Chronic beryllium disease (CBD) is a granulomatous lung disorder caused by be exposure in the workplace and is characterized by the accumulation of Be-specific, Th1-type cytokine-secreting CD4+ T cells in the lung. Genetic susceptibility is strongly linked to HLA-DP alleles that contain a glutamic acid at the 69th position of the ?-chain (?Glu69), and the majority of CD4+ T cells recognize is in an HLA-DP-restricted manner. We have developed an HLA-DP2 transgenic (Tg) mouse model of CBD that replicates many of the findings seen in the human disease. Be oxide (BeO)-exposed HLA-DP2 Tg mice develop mononuclear infiltrates in a peribronchovascular distribution that are predominantly composed of effector and regulatory CD4+ T cells. Be-responsive, HLA-DP2- restricted CD4+ T cells are present in BeO-exposed HLA-DP2 Tg mice but not in wild-type mice. Depletion of Treg cells in BeO-exposed HLA-DP2 Tg mice exacerbates lung inflammation and enhances granuloma formation, suggesting that Treg cells inhibit Be-specific effector CD4 T cells and granulomatous inflammation. In addition, + we have recently identified Be-dependent mimotopes and self-peptides, including those derived from plexin A proteins, that stimulate Be-specific CD4+ T cells derived from the lungs of CBD patients. Using Be-loaded HLA- DP2-plexin A4 tetramers, CD4+ T cells specific for this ??TCR ligand have been identified in the bronchoalveolar lavage (BAL) fluid of all HLA-DP2-expressing CBD patients and the majority of BeO-exposed HLA-DP2 Tg mice. Furthermore, a subset of HLA-DP2-plexin A4/Be tetramer-staining CD4+ T cells in the lung of CBD patients and BeO-exposed mice express FoxP3, indicating the induction of epitope-specific Treg cells. The factors driving the recruitment and/or expansion of antigen-specific effector T cells and Treg cells in the lungs of BeO-exposed HLA- DP2 Tg mice, the interplay between these T cell subsets and how they modulate granuloma development form the basis of the current proposal. Thus, we hypothesize that Be exposure induces a dynamic interplay between Be-specific effector CD4 T cells and Treg cells and that the expansion of these distinct antigen-specific T cell subsets modulates the immune response to Be. Using retrogenic TCR HLA-DP2 Tg mice, the first specific aim will determine the pathogenicity of Be-specific CD4+ T cells in the generation of Be-induced granulomatous inflammation while the second aim will assess the role of Treg cells in the generation of a Be-specific granulomatous immune response. In the third specific aim, we will translate our findings from HLA-DP2 Tg mice to human subjects with CBD. Unlike any other human lung disease, the novelty of our proposal stems from our ability to study the development of an adaptive immune response in the lungs of mice and humans in an antigen- specific manner and analyze the interaction between effector and Treg cells specific for the same antigenic complex. Together, these studies will strengthen our understanding of immunopathogenesis of CBD and potentially lead to therapeutic alternatives to immunosuppressive agents.

Public Health Relevance

This translational study will utilize blood and lung specimens from mice and human subjects exposed to beryllium to further our understanding of the beryllium-induced immune response that leads to granuloma formation and inflammation. We will utilize our murine model of chronic beryllium disease to investigate the interplay between beryllium-specific T cell subsets and translate our murine findings to human subjects with this granulomatous occupational lung disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES025534-02
Application #
9198986
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nadadur, Srikanth
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2017-01-01
Budget End
2017-12-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Fontenot, Andrew P; Falta, Michael T; Kappler, John W et al. (2016) Beryllium-Induced Hypersensitivity: Genetic Susceptibility and Neoantigen Generation. J Immunol 196:22-7