NF-X1: Novel Target for Inhibition of MHC Class II Transcription and Autoimmune Disease
Summary The class II MHC molecules function in the presentation of processed peptides to helper T cells during an immune response. Dysregulated expression of class II major histocompatibility complex (MHC) molecules is hypothesized to contribute to the pathogenesis of a severe combined immunodeficiency syndrome and certain autoimmune diseases. Due to the central role these molecules play in the initiation of the immune response and disease, considerable effort is focused on elucidating the mechanisms governing the proper tissue-specific and developmental regulation of the class II MHC's.
Researchers at Harvard University have discovered a novel polypeptide that encodes a potent and biologically relevant repressor of the class II MHC HLA-DRA transcription. Overexpression of NF-X1 from a retroviral construct strongly decreases transcription from the HLA-DRA promoter, and 2) the NFX.1 transcript is markedly induced late after induction with interferon-gamma, coinciding with post-induction attenuation of HLA-DRA transcription. Further studies also revealed that NF-X1 interacts specifically with the conserved X1 box regulatory element found in the proximal promoters of class II MHC genes
Applications Broad Applications For NF-X1 1) Diagnostic Immunoassays: Antibodies directed towards NF-X1 in histological sections of tissues such as skin, muscle, heart, lung, pancreas, kidney, tonsil, liver, bone, intestine, brain, spleen and bladder for diagnostic purposes in a diseased individual. In addition to immunohistochemistry, solution assay methods including calorimetric, chemiluminescent or fluorescent immunoassays may be sued in addition to Western blot and other techniques to detect and quantitate proteins cross-reactive with NF-X1 in a patient.
2) Screen Genomic DNA Samples from Individuals Suspected to be Genetically Predisposed to Develop Diseases. Mutations or particular alleles of the NFX.1 gene may be detected by assays based upon nucleic acid hybridization or polymerase chain reaction. Assays based on the sequences provided by this invention can be used in epidemiologic studies to establish whether certain alleles or mutations in the NFX.1 gene are associated with the development of particular autoimmune or immune-initiated disorders.
3) Therapy using NF-X1: Useful in Prolonging Graft Survival: Due to the central and early role of class II MHC molecules in the immune response, a biological reagent which can repress the expression of these genes is valuable as the basis for novel approaches toward the treatment of immunologic diseases as well as in the promotion of graft survival. A natural protein which, when overexpressed, can repress expression of these molecules may therefore form the basis of novel therapeutics that contribute to the prevention or management of this class of diseases.
Publications: Song Z et al. A novel cysteine-rich sequence-specific DNA-binding protein interacts with the conserved X-box motif of the human major histocompatibility complex class II genes via a repeated Cys-His domain and functions as a transcriptional repressor. J Exp Med. 1994 Nov 1; 180(5):1763-74.
U.S Patent 5,840, 832
Strominger, Jack L.
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