Adduction of Soluble Proteins with Malondialdehyde‐Acetaldehyde (MAA) Induces Antibody Production and Enhances T‐Cell Proliferation

Willis, Monte S.; Klassen, Lynell Warren; Tuma, Dean J.; Sorrell, Michael F.; Thiele, Geoffrey M.

doi:10.1111/j.1530-0277.2002.tb02436.x

Cited by 56 publications

(32 citation statements)

References 57 publications

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“…Accordingly, in many experimental models, the detection and analysis of intrinsic immuneenhancing signals has been masked or blurred by the formulation of aldehyde-Ag adducts in strong exogenous adjuvants and the frequent use of reducing conditions to increase reaction efficiencies (19,41,44). Increased immunogenicity of MDA adducts has been reported in a few publications using nonreduced and nonadjuvanted samples, but the immunomodulatory structures were not elucidated, and the role of RC was not investigated (20,39,40,45). By contrast, our data underscore the intrinsic RC-driven immune-enhancing properties of HNE and MDA protein adducts by 1) excluding extrinsic adjuvants; 2) monitoring adaptive responses against the native B cell and T cell epitopes; 3) demonstrating that the major non-RC adducts present in the reduced preparations are nonimmunogenic.…”

Section: Discussionmentioning

confidence: 99%

Reactive Carbonyls Are a Major Th2-Inducing Damage-Associated Molecular Pattern Generated by Oxidative Stress

Moghaddam

Gartlan

Kong

et al. 2011

The Journal of Immunology

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Oxidative stress is widespread and entwined with pathological processes, yet its linkage to adaptive immunity remains elusive. Reactive carbonyl (RC) adduction, a common feature of oxidative stress, has been shown to target proteins to the adaptive immune system. Because aldehydes are important mediators of carbonylation, we explored the immunomodulatory properties of model Ags modified by common bioactive aldehyde by-products of oxidative stress: 4-hydroxy-2-nonenal, malondialdehyde, and glycolaldehyde. Ag modification with all three aldehydes resulted in Ag-specific IgG1-dominated responses in adjuvant-free murine immunizations in an RC-dependent manner. The central role of RCs was confirmed, as their reduction into nonreactive groups abrogated all adaptive responses, despite the presence of other well-known aldehyde-driven adducts such as Nε-carboxymethyllysine and glycolaldehyde–pyridine. Moreover, Ag-specific Ab responses robustly correlated with the extent of RC adduction, regardless of the means of their generation. T cell responses mirrored the Th2-biased Ab isotypes by Ag-specific splenocyte production of IL-4, IL-5, and IL-13, but not IFN-γ. The RC-induced Th2 response was in sharp contrast to that induced by Th1/Th2 balanced or Th1-biasing adjuvants and was maintained in a range of mouse strains. In vitro studies revealed that RC adduction enhanced Ag presentation with Th2 polarization in the absence of conventional dendritic cell activation. Taken together, these data implicate commonly occurring RC as an important oxidation-derived Th2 immunomodulatory damage-associated molecular pattern with potentially important roles in health and disease.

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Section: Discussionmentioning

confidence: 99%

Reactive Carbonyls Are a Major Th2-Inducing Damage-Associated Molecular Pattern Generated by Oxidative Stress

Moghaddam

Gartlan

Kong

et al. 2011

The Journal of Immunology

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“…The use of the Schiff base-forming agent tucaresol, in addition, during immunization with protein antigen increased T cell dependent immune response. Direct modification of protein antigen has been shown to be required for the enhancement of the immune response [6,[9][10][11][12].…”

