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Reaction by Staphylococcal Protein a Cell Superantigen: Elicitation of An In Vivo Inflammatory Response to a Prototypic B Cell Superantigen: Elicitation of an Arthus Reaction by Staphylococcal Protein A This information is current as Lisa M. Kozlowski, Weiping Li, Michael Goldschmidt and Arnold of October 1, 2021. I. Levinson J Immunol 1998; 160:5246-5252; ; http://www.jimmunol.org/content/160/11/5246 Downloaded from References This article cites 50 articles, 28 of which you can access for free at: http://www.jimmunol.org/content/160/11/5246.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 1, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 1998 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. In Vivo Inflammatory Response to a Prototypic B Cell Superantigen: Elicitation of an Arthus Reaction by Staphylococcal Protein A1 Lisa M. Kozlowski,2* Weiping Li,* Michael Goldschmidt,† and Arnold I. Levinson3* Staphylococcal protein A (SpA) is representative of a new class of Ags, the B cell superantigens (SAgs). These SAgs, unlike conventional Ags, bind to the Fab regions of Ig molecules outside their complementarity-determining regions. In addition, B cell SAgs can react with a substantial amount of a host’s serum Igs by virtue of their ability to interact with many members of an entire variable heavy chain (VH) or variable light chain gene family. For example, SpA reacts with the Fabs of most human Igs using 1 heavy chains from the VH3 gene family (VH3 ). Members of this gene family are expressed on 30 to 60% of human peripheral B cells. We sought to determine whether the interaction of a B cell SAg with its reactive Igs can elicit immune complex-mediated Downloaded from tissue injury. Using the Arthus reaction in rabbits as an in vivo model of immune complex-mediated tissue inflammation, we demonstrated that untreated rabbits, which were administered SpA intradermally (i.d.), do not develop a cutaneous inflammatory response. However, when rabbits were pretreated i.v. with human IgG (hIgG), i.d. injections of SpA induced an inflammatory response with the classical histologic features of an Arthus reaction. To determine whether this Arthus-like response occurred via a B cell superantigenic mechanism, the rabbits were pretreated with VH3-depleted hIgG and then were administered SpA i.d. We 1 found that the induction of a prominent inflammatory response by SpA was dependent upon the presence of VH3 molecules in http://www.jimmunol.org/ the hIgG pretreatment. These results provide compelling evidence that an interaction of the B cell SAg, SpA, with its reactive 1 (VH3 ) IgGs leads to an immune complex-mediated inflammatory response in vivo. The Journal of Immunology, 1998, 160: 5246–5252. taphylococcal protein A (SpA)4, a cell wall component of ability of this bacterial cell wall protein to activate human B cells Staphylococcus aureus, binds to the Fc fragment of IgG. inaVH-selective manner (6). These properties are reminiscent of S In addition, an alternative site on SpA has been defined those of a T cell superantigen (SAg) and have led SpA to be char- that binds to the Fab region of Igs independently of the heavy acterized as a B cell SAg (9, 10, 14–18). Recently, several other chain isotype (1–6). Studies have mapped the Fab determinants to proteins have also been defined as B cell SAgs, including HIV by guest on October 1, 2021 framework regions 1 and 3 in the variable heavy chain (VH) region gp120, protein Fv (a human liver sialoprotein), protein L (a coat (7–9), with a possible contribution of residues in complementarity- protein of Peptostreptococcus magnus), and staphylococcal determining region 2 (8). The binding of this alternative site on enterotoxin D (19–22). SpA is restricted to human Igs using heavy chains from the VH3 1 Given its ability to react with a large amount of Ig molecules, a gene family (VH3 ) (9, 10). The VH3 gene family is the largest of B cell SAg could inflict tissue damage through a number of in- the seven human VH gene families and is expressed by 30 to 60% flammatory mechanisms. Its interaction with cytophilic IgG, IgE, of human peripheral B cells (11–13). The cross-linking of mem- or IgA molecules could lead to the cross-linking of the respective brane IgM by the alternative binding site on SpA accounts for the Ig FcRs on inflammatory cells, thereby resulting in the release of inflammatory mediators. Indeed, SpA, protein L, and protein Fv *Division of Allergy and Immunology, University of Pennsylvania School of Med- induce histamine release from human basophils by interacting with icine and †Laboratory of Pathology, University of Pennsylvania