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A B cell superantigen-induced persistent "Hole" in the B-1 repertoire.

Silverman GJ, Cary SP, Dwyer DC, Luo L, Wagenknecht R, Curtiss VE - J. Exp. Med. (2000)

Bottom Line: In studies of different SpA forms, the magnitude of the induced deletion directly correlated with the V(H)-specific binding affinity/avidity.SpA treatment also induced a persistent loss of splenic S107-mu 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California at San Diego, La Jolla, California 92093-0663, USA. gsilverman@ucsd.edu

ABSTRACT
The bacterial toxin protein A from Staphylococcus aureus (SpA) interacts with B cell antigen receptors encoded by variable region heavy chain (V(H)) 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/V(H) S107 family-expressing lymphocytes. In studies of different SpA forms, the magnitude of the induced deletion directly correlated with the V(H)-specific binding affinity/avidity. Upon cessation of SpA exposure, the representation of conventional splenic (B-2 subset) lymphocytes normalized; however, we found that the V(H) family-restricted deficit of peritoneal B-1 cells persisted. SpA treatment also induced a persistent loss of splenic S107-mu 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.

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A scheme of sets of murine VH genes and SAg reactivity. In many strains, genes from clan I and clan II are the source of most of the repertoire, whereas clan III represents a nonoverlapping set. Most clan III products interact with the Fab-binding site of SpA and also with LJ-26, a recombinant avian mAb. Each recognizes similar but nonidentical sets. These also identify S107-encoded antibodies, including those expressing the T15-specific VS107.1 rearrangement that generally display among the highest levels of SpA-binding affinity.
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Figure 1: A scheme of sets of murine VH genes and SAg reactivity. In many strains, genes from clan I and clan II are the source of most of the repertoire, whereas clan III represents a nonoverlapping set. Most clan III products interact with the Fab-binding site of SpA and also with LJ-26, a recombinant avian mAb. Each recognizes similar but nonidentical sets. These also identify S107-encoded antibodies, including those expressing the T15-specific VS107.1 rearrangement that generally display among the highest levels of SpA-binding affinity.

Mentions: The frequencies of Ig- and specific antibody–secreting splenocytes and bone marrow were quantitated as described previously 15. In parallel studies, wells were coated with either goat affinity-purified anti–mouse IgM or IgG (Jackson ImmunoResearch Laboratories), MSpA, control protein antigens of OVA, HEL, or FCS, LJ-26 12, AB1-2, T139.2, Tc54.8 (Fig. 1), or isotype controls.


A B cell superantigen-induced persistent "Hole" in the B-1 repertoire.

Silverman GJ, Cary SP, Dwyer DC, Luo L, Wagenknecht R, Curtiss VE - J. Exp. Med. (2000)

A scheme of sets of murine VH genes and SAg reactivity. In many strains, genes from clan I and clan II are the source of most of the repertoire, whereas clan III represents a nonoverlapping set. Most clan III products interact with the Fab-binding site of SpA and also with LJ-26, a recombinant avian mAb. Each recognizes similar but nonidentical sets. These also identify S107-encoded antibodies, including those expressing the T15-specific VS107.1 rearrangement that generally display among the highest levels of SpA-binding affinity.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC1887708&req=5

Figure 1: A scheme of sets of murine VH genes and SAg reactivity. In many strains, genes from clan I and clan II are the source of most of the repertoire, whereas clan III represents a nonoverlapping set. Most clan III products interact with the Fab-binding site of SpA and also with LJ-26, a recombinant avian mAb. Each recognizes similar but nonidentical sets. These also identify S107-encoded antibodies, including those expressing the T15-specific VS107.1 rearrangement that generally display among the highest levels of SpA-binding affinity.
Mentions: The frequencies of Ig- and specific antibody–secreting splenocytes and bone marrow were quantitated as described previously 15. In parallel studies, wells were coated with either goat affinity-purified anti–mouse IgM or IgG (Jackson ImmunoResearch Laboratories), MSpA, control protein antigens of OVA, HEL, or FCS, LJ-26 12, AB1-2, T139.2, Tc54.8 (Fig. 1), or isotype controls.

Bottom Line: In studies of different SpA forms, the magnitude of the induced deletion directly correlated with the V(H)-specific binding affinity/avidity.SpA treatment also induced a persistent loss of splenic S107-mu 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of California at San Diego, La Jolla, California 92093-0663, USA. gsilverman@ucsd.edu

ABSTRACT
The bacterial toxin protein A from Staphylococcus aureus (SpA) interacts with B cell antigen receptors encoded by variable region heavy chain (V(H)) 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/V(H) S107 family-expressing lymphocytes. In studies of different SpA forms, the magnitude of the induced deletion directly correlated with the V(H)-specific binding affinity/avidity. Upon cessation of SpA exposure, the representation of conventional splenic (B-2 subset) lymphocytes normalized; however, we found that the V(H) family-restricted deficit of peritoneal B-1 cells persisted. SpA treatment also induced a persistent loss of splenic S107-mu 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.

Show MeSH
Related in: MedlinePlus