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Carl S Goodyear

Publications and source records attributed to Carl S Goodyear.

11 recordsLinked to original sources
PubMed2006

Temporal and dose-dependent relationships between in vivo B cell receptor-targeted proliferation and deletion-induced by a microbial B cell toxin.

The effective functioning of the adaptive immune system requires careful clonal regulation within the B cell compartment. Some microbial pathogens produce virulence factors, like staphylococcal protein A, which interact at high frequencies with B lymphocyte through unconventional binding sites in BCR variable region frameworks conserved during evolution. We have characterized the in vivo effect of staphylococcal protein A treatment on peripheral B cells bearing susceptible BCR, and found a dose-dependent direct relationship over the range of 2 mg to <0.2 microg in the magnitude of induced BCR-targeted supraclonal cell death. Significantly, some level of targeted B cell proliferation was always detectable, with greatest interim supraclonal expansion demonstrated at 2 days after 20-microg treatment. Subsequently, this transient expansion always collapsed. In direct comparisons, i.p. treatment was more efficacious than i.v. treatment, although at higher doses this finding was less marked. These studies elucidate a general paradigm in which in vivo encounters with a B cell superantigen are uniformly associated with proliferative expansion followed by deletion that is more rapid and complete with higher doses, whereas lower doses lead to greater transient in vivo expansion with delayed deletion to levels at later times that are still quantitatively proportional to the dose. Our results document the potent in vivo B cell-targeted properties of a microbial B cell superantigen, even at submicrogram doses associated with great molar excess of circulating Ig, and clearly illustrate the intertwined relationships between targeted proliferative cycling and apoptotic death that is induced by a microbial B cell superantigen.

Animals↗
PubMed2006

Confounding B-cell defences: lessons from a staphylococcal superantigen.

Studies of microbial superantigens that target large clonal sets of B cells through conserved antigen-receptor-variable-region sites are providing new insights into the mechanisms of B-cell activation-induced cell death. These investigations have shown differences between the clonal regulation of follicular B cells (B2 cells) and the innate-like marginal-zone B cells and B1 cells, and have also shown how B-cell superantigens can affect specialized host defences against infection. Agents designed to emulate the properties of B-cell superantigens might also provide new approaches for the treatment of B-cell-mediated autoimmune and neoplastic diseases.

Animals↗
PubMed2005

B cell superantigens: a microbe's answer to innate-like B cells and natural antibodies.

Marginal zone B cells and B-1 cells have been termed innate-like B cells as they express limited repertoires that play special roles in immune defenses against common infections. These B cells are the sources of natural antibodies and are capable of highly accelerated clonal responses that help counter blood-borne infections. We have characterized a class of microbial product with highly adapted binding interactions with host immunoglobulins/B cell receptors (BCRs), which enable the targeting of large supra-clonal sets of B cells for activation-associated apoptotic death. In recent studies, we have shown that all B cells with V region-targeted BCRs are susceptible. However, compared to follicular B cells, in vivo exposure preferentially causes innate-like B cells to undergo induced death with subsequent long-lasting supra-clonal depletion and immune tolerance. Based on these properties, it is likely that B cell superantigens influence the pathogenesis of some common infections, but also may provide novel therapeutic opportunities to treat B cell neoplastic and autoimmune diseases.

Animals↗
PubMed2004

Structural, expression, and evolutionary analysis of mouse CIAS1.

Mutations in the human CIAS1 (hCIAS1) gene have been identified in a continuum of inflammatory disorders including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset multisystem inflammatory disease (NOMID). CIAS1 codes for the protein Cryopyrin, which appears to play a role in innate immune function by regulating the production of proinflammatory cytokines. Human and mouse Cryopyrin are highly conserved and consist of three functional domains including a pyrin domain, an NACHT domain, and a leucine-rich repeat (LRR) domain that are characteristics of the NALP family of proteins. The pyrin and NACHT domains of Cryopyrin and other NALP proteins are highly conserved among primate and nonprimate mammals, suggesting purifying selection throughout mammalian evolution. Cryopyrin expression is also very similar in human and mouse with mouse CIAS1 mRNA expression found primarily in peripheral blood leukocytes consistent with the postulated inflammatory function. We also detected significant expression in mouse eye and skin tissue, which is consistent with symptoms observed in human Cryopyrin-associated diseases.

Amino Acid Sequence↗
PubMed2004

Staphylococcal toxin induced preferential and prolonged in vivo deletion of innate-like B lymphocytes.

Contributing to host defenses from the adaptive immune system, splenic marginal zone (MZ) B cells, with their preactivated state and special topographical location, serve essential roles as primary defenders from blood-borne microbes. From studies designed to define the immunologic impact of protein A of Staphylococcus aureus (SpA), a virulence factor with targeted B cell antigen receptor-binding properties, we found that within minutes of in vivo exposure, SpA became surface associated with B lymphocytes and induced trafficking. Within several hours, MZ were completely effaced of affected B cells. This was rapidly followed by massive B cell apoptosis, with accelerated preferential deletion of targeted MZ B cells and impaired responsiveness to T independent immunogens. Subsequently, the temporal recovery of MZ B cells was significantly delayed compared to peripheral follicular B cells (B-2 cells). These studies elucidate the cellular program induced by a natural toxin that is shown to be highly efficient at depleting innate-like B cells important for defense from systemic infection.