Section: Oxidation and Immune Responsementioning

confidence: 99%

Autoimmunity and oxidatively modified autoantigens

Kurien

Scofield

2008

Autoimmunity Reviews

235

194

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Oxidative damage mediated by reactive oxygen species results in the generation of deleterious byproducts. The oxidation process itself and the proteins modified by these molecules are important mediators of cell toxicity and disease pathogenesis. Aldehydic products, mainly the 4-hydroxy-2-alkenals, form adducts with proteins and make them highly immunogenic. Proteins modified in this manner have been shown to induce pathogenic antibodies in a variety of diseases including systemic lupus erythematosus (SLE), alcoholic liver disease, diabetes mellitus (DM) and rheumatoid arthritis (RA). 8-oxodeoxyguanine (oxidatively modified DNA) and low density lipoproteins (LDL) occur in SLE, a disease in which premature atherosclerosis is a serious problem. In addition, immunization with 4-hydroxy-2-nonenal (HNE) modified 60 kD Ro autoantigen induces an accelerated epitope spreading in an animal model of SLE. Advanced glycation end product (AGE) pentosidine and AGE modified IgG have been shown to correlate with RA disease activity. Oxidatively modified glutamic acid decarboxylase is important in type 1 DM, while autoantibodies against oxidized LDL are prevalent in Behcet's disease. The fragmentation of scleroderma specific autoantigens occurs as a result of oxidative modification and is thought to be responsible for the production of autoantibodies through the release of cryptic epitopes. The administration of antioxidants is a viable untried alternative for preventing or ameliorating autoimmune disease, particularly on account of the overwhelming evidence for the involvement of oxidative damage in autoimmunity. However, this should be viewed in the light of disappointing results obtained with the use of antioxidants in cardiovascular disease. Keywordslupus; autoimmunity; epitopes; autoantibodies; antigens Free radicalsReactive oxygen species (ROS) are oxygen-based molecules possessing high chemical reactivity. These include free radicals (superoxide and hydroxyl radicals) and non-radical species (hydrogen peroxide) which can be produced even at basal conditions by a number of ways. Free radicals are active species containing atoms or molecules with one or more unpaired electrons occupying an outer orbital. They can arise either by the univalent pathway of oxygen

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“…Acetaldehyde produced in the liver may interact with proteins to generate adducts that are able to activate immune cells. 1 Although the toxicity of hepatic acetaldehyde is clearly established, the presence of endotoxins in the blood appears to be a prerequisite to cirrhosis, which develops in 10 to 20% of chronic alcoholics. 2 Indeed, several studies have revealed that endotoxemia was strongly associated with the occurrence and severity of cirrhosis in humans.…”

mentioning

confidence: 99%

Impairment of the Intestinal Barrier by Ethanol Involves Enteric Microflora and Mast Cell Activation in Rodents

Ferrier

Bérard

Debrauwer

et al. 2006

The American Journal of Pathology

215

202

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Alcohol hepatic toxicity in heavy drinkers is associated with high endotoxin blood levels and increased intestinal permeability. Because endotoxins can cross damaged mucosa, we investigated the mechanisms through which ethanol impairs the colonic epithelium of rats submitted to acute alcohol intake. Colonic permeability to 51 Cr-ethylenediamintetraacetic acid was increased 24 hours after 3.0 g/kg ethanol intake (3.2 ؎ 0.2% versus 2.2 ؎ 0.2%) and was associated with significant endotoxemia. Antibiotics and doxantrazole (a mast cell membrane stabilizer) significantly inhibited the effect of ethanol. Two hours after intake, plasma concentrations of ethanol were twofold higher in antibiotictreated rats than in controls (155.8 ؎ 9.3 mg/dl versus 75.7 ؎ 7.6 mg/dl, P < 0.001). Lumenal concentrations of acetaldehyde were markedly increased after ethanol intake (132.6 ؎ 31.6 mol/L versus 20.8 ؎ 1.4 mol/L, P < 0.05) and antibiotics diminished this increase (86.2 ؎ 10.9 mol/L). In colonic samples mounted in Ussing chambers, acetaldehyde but not ethanol increased dextran flux across the mucosa by 54%. Doxantrazole inhibited the effect of acetaldehyde. This study demonstrates that an acute and moderate ethanol intake alters the epithelial barrier through ethanol oxidation into acetaldehyde by the colonic microflora and downstream mast cell activation. Such alterations that remain for longer periods could result in excessive endotoxin passage, which could explain the subsequent endotoxemia frequently observed in patients with alcoholic liver disease.

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Adduction of Soluble Proteins with Malondialdehyde‐Acetaldehyde (MAA) Induces Antibody Production and Enhances T‐Cell Proliferation

Cited by 56 publications

References 57 publications

Reactive Carbonyls Are a Major Th2-Inducing Damage-Associated Molecular Pattern Generated by Oxidative Stress

Reactive Carbonyls Are a Major Th2-Inducing Damage-Associated Molecular Pattern Generated by Oxidative Stress

Autoimmunity and oxidatively modified autoantigens

Impairment of the Intestinal Barrier by Ethanol Involves Enteric Microflora and Mast Cell Activation in Rodents

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