Rheumatoid factor IgM autoantibodies control IgG homeostasis

Abstract

Rheumatoid arthritis is an autoimmune disease characterized by joint inflammation due to autoantibodies targeting multiple self-proteins. Most patients with poor prognosis show elevated titers of IgM antibodies specifically binding to IgG. Such autoreactive antibodies are referred to as rheumatoid factor (RF). However, their biological function and contribution to disease progression remains elusive. We have recently shown that autoreactive antibodies are present in healthy individuals and play an important role in regulating physiological processes. This regulatory mechanism is determined by the class and affinity of the autoreactive antibody, as low-affinity autoreactive IgM neutralizes the recognized autoantigen while high-affinity IgM protects its autoantigen from degradation. Here, we show that RFs possessing a high affinity and mono-specificity to IgG have a stabilizing effect on IgG, whereas low-affinity polyreactive RFs neutralize IgG in vivo. These results suggest that autoreactive IgM antibodies recognizing IgG play a crucial role in regulating IgG homeostasis and that a disbalance between IgM-mediated IgG degradation and stabilization might affect the onset and progression of autoimmune diseases. Consequently, restoring this balance using low-affinity anti-IgG IgM might be a promising therapeutic approach for autoimmune diseases involving autoreactive IgG.

IgM kappa proliferative glomerulonephritis with monoclonal immunoglobulin deposition complicated with nocardiosis dermatitis: a case report and review of literature

“…Recent studies show that RF IgM has different affinities. Similar to natural autoantibodies found in healthy people, the low-affinity RF IgM is polyreactive and reduces the level of disease-causing IgG autoantibodies in the body by neutralizing IgG (25). However, RF IgM with high affinity is monoreative, which can protect the antigen it recognizes from degradation.…”

“…However, RF IgM with high affinity is monoreative, which can protect the antigen it recognizes from degradation. RF IgM autoantibodies from rheumatoid arthritis patients typically bind with high affinity the Fc portion of IgG, which may protect and hence intensify the effect of pathogenic IgG (25,26). Therefore, it is of great significance to identify the polyreactive and monoreactive of IgM deposited in the kidney tissue of this patient to understand the pathogenic role of RF IgM in this patient.…”

Peptoniphilus gorbachii alleviates collagen-induced arthritis in mice by improving intestinal homeostasis and immune regulation

“…For instance, individuals with obesity have shown elevated concentrations of plasma IgM ( 46 ) along with an increase in IgM-bound gut microbiota ( 47 ). Patients with RA exhibited higher IgM and IgA levels compared to control ( 48 ), while most patients with poor prognosis displayed elevated levels of IgM antibodies specifically binding to IgG ( 49 ). Moreover, RA patients exhibited significantly higher levels of multiple antimicrobial response factors such as EndoCAb IgM and EndoCAb IgA, which are released into circulation in response to microbial exposure when compared to healthy individuals ( 48 ).…”

Cytokines, Vascular Endothelial Growth Factors, and PlGF in Autoimmunity: Insights From Rheumatoid Arthritis to Multiple Sclerosis

“…Another type of Ab regarded as a precise biomarker of RA diagnosis is rheumatoid factor which is a type of IgM directed against the Fc region of IgG ( 11 ). This autoreactive IgM with high affinity protects autoantigens from degradation leading to the accumulation of autoantibodies occurring in AD ( 12 ). On the other hand, IL-6 is known to activate osteoclasts which induce bone destruction and suppress osteoblasts which oppositely repair the damaged bones of patients with RA ( 13 ).…”