Nitration immunology

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Nitration of tyrosine residues on proteins in the respiratory tract has been shown to occur during inflammatory lung diseases including asthma, chronic obstructive pulmonary disease, cystic fibrosis, and bronchiolitis obliterans. Formation of nitrotyrosine occurs inorganically, but also is catalyzed by enzymes of polymorphonuclear leukocytes including eosinophil peroxidase and neutrophil myeloperoxidase. Nitrotyrosine bears pronounced structural and chemical similarity to many well-described haptens--low molecular weight compounds that when covalently bound to proteins incite immune responses. We hypothesize that nitrotyrosine--formed during nitration of proteins early during innate immune processes--functions as a hapten and is a key factor initiating acquired immune responses against the protein in which it is bound. We plan initially to evaluate this hypothesis with respect to nitration of inhaled allergens. We will determine optimum chemical conditions for nitration of natural and recombinant dust mite proteins, and compare these conditions to those found in the airways during inflammation such as occurs with the common cold. Expanding upon supportive preliminary data, we will concurrently investigate the potential of nitrated allergen to augment immune responses by evaluating in vitro the proliferative responses of human peripheral blood mononuclear cells upon exposure to nitrated allergen in comparison to non-nitrated allergen. Further, we will seek immune responses to nitrated allergen in humans by assaying for specific antibody to nitrated proteins with skin testing and serum assays. We anticipate that, consistent with preliminary data, nitration of proteins will initiate and augment immune responses. The pro-inflammatory signals should then be eliminated as nitrated proteins are removed from the tissue. This novel project may serve to elucidate an important link between innate and acquired immunity--identifying a highly novel mechanism for both inciting and regulating immune responses.