Occupational or environmental exposure to certain pollutants or chemicals can result in the development of toxic manifestations that can lead to various immune dysfunctions. Administration of several therapeutic drugs is also responsible for the occurrence of abnormal immune reactions. The mechanisms by which certain molecules or toxicants trigger a specific loss of tolerance to defined self-antigens in susceptible individuals are unknown. Chemically-induced autoimmunity in H-2S represents a unique experimental model for studying chemically- induced immune syndromes in humans. Mercuric chloride injection in H- 2S mice trigger a complex syndrome with polyclonal lymphocytic activation, hyperglobulinemia, immune complex deposits with proteinuria and production of highly specific autoantibodies to nucleolar antigens. Exploring this model will help us understand the mechanisms behind chemically-induced autoimmunity. The conventional view about chemically-induced autoimmunity is that the induction phase is Th2-mediated, whereas the resolution phase is Th1- dependent. Based upon our own preliminary data, we believe that this is an over-simplification of the problem and our hypothesis is that both the Th1 and Th2 subsets are involved in the induction of this syndrome. This has important therapeutic implications since treatment of human chemically-induced immune dysfunction would then have to be more refined than merely altering the Th1-Th2 balance. We will first test our hypothesis by identifying the cytokines that are expressed (both at the RNA and protein level) in this model. The importance of these cytokines in the manifestation of this syndrome will then be verified by manipulating their levels via anti-cytokine antibodies, antagonistic cytokines, and the use of cytokine knock-out mouse strains. Lastly, to determine the importance of cognate T-B interactions participate in the induction of this syndrome, we will investigate the role of co-stimulatory molecules, such as CD40 and B7-1/B7-2. These last experiments are also relevant to the unifying theme of this application, since interactions among different co-stimulatory molecules can bias an immune response towards the Th2 or Th2 pathway.
| Vas, Jaya; Mattner, Jochen; Richardson, Stewart et al. (2008) Regulatory roles for NKT cell ligands in environmentally induced autoimmunity. J Immunol 181:6779-88 |
| Zheng, Yan; Gallucci, Stefania; Gaughan, John P et al. (2005) A role for B cell-activating factor of the TNF family in chemically induced autoimmunity. J Immunol 175:6163-8 |
| Rowley, Benjamin; Monestier, Marc (2005) Mechanisms of heavy metal-induced autoimmunity. Mol Immunol 42:833-8 |
| Zheng, Yan; Jost, Monika; Gaughan, John P et al. (2005) ICOS-B7 homologous protein interactions are necessary for mercury-induced autoimmunity. J Immunol 174:3117-21 |
| Zheng, Yan; Monestier, Marc (2003) Inhibitory signal override increases susceptibility to mercury-induced autoimmunity. J Immunol 171:1596-601 |
| Bagenstose, L M; Class, R; Salgame, P et al. (2002) B7-1 and B7-2 co-stimulatory molecules are required for mercury-induced autoimmunity. Clin Exp Immunol 127:12-9 |
| Monestier, M; Zouali, M (2002) Receptor revision and systemic lupus. Scand J Immunol 55:425-31 |
| Bagenstose, L M; Mentink-Kane, M M; Brittingham, A et al. (2001) Mercury enhances susceptibility to murine leishmaniasis. Parasite Immunol 23:633-40 |
