GPCRs respond to a broad spectrum of chemical entities ranging from photons, protons and calcium ions to small organic molecules (including odorants and neurotransmitters), peptides and glycoproteins (including functional autoantibodies). The classical role of a GPCR is to recognize the presence of an extracellular agonist, transmit the information across the plasma membrane, and activate a cytoplasmic heterotrimeric G protein, resulting in modulation of downstream effector proteins. Binding of an extracellular ligand to the extracellular loops of the receptor protein triggers a cycle of G protein activation and inactivation localized to the intracellular receptor site, which modulates the activity of enzymes and ion channels downstream, regulating the formation and concentration of cytosolic second messengers (Wang W et al. 2018).
After physiological and pharmacological ligand binding to a receptor, excessive receptor modulation is controlled by preventive mechanisms such as receptor down-regulation and desensitization of signal transduction. This control mechanism is crucial for physiological receptor activity.
Such control mechanisms are absent when GPCR-AAB bind to target receptors. It is suggested that GPCA-AAB are capable of cross-linking and permanently activating receptors due to their bivalent IgG structure. This has been demonstrated for β1-AAB, for autoantibodies directed against the β2-adrenergic receptor (β2-AAB) and the muscarinic 2 receptor (M2-AAB) (Hoebeke J (1996). Consequently, GPCR-AAB lead to disturbed metabolic balance and pathological conditions. They are a key event in GPCR-AAB-associated autoimmunity.
It is likely that GPCR-AAB-induced receptor cross-linking is one of the key events responsible for the absence of regulatory mechanisms such as receptor desensitization and internalization, resulting in excessive and prolonged receptor stimulation that may lead to disturbed metabolic balance and pathological conditions. This is in marked contrast to the state of receptors after binding of physiological or pharmacological ligands, where receptor internalization and desensitization counteract overboarding and prolonged receptor activation and signal transduction, thus protecting individuals from disturbed metabolic balance and pathological states. The absence of tachyphylaxis has been observed in several GPCR-AABs and thus most likely plays a key role in the pathogenesis of GPCR-AAB-associated diseases (Wallukat G et al. (1999).
Evidence suggests that GPCR autoantibodies appear to have pathogenic effects only in damaged tissue. In systemic sclerosis, receptor stimulation by AT1- and ETA-AAB affect interleukins, oxygen species, and ultimately growth factor balance, chemotaxis, cell migration, proliferation, angiogenesis, thrombosis, and fibrosis, among others (Cabral-Marques O et al. 2016).
For Chagas cardiomyopathy, there is evidence of how self-tolerance is breached. Antigens presented by the T. cruzi parasite, such as ribosomal P and B13 proteins, and animal and human cardiac antigens are cross-reactive; this involves the β1- and β2-adrenergic receptors as well as the muscarinic 2 receptor (Cunha-Neto E et al. 2011). The corresponding agonistic autoantibodies are frequently found in patients with Chagas heart failure. They bind on the first or second extracellular loop of β1-adrenergic receptors, among others (Wallukat G et al. 2010, L. Sterin-Borda L et al. 1976; Borda E et al. 1984).
Antibody evidence can also be detected in many other diseases such as diabetes mellitus and Alzheimer's disease. In patients with type II diabetes mellitus, α1-AAB have been found, although their prevalence in diabetics is not precisely known (Hempel P et al. 2009).
Inhibitory GPCR-AAB such as the autoantibodies directed against the β2-adrenergic receptor found in patients with allergic asthma block receptor activation by corresponding agonists. These autoantibodies are directed against the third extracellular receptor loop (Wallukat G et al. 1991).