GPCR-specific autoantibody signatures are associated with physiological and pathological immune homeostasis

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.

Antibodies Targeting Chemokine Receptors CXCR4 and ACKR3

“…Autoantibodies against CXCR4 have been reported in patients with systemic sclerosis (Weigold et al, 2018). While most autoantibodies directed at GPCRs were shown to have agonistic properties (Wallukat and Schimke, 2014;Cabral-Marques et al, 2018), the functionality and binding epitopes of the reported CXCR4 autoantibodies have not been described (Recke et al, 2018). In contrast, antagonistic properties would be advantageous in therapeutic antibodies to block receptor function involved in disease progression.…”

Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Autoantibodies against b2 adrenergic receptors (b2R) were found to be upregulated in a subset of patients with ME/CFS (53). Such Abs belong to a network of natural Abs against adrenergic, acetylcholine (cholinergic), and other GPCR receptors that were shown to be dysfunctional in various autoimmune diseases (54). Autonomic dysregulation is a hallmark of ME/CFS.…”

Role of autoantibodies against cardiomyocyte antigens in the development of cardiac arrhythmiae and sudden cardiac death

“…Более того, согласно современным представлениям, ауто-АТ не связаны исключительно с патогенными эффектами и с развитием заболеваний. Было показано, что, по крайней мере, ауто-АТ против рецепторов, связанных с G-белками, у здоровых доноров заурядно присутствуют в крови и обеспечивают гомеостатические функции, формируя типичные паттерны спектра физиологического аутоиммунитета [35]. Отклонения от нормального паттерна содержания ауто-АТ могут служить отражением патологических изменений в тех или иных органах (в соответствии с предложенной независимо А.Б.Полетаевым в нашей стране и И.Коэном -в Израиле концепцией «Иммункулуса -Иммунного Гомункулуса», согласно которой совокупность естественных ауто-АТ представляет собой целостный внутренний иммунологический образ индивида, отражающий особенности его молекулярного (антигенного) состава) [36], и даже способствовать прогрессированию заболеваний, ранее считавшихся не связанными с развитием аутоиммунных реакций.…”