School of Veterinary the Fab region of IgE molecules that are bound to FceR on these Medicine, Philadelphia, PA 19104 cells (23–25); protein L and protein Fv also degranulate human Received for publication October 10, 1997. Accepted for publication January 29, 1998. mast cells (24, 25). The interaction of a B cell SAg with fluid- phase IgG could lead to immune complex-mediated tissue injury, The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance a possibility that has not been formally investigated. However, with 18 U.S.C. Section 1734 solely to indicate this fact. based on our recent findings (26), it is now known that the immune 1 This work was supported by a Biomedical Sciences Research grant from the Na- complexes that are formed by a B cell SAg with reactive serum Igs tional Arthritis Foundation and by National Institutes of Health Grant AI 22913. cause activation of the classical complement cascade. 2 Current address: Johns Hopkins University, 755 Ross Building, 1721 E. Monument Street, Baltimore, MD 21205. For many years, investigators have exploited the Arthus reaction 3 Address correspondence and reprint requests to Dr. Arnold Levinson, 726 Clinical as a model of in vivo immune complex-mediated tissue injury Research Building, 415 Curie Boulevard, Division of Allergy and Immunology, Uni- (27–30). In the classical model of the Arthus reaction, animals are versity of Pennsylvania School of Medicine, Philadelphia, PA 19104. immunized with an Ag until they have appreciable levels of pre- 4 Abbreviations used in this paper: SpA, staphylococcal protein A; VH, variable heavy cipitating IgG Abs. Intradermal (i.d.) injection of the same Ag chain; SAg, superantigen; HSA, human serum albumin; Mod SpA, staphylococcal protein A hyperiodinated to abrogate its IgG Fc-binding ability; Seph, CNBr-activated elicits a local inflammatory response (28). This response is char- 2 1 Sepharose 4B; hIgG, human IgG; VH3 hIgG, VH3-depleted human IgG; VH3 using 1 1 acterized grossly by erythema, edema, and hemorrhage and mi- heavy chains from the VH3 gene family; VH3 /non-VH3 hIgG, human IgG con- 1 1 croscopically by a prominent polymorphonuclear cell (PMN) in- taining both VH3 and non-VH3 IgGs; i.d., intradermal(ly); PMN, polymorphonu- clear cell. filtrate that peaks at 8 h after cutaneous challenge. Copyright © 1998 by The American Association of Immunologists 0022-1767/98/$02.00 The Journal of Immunology 5247 In the present study, we sought to determine whether a B cell termined again as described above. The effluent fractions were then passed SAg could elicit immune complex-mediated tissue injury. We now over their respective columns a second time, and the dialysis and concen- show that rabbits injected i.d. with the model B cell SAg, SpA, do tration procedures were repeated. not develop a cutaneous Arthus reaction, as previously reported (30). However, when rabbits are pretreated i.v. with human IgG ELISA for determining the binding of IgG fractions to Mod SpA (hIgG) from healthy donors, they do develop a cutaneous reaction or SpA with the histologic features of the Arthus reaction at the sites that Half-area microtiter plate wells (Costar, Cambridge, MA) were coated with were injected i.d. with SpA. This reaction is mediated by the Fab- 100 ml Mod SpA, SpA, or BSA (Calbiochem) at 10 mg/ml in PBS over- binding site on SpA, since it was not induced in animals that were night at 4°C. Each well was subsequently saturated with 100 ml 1% BSA/ pretreated with (hIgG) depleted of V 31 molecules (V 32hIgG). PBSfor2hatroom temperature. The wells were washed three times with H H 0.05% Tween-20 (Sigma) in PBS. We incubated 100 ml aliquots of varying These data provide the first evidence that the interaction of a B cell 1 concentrations of unfractionated hIgG or hIgG fractions from the Mod SAg, SpA, with its reactive (VH3 ) Igs leads to an immune com- SpA-Seph column or the Seph column for2hatroom temperature. The plex-mediated inflammatory reaction in vivo. wells were washed as described above, and peroxidase-conjugated goat 9 F(ab )2 anti-hIgG Fc Ab (Jackson ImmunoResearch Laboratories, West Grove, PA) was added for1hatroom temperature. Following this incu- Materials and Methods bation, the plates were washed as described above, the bound Ab was Animals detected by the addition of o-phenylenediamine substrate (Eastman Kodak, Male and female New Zealand white rabbits (2–4 kg) were obtained from Rochester, NY) in 20 mM citrate buffer (pH 4.0) plus 0.05% hydrogen Ace Animals (Boyertown, PA) and housed in the animal facility at the peroxide, and the OD was read spectrophotometrically at 450 nm.
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