Details

THE ROLE OF THE MACROPHAGE IN ASBESTOS INDUCED AUTOANTIBODY PRODUCTION

by Blake, David J.

Abstract (Summary)
Environmental exposure to silicate compounds such as silica and asbestos has been associated with increased autoimmune responses and the development of autoimmune disease in humans. Residents of Libby, MT have experienced significant asbestos exposure due to an asbestos contaminated vermiculite mine near the community over several decades. Residents have developed numerous asbestos-related diseases as well as increased autoimmune responses. However, the exact mechanism by which Libby amphibole asbestos generates autoimmune responses is unclear. To elucidate a possible mechanism for asbestos induced autoimmunity, the cellular effects of Libby amphibole asbestos were characterized in vitro using a phagocytic murine macrophage cell line, which are characteristic of alveolar macrophages. Our results indicate that Libby amphibole asbestos generates oxidative stress in murine macrophages similar to crocidolite asbestos. However, Libby asbestos induces distinct cellular effects compared to crocidolite asbestos. Therefore, the cellular effects of amphibole asbestos may be a combined consequence of its chemical composition as well as the activation of distinct cellular pathways during exposure. Libby amphibole asbestos also induces apoptosis in murine macrophages resulting in the translocation of SSA/Ro52 to cell surface blebs of apoptotic cells. These apoptotic cell surface blebs are recognized by autoantibodies from mice exposed to amphibole asbestos, suggesting that these cell surface structures may be antigenic when presented in a pro-inflammatory context. These results suggest that the induction of apoptosis may play a key role in environmentally induced autoimmunity. Interestingly, autoantibodies found in the sera of the Libby cohort also recognize the SSA/Ro52 autoantigen, indicating that humans and mice exposed to amphibole asbestos generate similar AA profiles and that the alterations of the immune response by amphibole asbestos may be comparable. We hypothesize that asbestos-induced autoimmunity is generated through a two hit mechanism. First, autoantigens become visible to the immune system during apoptosis, which results in the accumulation of autoantigens on the cell surface. The subsequent uptake and processing of apoptotic cells by antigen-presenting cells in a pro-inflammatory context will activate self-reactive T cells, inducing the loss of tolerance and generate the autoimmune responses.
Bibliographical Information:

Advisor:Michael F. Minnick; Jean C. Pfau; Jesse Hay; Scott Wetzel; Jean-Marc Lanchy

School:The University of Montana

School Location:USA - Montana

Source Type:Master's Thesis

Keywords:division of biological sciences

ISBN:

Date of Publication:02/06/2008

© 2009 OpenThesis.org. All Rights Reserved.