Soluble Proteins Modified with Acetaldehyde and Malondialdehyde Are Immunogenic in the Absence of Adjuvant

Abstract

Recent studies have shown that the alcohol metabolites malondialdehyde and acetaldehyde can combine to form a stable adduct (MAA) on proteins. This adduct has been detected in the livers of rats chronically consuming ethanol, and serum antibodies to MAA have been observed at significantly higher concentrations in ethanol-fed when compared with pair-fed or chow-fed control rats. More recently, preliminary studies have strongly suggested that the MAA adduct is capable of stimulating antibody responses to soluble proteins in the absence of adjuvants. The antibodies produced recognize either the MAA epitope or the carrier protein itself. Therefore, it was the purpose of this study to examine the potential immunogenicity of MAA-modified exogenous proteins in the absence of adjuvants. Balb/c mice were immunized in the presence or absence of adjuvant with different concentrations of unmodified or MAA-modified proteins. The antibody response to both the MAA epitope and unmodified protein epitopes were determined by ELISA. In the absence of adjuvant, significant antibody responses were induced to both the MAA epitope and nonmodified protein epitopes. Smaller immunizing doses of MAA-protein conjugate favored the production of antibodies to nonmodified proteins, whereas larger doses induced a strong anti-MAA response. In studies to begin determining a mechanism for the specificity of the response in the absence of adjuvants, peritoneal macrophages were found to bind and degrade MAA-adducted proteins through the use of a scavenger receptor. This indicated that MAA-adducted proteins may be specifically taken up and epitopes presented to the humoral immune system in the absence of adjuvants. Importantly, these are the first data showing that an alcohol-related metabolite can induce an antibody response in the absence of adjuvant and suggesting a mechanism by which antibody to the MAA adduct or its carrier (exogenous or endogenous) proteins may be generated in vivo.

Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease

“…17 As shown in Fig. 2, anti-MAA IgG titers were significantly increased in patients with alcohol-induced liver damage compared with healthy controls (mean optical density [OD], 0.418 Ϯ 0.22 vs. 0.092 Ϯ 0.04; P Ͻ .001).…”

“…16 The cyclic MAA adducts have strong immunogenic properties, and treatment with MAA-modified proteins leads to the production of antibodies that specifically recognize this epitope. 15,17 Recently, Xu et al 18 have reported the presence of circulating antibodies against the cyclic adduct MAA in rats chronically exposed to alcohol.…”

“…17,18 Because autoimmune reactions have been observed in connection with alcohol-induced liver injury, [33][34][35][36][37] the possibility that the presence of MAA antigens might favor the breaking of immune tolerance cannot be disregarded.…”

“…15 MAAprotein conjugates have strong immunogenic properties and induce the production of antibodies against both the MAA epitopes and the carrier protein. 17 MAA adducts have been detected in livers of ethanol-fed rats, 16 and their presence is associated with the development of circulating anti-MAA antibodies in alcohol-treated rats. 18 Because alcohol abuse stimulates lipid peroxidation in the liver along with acetalde-hyde production, [19][20][21][22] we have investigated the possibility that MAA antigens might also be formed in humans and contribute to the development of immunologic reactions associated with the development of ALD.…”

Delayed neuropathology after carbon monoxide poisoning is immune-mediated

“…Aldehydic lipid peroxidation products, such as malonylaldehyde (MDA), react with cell proteins and may alter protein ionic charge and͞or tertiary structure, and͞or render proteins immunogenic (15,16). Inflammatory responses play an important role in the pathogenesis of many brain disorders, including excitotoxicity (17,18).…”