Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2006 Feb;74(2):1196-203.
doi: 10.1128/IAI.74.2.1196-1203.2006.

Pathogenesis of B-cell Superantigen-Induced Immune Complex-Mediated Inflammation

Affiliations
Free PMC article

Pathogenesis of B-cell Superantigen-Induced Immune Complex-Mediated Inflammation

Amy L Anderson et al. Infect Immun. .
Free PMC article

Abstract

Staphylococcal protein A (SpA) is representative of a new class of antigens, the B-cell superantigens (SAgs). These antigens bind to the Fab regions of immunoglobulin molecules outside their complementarity-determining regions. SpA, the best-studied B-cell SAg, reacts with the Fabs of most VH3+ immunoglobulins, which are expressed on 30 to 60% of human peripheral B cells. Therefore, B-cell SAgs like SpA have great potential to elicit inflammatory responses in vivo. We previously reported that the interaction of SpA with VH3+ immunoglobulin molecules leads to activation of the complement cascade and produces a histologic pattern of inflammation in the skin of a rabbit indicative of immune complex injury. To elucidate the cellular and molecular events contributing to this type of unconventional immune complex-mediated inflammation, we established a mouse peritoneal Arthus reaction model. Mice treated intravenously with human polyclonal immunoglobulin G (IgG), followed by intraperitoneal injection of SpA, showed neutrophil influx into the peritoneal cavity with peak numbers appearing at 8 h. This inflammatory reaction was dependent on the interaction of SpA with VH3+ IgG. Mast cells, FcgammaRIII, complement components, and tumor necrosis factor alpha play obligatory roles, and the reaction is associated with the local release of the CXC chemokines macrophage inflammatory protein 2 and KC. The data provide further compelling evidence for the induction of immune complex-mediated injury by a B-cell SAg and highlight important factors contributing to the pathogenesis of this novel type of inflammatory reaction.

Figures

FIG. 1.
FIG. 1.
Kinetics of neutrophil infiltration in the peritoneal Arthus reaction. Inset indicates treatment conditions. BALB/c mice were treated i.v. with human polyclonal IgG and i.p. with SpA. At various points thereafter, their peritoneal cavities were subjected to lavage and the total number of neutrophils was determined. The number of neutrophils was highest at 8 h (n = 7 for each time point, mean ± standard deviation, P < 0.005).
FIG. 2.
FIG. 2.
Requirement of VH3+ hIgGs for SpA-induced neutrophil influx. SpA-induced inflammatory reactions were markedly reduced at 8 h in mice that had received hIgG depleted of molecules bearing VH3 heavy chains (n = 6, mean ± standard deviation, P < 0.0004).
FIG. 3.
FIG. 3.
Accumulation of KC and MIP-2 in SpA-hIgG-induced peritoneal Arthus reactions. Levels of the CXC chemokines KC and MIP-2 in the peritoneal cavity were determined with a Searchlight Multiplex assay after induction of the SpA-hIgG peritoneal Arthus reaction. Higher levels of both chemokines were seen at 4 h than at 8 h (n = 5 for each time point).
FIG. 4.
FIG. 4.
Neutrophil recruitment into the peritoneal cavities of TNF-α knockout, mast cell-deficient, and FcγRIII knockout mice 8 h after injection of hIgG and SpA. The number of neutrophils was markedly reduced in TNF-α knockout versus wild-type mice (n = 6 in each group, mean ± standard deviation, P < 0.0008), mast cell-deficient versus wild-type mice (n = 9 in each group, mean ± standard deviation, P < 0.0007) and mast cell-deficient versus mast cell-reconstituted mice (n = 9, mean ± standard deviation, P < 0.0001), and in FcγRIII knockout mice versus wild-type mice (n = 10 in each group, mean ± standard deviation, P < 0.007).
FIG. 5.
FIG. 5.
Dependence of SpA-hIgG-induced peritoneal Arthus reaction on complement. The 8-h SpA-induced peritoneal Arthus reaction was reduced 90% in C3-deficient versus wild-type mice (n = 8 in each group, mean ± standard deviation, P < 0.04) and 60% in C5-deficient versus wild-type mice (n = 4 in each group, mean ± standard deviation, P < 0.004). BALB/c mice treated with a C5aR inhibitor (50 μg) demonstrated a 64% reduction in the number of neutrophils in the peritoneal cavity 8 h after injection of hIgG and SpA compared to those treated with saline (n = 10 in each group, mean ± standard deviation, P < 0.001).

Similar articles

See all similar articles

Cited by 3 articles

Publication types

MeSH terms

LinkOut - more resources

Feedback