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Sex effect on the correlation of immunoglobulin G glycosylation with rheumatoid arthritis disease activity.

ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease which affects females more than males with a presence of autoantibodies. Immunoglobulin G (IgG) produced by adaptive arm has 2 functional domains, Fc and Fab. The Fc domain binds Fc gamma receptors and C1q proteins of the innate arm. Therefore, the IgG Fc domain serves as a bridge between the innate and adaptive arms and is regulated by an evolutionarily conserved N-glycosylation with variable structures. These glycans are classified as agalactosylated G0, monogalactosylated G1, and digalactosylated G2, which are further modified by core-fucosylation (F) and bisecting N-acetylglucosamine (B) moieties such as G0F and G0FB. Interestingly, proinflammatory G0F is shown to be regulated by estrogen in vivo. Here, it is hypothesized that the regulation of G0F by estrogen contributes to sex dichotomy in RA by setting up the level of IgG-dependent inflammation and therefore, RA disease activity (Das28-CRP3). To investigate this hypothesis, IgG glycosylation was characterized in serum samples from active RA patients (n = 232) and healthy controls (n = 232) by serum N-glycan analysis using the high performance liquid chromatography. According to the results, the IgG Fc glycan phenotype originates predominantly from the structure of G0F, and both G0F and G0FB correlate with Das28-CRP3 in females, but not in males. In conclusion, IgG G0F-dependent inflammation differs in males and females, and these differences point to the differential regulation of inflammation by sex hormone estrogen via IgG glycosylation.

SUBMITTER: Ercan A

PROVIDER: S-EPMC7759195 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Sex effect on the correlation of immunoglobulin G glycosylation with rheumatoid arthritis disease activity.

Ercan Altan A

Turkish journal of biology = Turk biyoloji dergisi 20201214 6

Rheumatoid arthritis (RA) is a chronic autoimmune disease which affects females more than males with a presence of autoantibodies. Immunoglobulin G (IgG) produced by adaptive arm has 2 functional domains, Fc and Fab. The Fc domain binds Fc gamma receptors and C1q proteins of the innate arm. Therefore, the IgG Fc domain serves as a bridge between the innate and adaptive arms and is regulated by an evolutionarily conserved N-glycosylation with variable structures. These glycans are classified as a ...[more]

PMID: 33402867

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Project description:BACKGROUND:Galactosylation of immunoglobulin G (IgG) is reduced in rheumatoid arthritis (RA) and assumed to correlate with inflammation and altered humoral immunity. IgG hypogalactosylation also increases with age. To investigate dependencies in more detail, we compared IgG hypogalactosylation between patients with RA, patients with axial spondyloarthritis (axSpA), and healthy control subjects (HC), and we studied it in RA on the background of HLA-DRB1 shared epitope (SE), anticitrullinated protein antibodies (ACPA), and/or rheumatoid factor (RF) status. METHODS:Patients with RA (n = 178), patients with axSpA (n = 126), and HC (n = 119) were characterized clinically, and serum IgG galactosylation was determined by capillary electrophoresis. Markers of disease activity, genetic susceptibility, and serologic response included C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), DAS28, SE, HLA-B27, ACPA, and RF. Expression of glycosylation enzymes, including beta 1-4 galactosyltransferase (B4GALT3) activity, were estimated from transcriptome data for B-cell development (GSE19599) and differentiation to plasma cells (GSE12366). RESULTS:IgG hypogalactosylation was restricted to RA and associated with increasing CRP levels (p < 0.0001). In axSpA, IgG hypogalactosylation was comparable to HC and only marginally increased upon elevated CRP. Restriction to RA was maintained after correction for CRP and age. Treatment with sulfasalazine resulted in significantly reduced IgG hypogalactosylation (p = 0.003) even after adjusting for age, sex, and CRP (p = 0.009). SE-negative/ACPA-negative RA exhibited significantly less IgG hypogalactosylation than all other strata (vs SE-negative/ACPA-positive, p = 0.009; vs SE-positive/ACPA-negative, p = 0.04; vs SE-positive/ACPA-positive, p < 0.02); however, this indicated a trend only after Bonferroni correction for multiple testing. In SE-positive/ACPA-negative RA IgG hypogalactosylation was comparable to ACPA-positive subsets. The relationship between IgG hypogalactosylation and disease activity was significantly different between strata defined by SE (CRP, p = 0.0003, pBonferroni = 0.0036) and RF (CRP, p < 0.0001, pBonferroni < 0.0012), whereas ACPA strata revealed only a nonsignificant trend (p = 0.15). Gene expression data indicated that the key enzyme for galactosylation of immunoglobulins, B4GALT3, is expressed at lower levels in B cells than in plasma cells. CONCLUSIONS:Increased IgG hypogalactosylation in RA but not in axSpA points to humoral immune response as a precondition. Reduced B4GALT3 expression in B cells compared with plasma cells supports relatedness to early B-cell triggering. The differential influence of RA treatment on IgG hypogalactosylation renders it a potential diagnostic target for further studies.

Project description:ObjectiveTo evaluate rheumatoid arthritis (RA) disease activity and risk of RA-associated interstitial lung disease (RA-ILD).MethodsWe investigated disease activity and risk of RA-ILD using the Brigham RA Sequential Study (BRASS, 2003-2016). All patients were diagnosed as having RA according to accepted criteria. Disease Activity Scores in 28 joints (DAS28) and covariate data were measured prospectively at annual study visits. Diagnosis of RA-ILD was determined by review of images from clinically indicated chest computed tomography scans. We analyzed patients without RA-ILD at baseline. We used Cox regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for RA-ILD, using annually updated DAS28 data, with adjustment for known RA-ILD risk factors (age, sex, smoking status, RA duration, and serologic status). We performed alternative analyses that did not censor at the time of missing DAS28 data and included adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, and presence of rheumatoid nodules.ResultsAmong 1,419 participants, the mean ± SD age was 55.8 ± 14.2 years, and 68.6% were seropositive for either cyclic citrullinated peptide or rheumatoid factor. We identified 85 incident cases of RA-ILD during a mean ± SD follow-up duration of 8.9 ± 4.2 years per patient. The moderate/high disease activity group had a multivariable HR of 2.22 (95% CI 1.28-3.82) for RA-ILD compared to the remission/low disease activity group. Risk of RA-ILD increased across disease activity categories: multivariable HR 1.00 (reference) for remission, 1.41 (95% CI 0.61-3.28) for low disease activity, 2.08 (95% CI 1.06-4.05) for moderate disease activity, and 3.48 (95% CI 1.64-7.38) for high disease activity (P for trend = 0.001). For each unit increase in the DAS28, the risk of RA-ILD increased by 35% (95% CI 14-60%). Results were similar in analyses that included follow-up for missing DAS28 data and with adjustment for use of methotrexate, use of glucocorticoids, presence of bone erosions, or presence of rheumatoid nodules.ConclusionActive articular RA was associated with an increased risk of developing RA-ILD. These results suggest that decreasing systemic inflammation may alter the natural history of RA-ILD development.

Dataset Information

Sex effect on the correlation of immunoglobulin G glycosylation with rheumatoid arthritis disease activity.

Publications

Sex effect on the correlation of immunoglobulin G glycosylation with rheumatoid arthritis disease activity.

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