Animals↗
PubMed2004

In vivo VL-targeted activation-induced apoptotic supraclonal deletion by a microbial B cell toxin.

To interfere with host immune responses, some microbial pathogens produce proteins with the properties of superantigens, which can interact via conserved V region framework subdomains of the Ag receptors of lymphocytes rather than the complementarity-determining region involved in the binding of conventional Ags. In recent studies, we have elucidated how a model B cell superantigen affects the host immune system by targeting a conserved V(H) site on the Ag receptors of B lymphocytes. To determine whether these findings represent a general paradigm, we investigated the in vivo immunobiologic properties of protein L of Peptostreptococcus magnus (PpL), a microbial Ig-binding protein specific for a V region site on Ig L chains. Our studies confirmed that PpL binding is restricted to a subset of murine Vkappa-expressing B cells, and found that B cells with stronger PpL-binding activity are associated with certain B cell subsets: splenic marginal zone (CD21(high) CD23(low)), splenic CD1(+), peritoneal B-1a (IgD(low) CD5(+)), and CD21(high) CD24(high) B cells in peripheral lymph nodes, mesenteric lymph nodes, and Peyer's patches. Infusion of PpL triggered a sequence of events in B cell receptor (BCR)-targeted B cells, with rapid down-regulation of BCR, 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, DNA fragmentation, and the deposition of B cell apoptotic bodies. These studies define a common pathway by which microbial toxins that target V region-associated BCR sites induce programmed cell death.

Adoptive Transfer↗
PubMed2003

The autoreactivity of anti-phosphorylcholine antibodies for atherosclerosis-associated neo-antigens and apoptotic cells.

Abs specific for phosphorylcholine (PC) are known to contribute to the immune defense against a variety of microbial infections. To assess for other types of binding interactions, we performed surveys of anti-PC Abs of diverse biologic origins and structural diversity and demonstrated a common autoreactivity for oxidatively modified low density lipoprotein and other oxidation-specific structures containing PC-Ags. We also found that cells undergoing apoptosis sequentially express a range of oxidation-specific neo-self PC determinants. Whereas natural Abs to PC recognized cells at early stages of apoptosis, by contrast, an IgG anti-PC Ab, representative of a T cell-dependent response, recognized PC determinants primarily associated with late stages of apoptosis. Cumulatively, these results demonstrate a fundamental paradigm in which Abs from both the innate and the T cell-dependent tiers of the B cell compartment recognize a minimal molecular motif arrayed both on microbes and as neo-self Ags linked to atherosclerosis and autoimmune disease.

Animals↗
PubMed2003

Pneumococcal vaccination decreases atherosclerotic lesion formation: molecular mimicry between Streptococcus pneumoniae and oxidized LDL.

During the progression of atherosclerosis, autoantibodies are induced to epitopes of oxidized low-density lipoprotein (oxLDL) and active immunization of hypercholesterolemic mice with oxLDL ameliorates atherogenesis. We unexpectedly found that many autoantibodies to oxLDL derived from 'naive' atherosclerotic mice share complete genetic and structural identity with antibodies from the classic anti-phosphorylcholine B-cell clone, T15, which protect against common infectious pathogens, including pneumococci. To investigate whether in vivo exposure to pneumococci can affect atherogenesis, we immunized Ldlr(-/-) mice with Streptococcus pneumoniae. This induced high circulating levels of oxLDL-specific IgM and a persistent expansion of oxLDL-specific T15 IgM-secreting B cells primarily in the spleen, which were cross-reactive with pneumococcal determinants. Pneumococcal immunization decreased the extent of atherosclerosis, and plasma from these mice had an enhanced capacity to block the binding of oxLDL to macrophages. These studies show molecular mimicry between epitopes of oxLDL and S. pneumoniae and indicate that these immune responses can have beneficial effects.

Animals↗
PubMed2003

Death by a B cell superantigen: In vivo VH-targeted apoptotic supraclonal B cell deletion by a Staphylococcal Toxin.

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.

Animals↗
PubMed2002

A model B-cell superantigen and the immunobiology of B lymphocytes.

Recent reports have shown that protein A of Staphylococcus aureus (SpA) is a specific toxin for B cells by virtue of specific binding interactions with conserved sites on the V(H) region of the B-cell antigen receptor. The structural basis for these Fab-binding interactions has recently been revealed in crystallographic analyses, which have demonstrated many similarities with the interactions of T-cell superantigens. Investigations of the in vivo response to SpA have illustrated how a B-cell superantigen can be used to provide a window for examining fundamental principles that underlie the immunobiology of B lymphocytes.

Animals↗