Interrelationships of peroxidation and immunogenicity of cardiolipin: an oxidative lipidomics approach.
Frostegård-J; Tyurin-V; Tyurina-Y; Amoscato-A; Su-J; Balasubramanian-K; Maeda-A; Fadeel-B; Greenberger-J; Mallampali-R; Pitt-B; Kagan-V
Toxicologist 2012 Mar; 126(Suppl 1):165
The myriad of neoepitopes formed during lipid peroxidation trigger potent innate and adaptive immune responses. Experimental and clinical studies have been mostly focused on immunogenic properties of oxidized species of phosphatidylcholine (PCox) and phosphatidylserine (PSox). Lately, a mitochondria-specific anionic phospholipid, cardiolipin (CL), particularly its peroxidized molecular species (CLox) attracted attention as innate and adaptive immunogens and predictors of clinical outcomes and novel therapeutic modalities for vaccination. Specific interrelationships between the emergence of individual molecular species of CLs/CLox in circulation and the appearance of the respective antibodies remain unknown. This is due to the lack of specific/sensitive analytical tools to characterize a huge diversity of individual CL and CLox. Using mass spectrometry based oxidative lipidomics, we focused on the analysis of molecular species of CLs and CLox in plasma of mice exposed to total body irradiation (9.5 Gy) or bacterial infection (Pseudomonas aeruginosa, PA103) as well as in plasma from ARDS patients. In the latter cases, we were able to detect the presence of both host and bacterial CLs in LC/MS spectra of plasma lipids. While relatively low molecular mass species (m/z 1376 and 1418) are typical of bacterial CLs, larger CL molecules (with m/z from 1448) dominate in MS of mammalian plasma CLs. Simultaneously, antiCL/CLox antibodies were detected in plasma. We also found that CL-containing liposomes and CL-coated mitochondria were recognized and taken-up by RAW264.7 macrophages. The data are discussed in the context of possible roles that CLs/CLox play as PAMPs/DAMPs regulating adaptive and innate immune responses.
Lipid-peroxidation; Immune-reaction; Immunotoxins; Genetic-factors; Phospholipids; Oxidative-phosphorylation; Molecular-biology; Molecular-structure; Oxidative-processes; Irradiation; Laboratory-animals; Laboratory-testing; Bacterial-infections; Antibody-response; Lipids
The Toxicologist. Society of Toxicology 51st Annual Meeting and ToxExpo, March 11-15, 2012, San Francisco, California
University of Pittsburgh at Pittsburgh