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Lipopolysaccharide Injection Induces Relapses of Experimental Autoimmune Encephalomyelitis in Nontransgenic Mice via Bystander Activation of Autoreactive CD4⁺ Cells¹

Axel Nogai^2,*, Volker Siffrin^2,*, Kerstin Bonhagen^2,*,, Caspar F. Pfueller^*, Thordis Hohnstein^*, Rudolf Volkmer-Engert, Wolfgang Brück, Christine Stadelmann and Thomas Kamradt^3,*,

^* Deutsches Rheumaforschungszentrum Berlin, Berlin, Germany; Institut für Immunologie, Klinikum der Friedrich-Schiller-Universität Jena, Jena, Germany; Institut für Medizinische Immunologie, Universitätsklinikum Charité, Berlin, Germany; and Institut für Neuropathologie, Universität Göttingen, Göttingen, Germany

Infections sometimes associate with exacerbations of autoimmune diseases through pathways that are poorly understood. Ag-specific mechanisms such as cross-reactivity between a microbial Ag and a self-Ag have received no direct support. In this study, we show that injection of LPS induces experimental autoimmune encephalomyelitis in TCR-transgenic mice and relapse of encephalomyelitis in normal mice. This form of treatment induces proliferation and cytokine production in a fraction of effector/memory Th lymphocytes in vitro via physical contact of Th cells with CD4^– LPS-responsive cells. TCR-mediated signals are not necessary; rather what is required is ligation of costimulatory receptors on Th cells by costimulatory molecules on the CD4^– cells. This form of bystander activation provides an Ag-independent link between infection and autoimmunity that might fit the clinical and epidemiological data on the connection between infection and autoimmunity better than the Ag-specific models.