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* Department of immunology, Center for Immunotherapy of Cancer and Infectious Diseases, University of Connecticut School of Medicine, Farmington, CT 06030-1601;
Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06519;
Max-Planck Institut fur Immunobiologie, Freiburg, Germany; and
Division of Laboratory Medicine Geisinger Medical Center, Danville, PA 17822
TLR4 is the receptor for the Gram-negative bacterial cell wall component LPS. TLR4 signaling is controlled by both positive and negative regulators to balance optimal immune response and potential sepsis. Unchecked TLR4 activation might result in autoimmune diseases, a hypothesis that has not been formally resolved. In this study, we found that TLR4 signaling to LPS can be positively enforced by expressing gp96 on cell surfaces through the chaperone function of, but not the direct signaling by, gp96; TLR4 as well as the commensal flora are essential for the production of anti-dsDNA Ab and the immune complex-mediated glomerulonephritis in transgenic mice that express surface gp96. Moreover, a similar constellation of autoimmunity was evident in mice that encode multiple copies of tlr4 gene. Our study has revealed that increased TLR4 signaling alone without exogenous insult can break immunological tolerance. It provides a strong experimental evidence for TLR4 dysregulation as an etiology of lupus-like renal disease.
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 with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by National Institutes of Health Grants CA90337 and CA100191 (to Z.L.) and SP "Angeborene Immunität" (FR 448/4-3; to M.A.F.). Z.L. is a clinical scholar of the Leukemia and Lymphoma Society. R.M. is an investigator of the Howard Hughes Medical Institute.
2 Address correspondence and reprint requests to Dr. Zihai Li, Center for Immunotherapy of Cancer and Infectious Diseases, Department of Immunology, University of Connecticut School of Medicine, MC1601, 263 Farmington Avenue, Farmington, CA 06030-1601. E-mail address: zli{at}up.uchc.edu
3 Abbreviations used in this paper: TIRAP, Toll-IL-1R domain-containing adapter protein; ER, endoplasmic reticulum; HSP, heat shock protein; DC, dendritic cell; Tg, transgenic; 96tm-Tg, 96tm-expressing Tg; BMDM, bone marrow-derived macrophage; WT, wild type; ANA, anti-nuclear Ab; IC, immune complex; Ad-LacZ, β-galactosidase; GN, glomerulonephritis; EM, electron microscopy.
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