With a known antigen and an accessible target organ, chronic beryllium disease (CBD) serves as an important organ-specific, immune-mediated disease. CBD results from beryllium exposure and is associated with the accumulation of beryllium-specific, Thi-type cytokine-secreting CD4* T cells in the lung. Previous studies have helped identify the genetic and functional importance of the T cell antigen receptor (TCR) and HLA-DP2 in CBD immunopathogenesis. Despite the advances in our understanding of the immunopathogenesis of beryllium-induced disease, how beryllium binds to the major histocompatibility complex class 11 (MHCII) molecule and is subsequently recognized by beryllium-specific 004* T cells remains unknown. Recently, the crystallization of HLA-DP2 by our group has revealed a potential beryllium binding site to glutamic acid residues at amino acid positions in the p-chain and the peptide backbone. Data suggest that beryllium directly binds to HLA-DP2 and that particular peptides are required to complete the apTCR ligand. The central goal of this revision of Project 1 is to characterize the beryllium antigen responsible for CD4* T cell activation. A series of experiments has been designed to identify the HLA-DP2 peptide epitopes required to complete the apTCR ligand and activate beryllium-specific CD4* T cells. Using established methods and cell model systems, specific experiments will: 1) Define the sequence and motif of peptides that bind to HLA-DP2 and determine the binding affinities of those peptides, 2) Delineate which of the identified HLA-DP2 binding peptides in the presence of beryllium salt allow recognition of beryllium by antigen-specific TCRs, 3) Identify and characterize the TCRs expressed by the subset of T cells found in the bronchoalveolar lavage (BAL) of patients with CBD that respond to the different peptide sets identified, and 4) Determine whether HLA-DP2/peptide/beryllium complexes can be used to identify and characterize beryllium-reactive CD4+T cells in the blood and BAL of CBD patients, as a potential biomarker of disease and disease progression. This translational study is multidisciplinary, assembling immunologists, biochemists, HLA structural biologists, and physician-scientists to define the precise nature of the MHCII/Beryllium/Peptide/TCR relationship in CBD. Project 1 integrates with Project 2 by providing functional basis for genetic epidemiologic discoveries, and with Project 3 by testing immune biomarker outcome measures in parallel. The results will improve the understanding of metal antigen structure/function and result in data to support the use of peptide tetramers as clinical biomarkers.
This project will explain how a metal can interact with proteins to trigger an abnormal immune response in humans;identify how human T lymphocytes recognize an antigen composed of metal plus native peptides; pioneer the use of peptide multimers as clinical biomarkers that can trace the pathogenic T lymphocytes that produce granulomatous disease in a human, immune-mediated, environmentally-induced disorder.
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