Abstract
Autoantibodies have been associated with autoimmune diseases. However, studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. Here we provide evidence of a network of immunoglobulin G (IgG) autoantibodies targeting G protein-coupled receptors (GPCR) in HD compared to patients with systemic sclerosis, Alzheimer’s disease, and ovarian cancer. Sex, age and pathological conditions affect autoantibody correlation and hierarchical clustering signatures, yet many of the correlations are shared across all groups, indicating alterations to homeostasis. Furthermore, we identify relationships between autoantibodies targeting structurally and functionally related molecules, such as vascular, neuronal or chemokine receptors. Finally, autoantibodies targeting the endothelin receptor type A (EDNRA) exhibit chemotactic activity, as demonstrated by neutrophil migration toward HD-IgG in an EDNRA-dependent manner and in the direction of IgG from EDNRA-immunized mice. Our data characterizing the in vivo signatures of anti-GPCR autoantibodies thus suggest that they are a physiological part of the immune system.
Highlights
Autoantibodies have been associated with autoimmune diseases
Disease-specific signatures of aab targeting G protein-coupled receptors (GPCR). Since both elevated and decreased concentrations of aab have been associated with the development of immune-mediated diseases[14,15,16,17,18,19,20,21,22,23,24], we suspected that anti-GPCR aab are an intrinsic part of the immune system after observing altered levels of multiple antiGPCR aab in sera from patients with different autoimmune diseases, such as SLE, SSc, GPA, and RA, compared with healthy subjects (Fig. 1a–c, Supplementary Fig. 1)
While the levels of some anti-GPCR aab were similar between the healthy donors (HD) and disease groups, SSc and RA patients exhibited both elevated and decreased aab concentrations, and patients with GPA frequently demonstrated lower anti-GPCR aab concentrations compared with HD
Summary
Autoantibodies have been associated with autoimmune diseases. studies have identified autoantibodies in healthy donors (HD) who do not develop autoimmune disorders. The most common theories proposed to explain aab production are based on molecular mimicry and immune dysregulation[4,6] These theories mainly aim to integrate the mechanisms of aab production with the commonly accepted paradigm that associates aab with autoimmune diseases. They are unable to fully explain the occurrence of selfreactive B cells in mice and humans[7] and the production of immunogobulin G (IgG) aab that are naturally present in sera from HD. When the production of anti-GPCR aab becomes dysregulated, they may trigger the development of autoimmune diseases
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