IgA Immune Complexes Induce Osteoclast-Mediated Bone Resorption.

Annelot C Breedveld,Marjolein Van Egmond,Melissa M J Van Gool,Conny J Van Der Laken,Myrthe A M Van Delft,Ineke D C Jansen,Teun J De Vries

doi:10.3389/fimmu.2021.651049

Abstract

ObjectiveAutoantibodies are detected in most patients with rheumatoid arthritis (RA) and can be of the IgM, IgG or IgA subclass. Correlations between IgA autoantibodies and more severe disease activity have been previously reported, but the functional role of IgA autoantibodies in the pathogenesis of RA is ill understood. In this study, we explored the effect of IgA immune complexes on osteoclast mediated bone resorption.MethodsAnti-citrullinated peptide antibody (ACPA) and anti-carbamylated protein (anti-CarP) antibody levels of the IgA and IgG isotype and rheumatoid factor (RF) IgA were determined in synovial fluid (SF) of RA patients. Monocytes, neutrophils, and osteoclasts were stimulated with precipitated immune complexes from SF of RA patients or IgA- and IgG-coated beads. Activation was determined by neutrophil extracellular trap (NET) release, cytokine secretion, and bone resorption.ResultsNET formation by neutrophils was enhanced by SF immune complexes compared to immune complexes from healthy or RA serum. Monocytes stimulated with isolated SF immune complexes released IL-6 and IL-8, which correlated with the levels of ACPA IgA levels in SF. Osteoclasts cultured in the presence of supernatant of IgA-activated monocytes resorbed significantly more bone compared to osteoclasts that were cultured in supernatant of IgG-activated monocytes (p=0.0233). Osteoclasts expressed the Fc receptor for IgA (FcαRI; CD89) and Fc gamma receptors. IgA-activated osteoclasts however produced significantly increased levels of IL-6 (p<0.0001) and IL-8 (p=0.0007) compared to IgG-activated osteoclasts. Both IL-6 (p=0.03) and IL-8 (p=0.0054) significantly enhanced bone resorption by osteoclasts.ConclusionIgA autoantibodies induce release of IL-6 and IL-8 by immune cells as well as osteoclasts, which enhances bone resorption by osteoclasts. We anticipate that this will result in more severe disease activity in RA patients. Targeting IgA-FcαRI interactions therefore represents a promising novel therapeutic strategy for RA patients with IgA autoantibodies.

Highlights

Rheumatoid arthritis (RA) is a heterogeneous chronic inflammatory disease that is mainly characterized by swelling and pain in the joints
In this study we investigated the effect of IgA complexes and immune complexes isolated from synovial fluid of RA patients on bone resorption
Since we previously demonstrated that Rheumatoid Factor (RF) IgA levels were significantly elevated in RA patients [27], we determined RF IgA in this study

Summary

Introduction

Rheumatoid arthritis (RA) is a heterogeneous chronic inflammatory disease that is mainly characterized by swelling and pain in the joints. The majority of RA patients develop antibodies against the Fc region of IgG (rheumatoid factor; RF). Antibodies against post-translationally modified proteins including anti-citrullinated protein antibodies (ACPAs) and anti-carbamylated protein (anti-CarP) antibodies are highly specific. ACPAs can be locally produced by plasma cells in joints of RA patients and are detected in sera of up to 70% of RA patients [6]. They recognize citrullinated proteins or peptides, which can be found throughout the body including cartilage and bone. Anti-CarP antibodies are detected in sera of 45% of RA patients and recognize carbamylated proteins [7]

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Conclusion