Background Immunoglobulins (Ig) and immune complexes (ICs) intervening with complement and Fc receptors (FcR) are important for the pathogenesis of rheumatoid arthritis (RA). Thus, B-cells are interesting targets for controlling chronic inflammation and autoantibody production (rheumatoid factors (RF) and ACPAs), especially in seropositive disease. In inflamed RA joints, accumulated FcR bearing monocytes/macrophages contribute to inflammation by cytokine release and antigen presentation. These cells consist of subpopulations with different features and may be defined by the composition of specific membrane receptors. However, the association between RA-specific antibodies and monocyte function in early RA is poorly studied.
Objectives We have previously reported on altered monocyte FcR expressions, FcγR function and IgG load in an early RA cohort which reflected joint disease activity (ref). Here we were interested in evaluating the systemic B-cell activity in the same patients and related these findings to monocyte subpopulations, the FcγR function and to treatment response.
Methods The sera of 20 early DMARD- and steroid naïve RA patients and 33 matched HCs were analyzed for Ig isotypes, IgG subclasses, the IgM, IgG and IgA RF isotypes and ACPA-IgG with standardized methods or with ELISA kits. Correlations of the Ig measurements with available data on the patients' monocyte FcγR function (eq. IgG1/IgG3 IC binding and TNFα production after IgG1/IgG3 stimulation) and monocyte subpopulations (defined by CD14/CD16 expression) were performed. The patients were evaluated before and after 3 months of treatment with methotrexate (MTX) and prednisolone (PRED). At follow up the individual treatment effect was determined using the EULAR response criteria. The distribution and the amount of the 3 RF isotypes among the responder groups were determined.
Results The RA patients presented higher levels of total IgG, the IgG1 and IgG3, and all tested RF isotypes than the HCs. These findings correlated negatively with the monocyte FcγR function; high levels of all 3 RF isotypes reflected low IgG1-IC binding capacity, and high IgA-RF titers were associated with low monocytic TNFα release after IgG1- and IgG3-IC stimulation. These findings did not apply to the ACPA-IgG titers. A general observation of higher pre-treatment levels of Igs and auto-antibodies in the non responders was made, these individuals also maintained high levels of IgG3 and IgM-RF at follow up. Interestingly, an increase in the classical monocyte subset was seen in the non responders compared to the HC. And these non responders also had fewer non classical monocytes compared with the good responders. A good treatment response was observed in those patients who initially presented with few concurrent RF isotypes and low titers thereof.
Conclusions In early naïve seropositive RA elevated specific IgG subclasses and RFs reflect an immune state of decreased monocyte FcγR function. An altered distribution of the monocyte subpopulations can be observed which may reflect the patients' treatment response. A good response to a combined MTX/PRED therapy is more likely to be observed in those patients who present low systemic B-cell activity.
P Matt et al: Elevated Membrane and Soluble CD64: A Novel Marker Reflecting Altered FcγR Function and Disease in Early Rheumatoid Arthritis That Can Be Regulated by Anti-Rheumatic Treatment. DOI: 10.1371/journal.pone.0137474
Disclosure of Interest None declared
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