Eur. J. Immunol. 1994.24: 1161-1166 Experimental zyxwvu Staphylococcus aureus arthritis in mice 1161 zy Arturo AbdelnourO, Tomas Bremelloo, Rikard Holmdahl. and Andrzej Tark0wski.O Departments of Rheumatology. and Clinical Immunologyo, University of Goteborg, Goteborg and Department of Medical Inflammation Research, University of Lund, Lunol Clonal expansion of T lymphocytes causes arthritis and mortality in mice infected with toxic shock syndrome toxin-1-producing staphylococci* Erosive arthritis is a common and feared complication of staphylococcal infection. The reason(s) for the progressive course of the arthritis is unknown. It has been recently established that enterotoxins produced by zyx Staphylococcus aureus display superantigen properties leading to stimulation of T cells carrying distinct T cell receptor Vg elements. This finding provides a potential connection between staphylococcal exoproteins and endogenous immune mechanisms participating in the infectious process. We have recently described successful induction of infectious arthritis in mice after intravenous inoculation of a toxic shock syndrome toxin-1 (TSST-1)-producing S. aureus LS-1 strain. Using this model we have now found a clonal expansion of T cells expressing Vp11+ Tcell receptor in the synovial tissue of arthritic mice. The role of TSST-1 as a superantigen inducing oligoclonal expansion was confirmed in an in vim culture system.The expansion of VPll+ T cells proved to be of arthritogenic significance since mice genomically deleted of theVBll+ Tcells did not develop arthritis and since pretreatment of healthy mice with anti-CD4 or anti-Vpll monoclonal antibodies inhibited arthritis. In addition, CD4+ and Vp11+ T cells showed themselves to be of pathogenic significance in staphylococcal-induced mortality, since mice depleted of such populations showed increased survival. We propose that in hematogenously spread S. aureus-induced arthritis the TSST-1-dependent clonal expansion of CD4+ Vp11+ T cells is a driving pathogenic force. 1 Introduction Bacterial arthritis is a serious infectious disease with significant morbidity and mortality [l]. In spite of this, little progress has been made in the last two decades in under- standing the pathogenesis of the disease [2]. This could be due to the difficulty in performing studies in humans, since the exact time of onset of infection is uncertain and tissue samples from synovial membrane and cartilage are not readily available for analysis. Studies with animal models of bacterial arthritis overcome the limitations encountered in humans [3]. We have recently described a murine model of bacterial arthritis in which a single intravenous injection of toxic zyxwv [I 125961 zyxwvu * Supported by grants from the Goteborg Medical Society, the Swedish Medical Society, the Swedish Association against Rheumatism, the King Gustafs 80 Years Foundation, the Nanna Svartz Foundation, the Swedish Board of Technical Develop- ment, the Swedish Medical Research Council, and the Swedish Agency for Research Cooperation with Developing Countries (SAREC) . Correspondence: Arturo Abdelnour, Department of Clinical Immunology, Guldhedsgatan 10, S-41346 Goteborg, Sweden (Fax: 46-31-82 67 91) Abbreviations: TSST-1: Toxic shock syndrome toxin-1 SEB: Staphylococcal enterotoxin B Key words: Septic arthritis zyxwvutsrqp I Staphylococcus aureus I Toxic schock syndrome toxin-1 I Superantigen I T cell receptor shock syndrome toxin-1 (TSST-1)-producing zy S. aureus strain LS-1 induces erosive polyarthritis [4, 5].This arthritis is of infectious origin since live bacteria are readily recovered from the affected joints 141. One of the charac- teristics of this model is the presence of activated T cells in the inflamed synovium (Abdelnour et al, submitted l).The staphylococcal component responsible for the activation of such cells, however, is presently unknown. It has been recently established that exoproteins produced by S. aureus display superantigen properties leading to stimulation of T cells carrying distinct T cell receptor variable p (TcR Vp) elements [6]. This finding provides a potential connection between staphylococcal exoproteins and endogenous immune mechanisms participating in the infectious pro- cess. A superantigen-induced oligoclonal expansion of Tcells has been proposed to be of critical importance for the development of rheumatoid arthritis [7]. However, direct experimental proof of such a mechanism is lacking. In the present study, we have characterized the TcR Vp usage of the infiltrating synovial Tcells in mice with staphylococcal arthritis as well as their pathogenic role in the disease process. 2 Materials and methods 2.1 Mice Male Swiss mice, 4 to 6 weeks old, originally obtained from ALAB (Stockholm, Sweden),were bred and maintained in the animal facility of the Department of Clinical Immuno- logy, University of Goteborg, Sweden. They were housed ten to a cage under standard conditions of temperature and light and fed standard laboratory chow and water ad libitum. 0 VCH Verlagsgesellschaft mbH, D-69451 Weinheim, 1994 0014-2980/94/050j - 1 161 $10.00 + .25/0