Interference of rheumatoid factor activity by aspartame, a dipeptide methyl ester

Abstract

Circulating autoimmune complexes of IgM rheumatoid factors (RF) bound to the Fc portions of normal, polyclonal IgG antibodies are frequently present in humans with rheumatoid arthritis (RA). The sweet tasting methyl ester of L-Asp-L-Phe (aspartame or APM) was found to relieve pain and improve joint mobility in subjects with osteo- and mixed osteo/rheumatoid arthritis [Edmundson, A. B. and Manion, C. V. (1998). Clin. Pharmac. Ther. 63, 580-593]. These clinical observations prompted the testing of the inhibition by APM of the binding interactions of human IgM RFs with IgG Fc regions. The propensity of APM to inhibit IgM RF binding was assessed by competitive enzyme immunoassays with solid-phase human IgG. Ten RA serum samples and three purified monoclonal cryoglobulins, all of which had RF activity, were tested in this system. We found that the presence of APM significantly reduced the binding of IgM RFs. The inhibitory propensity of APM with monoclonal RF cryoglobulins was increased by the addition of CaCl(2) to the binding buffer. Similar inhibition of the binding of RA derived RFs to IgG was observed for Asp-Phe and its amidated derivative, indicating that the methyl ester is not required for APM's interaction with IgM antibodies. A human (Mez) IgM known to bind octameric peptides derived from the Fc portion of a human IgG(1) antibody was tested for binding of dipeptides by the Pepscan method of combinatorial chemistry. The relative binding constants of Asp-Phe and Phe-Asp were ranked among the highest values for 400 possible combinations of the 20 most common amino acids. Possible blocking interactions of APM were explored by computer-assisted docking studies with the model of a complex of an RF Fab with the Fc of a human IgG(4) antibody. Modeling of ternary immune complexes revealed a few key residues, which could act as molecular recognition sites for APM. A structural hypothesis is presented to explain the observed interference with RF reactivity by APM. Extrapolations of the current results suggest that APM may inhibit the binding of IgG in a substantial proportion of IgM RFs. Interference of RF reactivity, especially in RA patients, may alleviate the pain and immobility resulting from chronic inflammation of the joints.

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“…Non-antibody interferents may include soluble targets that promote bridging of drug-derived reagents or aggregates found in labeled reagents used in the ADA assay (9)(10)(11). Several assay interference mitigation approaches have been reported to minimize non-antibody interferents that confound the detection of pre-existing drug-reactive antibodies and drug-induced ADAs (9,12).…”

Metabolite profiling reveals new insights into the regulation of serum urate in humans

“…Aspartame was shown to pose antipyretic, analgesic and anti-inflammatory action and to delay osteoarthritis in animal models (LaBuda and Fuchs 2001 ; Manion et al 2011 ; Pradhan et al 2011 ). Interference of aspartame with rheumatoid factor activity has been proposed to alleviate the pain and immobility resulting from chronic inflammation of joints (Ramsland et al 1999 ). Other (tryptophan-containing) dipeptides were shown to inhibit xanthine oxidase (Nongonierma and Fitzgerald 2012 ).…”

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“…[ 21 22 ] Interference of aspartame with rheumatoid factor activity has been proposed to alleviate the pain and immobility resulting from chronic inflammation of joints. [ 23 ]…”