Malondialdehyde‐Acetaldehyde Adducts and Anti–Malondialdehyde‐Acetaldehyde Antibodies in Rheumatoid Arthritis

Abstract

Objective As a product of oxidative stress associated with tolerance loss in other disease states, we investigated the presence of malondialdehyde-acetaldehyde (MAA) adducts and circulating anti-MAA antibody in rheumatoid arthritis (RA). Methods Synovial tissues from RA and osteoarthritis patients were examined for the presence of MAA-modified and citrullinated proteins. Anti-MAA antibody isotypes were measured in RA cases (n = 1720) and healthy controls (n = 80) by ELISA. Antigen-specific anti-citrullinated protein antibody (ACPA) was measured in RA cases using a multiplex antigen array. Anti-MAA isotype concentrations were compared in a subset of cases (n = 80) and matched controls (n = 80). Associations of anti-MAA antibody isotypes with disease characteristics, including ACPA, were examined in all RA cases. Results MAA adducts were increased in RA synovial tissues relative to osteoarthritis and co-localized with citrullinated protein. Anti-MAA antibody isotypes were increased in RA cases vs. controls (p < 0.001). Among RA cases, anti-MAA antibody isotypes were associated with ACPA and RF positivity (p < 0.001) in addition to select measures of disease activity. Higher anti-MAA antibody concentrations were associated with a higher number of positive antigen-specific ACPA analytes in high titer (p < 0.001) and a higher ACPA score (p < 0.001) independent of other covariates. Conclusion MAA adduct formation is increased in RA and appears to result in robust antibody responses that are strongly associated with ACPA. These results support speculation that MAA formation may be a co-factor that drives tolerance loss resulting in the autoimmune responses characteristic of RA.

Antioxidant Enzymes in Rheumatoid Arthritis

“…There is growing awareness that reactive oxygen species and free radicals may play an important role in mediating cellular injury and tissue damage in rheumatoid arthritis. Thiele et al [32] have reported malondialdehyde-acetaldehyde (MAA) adduct formation is increased in RA. They appear to result in robust antibody responses which are strongly associated with anti citrullinated protein antigens (ACPAs) suggesting that MAA formation may be a cofactor that drives tolerance loss, resulting in the autoimmune responses characteristic of RA.…”

Smoking and Air Pollution as Pro-Inflammatory Triggers for the Development of Rheumatoid Arthritis

“…These are: i) carbamylation involving the reaction of cyanate present in cigarette smoke with the primary amine group of protein/peptidyl-lysine, resulting in conversion to potentially autoantigenic protein/peptidyl-homocitrulline, which is potentiated by neutrophil/monocyte-derived myeloperoxidase [77]; and ii) ROSmediated lipid peroxidation, resulting in the formation of malondialdehyde and acetaldehyde which, in turn, form potentially autoantigenic protein adducts via reaction with primary amine groups of amino acids [77,78].…”

Aldehyde-modified proteins as mediators of early inflammation in atherosclerotic disease

“…This extremely stable ring structure, as well as its ability to generate a potent immune response as outlined below, may represent a mechanism through which oxidative stress and free radical formation potentiate inflammation and lead to both subclinical and clinical disease. Recently, it has been demonstrated that the proinflammatory characteristics of MAA-modified proteins are important in other inflammatory diseases, such as connective tissue disorders and abdominal aortic aneurysms [36][37][38]. However, the remainder of this review will focus on the potential role of MAA in the pathogenesis of atherosclerosis.…”