This proposal will investigate the role of heavy metals in autoimmunity. Autoimmune diseases are the third most common category of disease in the United States after cancer and heart disease. They occur when the immune system erroneously attacks the cells in the body that are normally recognized as ?self?. Although there is a genetic component to autoimmune disease, the rapid increase in these diseases in recent years suggests that environmental factors are also important in their development. While, despite much research, these factors remain elusive. There is some evidence that exposure to heavy metals may play a role in the induction or exacerbation of several autoimmune diseases. For example, in some animal models, mercury, silver, gold and cadmium (Cd2+) induce autoimmunity. Loss of T cell tolerance to key self-antigens is critical in many autoimmune diseases, since the T cells can act both as direct effectors of autoimmune damage and as well as helpers in B cell auto-antibody production. The exact mechanisms linking metals to autoimmunity are not as yet well understood. It is likely that the toxic effects of these metals contribute to some extent. However, T cell mediated allergies to these metals are common. Given that major histocompatibility complex (MHC) class II genes are often linked to the development of autoimmunity, an attractive hypothesis is that these metals may interact with MHC/self-peptide complexes to enhance the activation of self-reactive T cells. ?? T cells bearing antigen receptors (TCRs) usually recognize antigen in the form of peptides bound to MHC (pMHC). However, metals, for example nickel, and other small molecules can be unconventional components of TCR ligands and, in this form, can cause some of the most common allergic diseases. Recently we identified a novel calcium (Ca2+) coordination site on mouse MHCII, IAb, bound to an immunogenic peptide variant (3K) of a dominant self-peptide derived from the MHCII E? protein (E?). Binding of Ca2+ to IAb-3K modulated the binding affinity of one of the IAb-3K reactive TCRs, 2W20 for its ligand. Additionally, we discovered that Cd2+ can replace the Ca2+ ion and significantly enhance the binding affinity between the TCR and pMHCII, dramatically prolonging the binding half-life. We also demonstrated that Cd2+ can directly increase the activation and proliferation of 2W20 cells. A crystal structure confirmed that Cd2+ is ligated to acidic residues in the Ca2+ binding site composed of amino acids from both IAb and pE?. Our data suggest a model in which Cd2+ binding converts a self MHC/self-peptide combination against which the host T cells are normally tolerant into a neoantigen. Such a model is similar to that we recently proposed for allergies to beryllium. The heavy metal distorts the MHC/self-peptide combination, thus stimulates T cell responses to this now foreign antigen. We hypothesize that the metal ion continues to be there throughout the course of the disease therefore the disease is actually always driven by T cells responding to this self-MHC /self-peptide/heavy metal combination. The metal specific T cells could still help truly autoreactive B cells secrete autoantibodies. This proposal will investigate the possible molecular mechanism responsible for Cd2+ induced T cell activation and proliferation as a neoantigen. Our results could provide a plausible explanation of the role of heavy metals in autoimmune disease. We will elucidate the mechanism of presentation of IAb-3K/ Cd2+ to T cells, and test the impact of Cd2+ in IAb/single peptide mice. Our results could provide a plausible explanation of the role of heavy metals in autoimmune disease.

Public Health Relevance

Autoimmune diseases are the third most common category of disease in the United States after cancer and heart disease. However, the mechanisms leading to autoimmune diseases remain largely unknown. Environmental exposure to heavy metals may play an important role in the development of several autoimmune diseases. Our recent findings showed that heavy metal atoms can bind the T cell interacting amino acids of MHC and peptides directly, and activate these T cells. We propose to delineate the possible mechanism that heavy metals use to interact with MHC/self-peptide complexes to enhance the initiation of autoimmunity. The results will further our understanding of the mechanisms of metal induced autoimmune diseases and will provide the molecular basis upon which we may be able to design therapeutic compounds to prevent or treat these diseases.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Exploratory/Developmental Grants (R21)
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Systemic Injury by Environmental Exposure (SIEE)
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Humble, Michael C
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University of Colorado Denver
Schools of Medicine
United States
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Zhang, Yan; Wang, Yang; Anderson, Kirsten et al. (2017) Using DR52c/Ni2+ mimotope tetramers to detect Ni2+ reactive CD4+ T cells in patients with joint replacement failure. Toxicol Appl Pharmacol 331:69-75