Jerome A. Langer Associate Professor UMDNJ Department of Molecular Genetics and Microbiology UMDNJ Research Tower. Rm 729 Piscataway. NJ 08854 (732) 235-5224 FAX - 5223 langer@umdnj.edu

Structure and function of interferons and interferon receptors; development of Type I IFN antagonists; role of IFNs in autoimmune diseases such as lupus

We 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 Publications

Scaglione BJ, Salerno E, Gala K, Pan M, Langer JA, Mostowski HS, Bauer S, Marti G, Li Y, Tsiagbe VK, Raveche ES. (2008) Regulatory T cells as central regulators of both autoimmunity and B cell malignancy in New Zealand Black mice. J Autoimmun. 32(1):14-23.

Pan M, Kalie E, Scaglione BJ, Raveche ES, Schreiber G, Langer JA. (2008) Mutation of the IFNAR-1 receptor binding site of human IFN-alpha2 generates type I IFN competitive antagonists. Biochemistry. 47(46):12018-27.

Langer JA. (2007) Interferon at 50: new molecules, new potential, new (and old) questions.
Sci STKE. 2007(405):pe53.

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.