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A method to identify trace sulfated IgG N-glycans as biomarkers for rheumatoid arthritis.

ABSTRACT: N-linked glycans on immunoglobulin G (IgG) have been associated with pathogenesis of diseases and the therapeutic functions of antibody-based drugs; however, low-abundance species are difficult to detect. Here we show a glycomic approach to detect these species on human IgGs using a specialized microfluidic chip. We discover 20 sulfated and 4 acetylated N-glycans on IgGs. Using multiple reaction monitoring method, we precisely quantify these previously undetected low-abundance, trace and even ultra-trace N-glycans. From 277 patients with rheumatoid arthritis (RA) and 141 healthy individuals, we also identify N-glycan biomarkers for the classification of both rheumatoid factor (RF)-positive and negative RA patients, as well as anti-citrullinated protein antibodies (ACPA)-positive and negative RA patients. This approach may identify N-glycosylation-associated biomarkers for other autoimmune and infectious diseases and lead to the exploration of promising glycoforms for antibody therapeutics.Post-translational modifications can affect antibody function in health and disease, but identification of all variants is difficult using existing technologies. Here the authors develop a microfluidic method to identify and quantify low-abundance IgG N-glycans and show some of these IgGs can be used as biomarkers for rheumatoid arthritis.

SUBMITTER: Wang JR

PROVIDER: S-EPMC5606999 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Methotrexate (MTX) is the standard first-line therapy in rheumatoid arthritis (RA) with variable clinical efficacy that is difficult to predict. The glycosylation status of immunoglobulin G (IgG) is altered in RA and influenced by MTX treatment. We aimed to further investigate if IgG glycosylation in untreated early RA can predict therapeutic response to MTX.We used a shotgun proteomic approach to screen for the Fc glycopeptides in the serum of 12 control subjects and 59 untreated patients with early RA prior to and following MTX initiation. MTX treatment response was defined according to the European League Against Rheumatism at a median of 14 weeks (range 13-15) after treatment initiation. Seropositive patients were defined as those testing positive for anticitrullinated protein antibodies and/or rheumatoid factor at baseline (n = 44). Data analysis was performed using uni- and multivariate statistics.We could confirm a low abundance of galactosylated glycans in untreated patients with early RA compared with control subjects that was partially restored by MTX treatment. This was more evident among future nonresponders than among responders to MTX treatment. Results were further validated and confirmed by multivariate statistical analysis of the baseline Fc glycan, proteomic, and clinical data. We found that the ratio between the main agalactosylated (FA2) and main mono- and di-galactosylated Fc glycans (FA2G1 and FA2G2) of IgG1 ranked as the most prominent factor distinguishing responders from nonresponders. A low baseline ratio of FA2/[FA2G1 + FA2G2]-IgG1 was associated with nonresponse (OR 5.3 [1.6-17.0]) and was able to discriminate future nonresponders from responders to MTX therapy with a sensitivity of 70% (95% CI 46-88%) and a specificity of 69% (95% CI 52-83%). For seropositive patients (n = 44), this trend was improved with a sensitivity of 73% (95% CI 45-92%) for nonresponse and a specificity of 79% (95% CI 60-92%).We show that the FA2/[FA2G1 + FA2G2] of IgG1 is a biomarker candidate that is significantly associated with nonresponding patients and has potential value for prediction of MTX clinical response.

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A method to identify trace sulfated IgG N-glycans as biomarkers for rheumatoid arthritis.

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