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.
|Clayton, Gina M; Wang, Yang; Crawford, Frances et al. (2014) Structural basis of chronic beryllium disease: linking allergic hypersensitivity and autoimmunity. Cell 158:132-42|
|Mack, Douglas G; Falta, Michael T; McKee, Amy S et al. (2014) Regulatory T cells modulate granulomatous inflammation in an HLA-DP2 transgenic murine model of beryllium-induced disease. Proc Natl Acad Sci U S A 111:8553-8|
|Bowerman, Natalie A; Falta, Michael T; Mack, Douglas G et al. (2014) Identification of multiple public TCR repertoires in chronic beryllium disease. J Immunol 192:4571-80|
|Dai, Shaodong; Falta, Michael T; Bowerman, Natalie A et al. (2013) T cell recognition of beryllium. Curr Opin Immunol 25:775-80|
|Falta, Michael T; Pinilla, Clemencia; Mack, Douglas G et al. (2013) Identification of beryllium-dependent peptides recognized by CD4+ T cells in chronic beryllium disease. J Exp Med 210:1403-18|
|Chain, Jennifer L; Martin, Allison K; Mack, Douglas G et al. (2013) Impaired function of CTLA-4 in the lungs of patients with chronic beryllium disease contributes to persistent inflammation. J Immunol 191:1648-56|
|Newman, Kira L; Newman, Lee S (2012) Occupational causes of sarcoidosis. Curr Opin Allergy Clin Immunol 12:145-50|
|Van Dyke, Michael V; Martyny, John W; Mroz, Margaret M et al. (2011) Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry. Occup Environ Med 68:842-8|
|Martin, Allison K; Mack, Douglas G; Falta, Michael T et al. (2011) Beryllium-specific CD4+ T cells in blood as a biomarker of disease progression. J Allergy Clin Immunol 128:1100-6.e1-5|
|Sawyer, Richard T; Maier, Lisa A (2011) Chronic beryllium disease: an updated model interaction between innate and acquired immunity. Biometals 24:1-17|
Showing the most recent 10 out of 54 publications