreover, in the presence of anti-FN receptor antibodies, the ability of this immortalized pre-B cell line to proliferate when co-cultured with a supportive stromal cell line (M2–10B4 cells) was markedly reduced (down to 30% of control). This suggests that pre-B cell attachment to FN on stromal cells may be an important component of the mechanism by which stromal cells stimulate normal pre-B cell proliferation and one that is no longer operative to control their more differentiated progeny. Two differently transformed pre-B cell lines, both of which are autocrine, stromal-independent, tumorigenic in vivo, and partially or completely differentiation-arrested at a very early stage of pre-B cell development, did not bind to FN. In addition, anti-FN receptor antibodies were much less effective in diminishing the ability of these tumorigenic pre-B cells to respond to M2–10B4 cell stimulation, which could still be demonstrated when the tumorigenic pre-B cells were co- cultured with M2–10B4 cells at a sufficiently low cell density. Analysis of cell surface molecules immunoprecipitated from both the nontumorigenic and tumorigenic pre-B cell lines by an anti-FN receptor antibody showed an increase in very late antigen (VLA) alpha chain(s) in both tumorigenic pre-B cell lines and a decrease in the beta 1 chain in one. Interestingly, all of the pre-B cell lines expressed similar amounts of messenger RNA for the beta 1 chain of the FN receptor. These results suggest that alteration of FN receptor expression on pre-B cells may represent a mechanism contributing to the outgrowth of leukemic pre-B cells with an autocrine phenotype and capable of stromal cell-independent, autonomous growth.

scholarly journals WASP confers selective advantage for specific hematopoietic cell populations and serves a unique role in marginal zone B-cell homeostasis and function

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4139-4147 ◽  
Author(s):  
Lisa S. Westerberg ◽  
Miguel A. de la Fuente ◽  
Fredrik Wermeling ◽  
Hans D. Ochs ◽  
Mikael C. I. Karlsson ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Marginal Zone ◽  
Hematopoietic Cells ◽  
Selective Advantage ◽  
Relative Contribution ◽  
B Cell Homeostasis ◽  
And Function

Abstract Development of hematopoietic cells depends on a dynamic actin cytoskeleton. Here we demonstrate that expression of the cytoskeletal regulator WASP, mutated in the Wiskott-Aldrich syndrome, provides selective advantage for the development of naturally occurring regulatory T cells, natural killer T cells, CD4+ and CD8+ T lymphocytes, marginal zone (MZ) B cells, MZ macrophages, and platelets. To define the relative contribution of MZ B cells and MZ macrophages for MZ development, we generated wild-type and WASP-deficient bone marrow chimeric mice, with full restoration of the MZ. However, even in the presence of MZ macrophages, only 10% of MZ B cells were of WASP-deficient origin. We show that WASP-deficient MZ B cells hyperproliferate in vivo and fail to respond to sphingosine-1-phosphate, a crucial chemoattractant for MZ B-cell positioning. Abnormalities of the MZ compartment in WASP−/− mice lead to aberrant uptake of Staphylococcus aureus and to a reduced immune response to TNP-Ficoll. Moreover, WASP-deficient mice have increased levels of “natural” IgM antibodies. Our findings reveal that WASP regulates both development and function of hematopoietic cells. We demonstrate that WASP deficiency leads to an aberrant MZ that may affect responses to blood-borne pathogens and peripheral B-cell tolerance.

scholarly journals Ras Mediates Effector Pathways Responsible for Pre-B Cell Survival, Which Is Essential for the Developmental Progression to the Late Pre-B Cell Stage

2000 ◽  
Vol 192 (2) ◽  
pp. 171-182 ◽  
Author(s):  
Hitoshi Nagaoka ◽  
Yoshimasa Takahashi ◽  
Reiko Hayashi ◽  
Tohru Nakamura ◽  
Kumiko Ishii ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Chain Gene ◽  
B Cell Differentiation ◽  
Antigen Receptors ◽  
Cell Stage ◽  
Light Chain Gene ◽  
B Cell Survival ◽  
Effector Pathways

Ras is essential for the transition from early B cell precursors to the pro-B stage, and is considered to be involved in the signal cascade mediated by pre-B cell antigen receptors. To examine the role of p21ras in the late stage of B cell differentiation, we established transgenic mice (TG) expressing a dominant-inhibitory mutant of Ha-ras (Asn-17 Ha-ras) in B lineage cells at high levels after the early B cell precursor stage. Expression of p21Asn-17 Ha-ras was associated with a prominent reduction in the number of late pre-B cells, but had little effect on proliferation of early pre-B cells. Inhibition of p21ras activity markedly reduced the life span of pre-B cells, due, at least in part, to downregulation of the expression of an antiapoptotic protein, Bcl-xL. Thus, the apparent role for p21ras activity in pre-B cell survival may explain the decreased numbers of late pre-B cells in Asn-17 Ha-ras TG. Consistent with this possibility, overexpression of Bcl-2 in Asn-17 Ha-ras TG reversed the reduction in the number of late pre-B cells undergoing immunoglobulin light chain gene (IgL) rearrangement and progressing to immature B cells. These results suggest that p21ras mediates effector pathways responsible for pre-B cell survival, which is essential for progression to the late pre-B and immature B stages.

scholarly journals OVERLAP STIMULATION OF PRIMARY AND SECONDARY B CELLS BY CROSS-REACTING DETERMINANTS

1973 ◽  
Vol 138 (5) ◽  
pp. 1276-1281 ◽  
Author(s):  
N. R. Klinman ◽  
J. L Press ◽  
G. P. Segal
Keyword(s):  
B Cells ◽  
B Cell ◽  
Antigen Receptors ◽  
Cell Stimulation ◽  
Stimulation Of

Experiments were carried out to test the validity of the hypothesis that postulated differences in the nature of the antigen receptors of primary and secondary B cells should be reflected in a greater specificity in primary B-cell stimulation (2). Enumeration of clonal precursors stimulated by either DNP-Hy, TNP-Hy, or a mixture of both antigens confirmed this hypothesis. Since the sum of primary B cells stimulated by DNP-Hy and TNP-Hy is approximately equal to the number stimulated by a mixture of both, overlap stimulation of primary B cells by these antigens could be considered negligible. In contrast, the stimulation of B cells from mice previously immunized with DNP-Hy showed extensive overlap of stimulation by DNP-Hy and TNP-Hy. Thus secondary B cells appear less fastidious in their affinity requirements for stimulation than primary B cells.

Sign in / Sign up

Export Citation Format

Share Document