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Structure and function of interferons and interferon receptors; development of Type I IFN antagonists; role of IFNs in autoimmune diseases such as lupusWe are currently interested in 2 related areas: (1) understanding the differential action of the 17 human Type I interferons (IFNs); (2) the role of IFNs in systemic lupus erythematosus ("lupus") and autoimmunity, including the development of IFN analogues that act as competitive antagonists to endogenous IFNs. The 13 IFN-alphas, and IFN-beta, IFN-omega, IFN-kappa and IFN-epsilon produce differential activation of cells and, in some cases, different physiological and clinical efficacies. However, they all act through a common heterodimeric cell-surface receptor, IFNAR. Recent evidence suggests that, to a first approximation, some of the differential effects come from different interactions of the IFNs with the low-affinity receptor subunit IFNAR-1. Dr. Langer's group previously identified regions of IFNAR-1 that are involved in binding IFNs. More recently, his group has used mutagenesis to help identify critical regions of Type I IFNs that interact with IFNAR-1. Continued mutagenesis and structure/function studies will help us understand the degree to which these interactions modulate IFN responses. Our work on understanding the IFN/IFNAR-1 interaction is critical to our efforts to develop novel competitive antagonists for Type I IFNs. There is good evidence that the aberrant production of Type I interferons in people with lupus helps drive the progression of this disease. Type I IFNs may also be involved in the pathogenesis of several other autoimmune diseases, and in other clinical situations. Dr. Langer’s group is trying to genetically engineer and produce Type I interferon variants that can block the receptor binding and activity of endogenous Type I interferons, i.e., they will act as competitive antagonists. Antagonists are being designed and tested both for use in humans and for animal models. Selected PublicationsLanger JA. (2007) Interferon at 50: new molecules, new potential, new (and old) questions. Kotenko SV. Langer JA. (2004) Full house: 12 receptors for 27 cytokines. Int Immunopharmacol. 4(5):593-608. Langer JA. Cutrone EC. Kotenko S. (2004) The Class II cytokine receptor (CRF2) family: overview and patterns of receptor-ligand interactions. Cytokine Growth Factor Rev. 15(1):33-48. Kotenko. S.V.. Gallagher. G.. Baurin. V.V.. Lewis-Antes. A.. Shen. M.. Shah. N.K.. Langer. J.A.. Sheikh. F.. Dickensheets. H. and Donnelly. R.P. (2003). IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nature Immunol. 4(1):69-77. Cutrone. E.C. and Langer. J.A. (2001) Identification of critical residues in bovine IFNAR-1 responsible for interferon binding. J. Biol. Chem. 276:17140-48. Goldman. L.A.. Cutrone. E.C.. Dang. A.. Hao. X.. Lim. J.-k.. and Langer. J.A. (1998) Mapping human interferon-alpha (IFN-α2) binding determinants of the Type I interferon receptor subunit IFNAR-1 with human/bovine IFNAR-1 chimeras. Biochemistry 37:13003-13010. Cutrone. E.C. and Langer. J.A. (1997) Differential binding of Type I interferons by human interferon receptors. FEBS Lett. 404:197-202. |
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