Review abstract:
Antibodies Against GPCR, by Carlotta Meyer, Harald Heidecke in Front Biosci (Landmark Ed). 2018 Jun 1;23:2177-2194.
G-protein-coupled receptors (GPCRs) are the largest family of receptors in humans.
GPCRs are seven-transmembrane receptors that are activated by the binding of a ligand to the extracellular domain. In addition to the endogenous ligands, auto-antibodies (aab) can also bind to the GPCRs. They can activate different and specific cellular pathways which contribute to various diseases.
In this review, the authors summarize the knowledge about antibodies targeting GPCRs and their effects and relevance in the pathogenesis of various diseases and their use in clinical diagnostics. We highlight the role of different activating anti-GPCR aab in solid organ transplantations, stem cell transplantations, systemic sclerosis, preeclampsia, chronic fatigue syndrome, cardiovascular diseases, Alzheimer’s disease, and cancer.
Ligand–receptor interactions provide the fundamental basis for the mechanism of action of all drugs. (Motiejunas & Wade 2007)
5.1. Chronic Fatigue Syndrome (CFS/ME)
Chronic Fatigue Syndrome has an estimated prevalence of 0.2–0.3% (82); it is a frequent and severe chronic disease. Scheibenbogen et al. determined antibodies against alpha and beta adrenergic receptors, muscarinic cholinergic receptors 1-5, dopamine receptors, serotonin receptors, AT1R, and ETAR by ELISA (CellTrend GmbH) in sera from chronic fatigue syndrome patients (n=268) and healthy controls (n=108). Anti-beta-2 adrenergic receptors, anti-muscarinic cholinergic receptors 3 and anti-muscarinic cholinergic receptors 4 aab were significantly elevated in CFS patients compared to controls (83).
In addition, pre and post-treatment samples from 25 patients treated during the KTS-2 rituximab trial were analyzed for aab against GPCR (84, 85). In patients receiving rituximab and responded to therapy, anti-beta-2 adrenergic receptor and anti-muscarinic cholinergic receptor 4 aab significantly decreased. In contrast, the aab levels in non-responders did not reduce. This is the first sign that anti-beta-2 adrenergic receptor and the anti-muscarinic cholinergic receptor 4 aab could be used as a companion diagnostic for rituximab treatment in chronic fatigue syndrome.
In addition, Scheibenbogen et al. showed that immunoadsorption (IA) was effective to remove anti-beta-2 adrenergic receptors aab in chronic fatigue syndrome patients and improve their outcome (86). In detail, elevated anti-beta-2 adrenergic receptor aab rapidly decreased during IA in 9 of 10 patients. Furthermore 6 months later anti-beta-2 adrenergic receptors aab were significantly lower compared to pretreatment. A rapid improvement of symptoms was reported by 7 patients during the IA. 3 of these patients had long lasting and ongoing moderate to marked improvement for 6 – 12 months, 2 patients had short improvement only and 2 patients improved for several months following initial worsening.
Kämpf et al. described for the first time an association between anti-muscarinic cholinergic receptors 3 and anti-muscarinic cholinergic receptors 4 aab and cancer related fatigue syndrome (87).
8. CONCLUSIONS
Antibodies against GPCR are present in autoimmune and non-autoimmune diseases. Both elevated as well as decreased anti-GPCR ab are present in diseases (119). There are a growing number of antibodies against different GPCR. Current researches indicate the role of anti-GPCR aab patterns as markers of diseases. The role of anti-GPCR aab in disease pathogenesis is an emerging field in different diseases. In addition, studies determining quantity and quality biological spectrum of aab targeting GPCRs in healthy subjects according to sex, age and geographic areas will bring valuable parameters for future investigations.
A major challenge in the field of anti-GPCR aab is the determination of the aab with reliable assays. There are two methods in general, functional assays (so called bioassays) and IgG-binding assays using a variety of antigenic target molecules (ELISAs or similar methods). Many ELISAs employ peptid homologues of the presumed target epitope as capture antigen. Current belief holds that these may not be useful in many cases (63). ELISAs using the full GPCR protein are reliable and have high-through-put ability. A few of these (e.g. anti-AT1R-Ab and anti-ETAR-Ab, CellTrend GmbH) are registered as in vitro diagnostics (IvD). Table 1 gives an overview of, which type of assay has been used in the characterisation of GPCR-aab in the various diseases discussed here.
Anti-GPCR aab are another ligand of the receptor with specific effects on the receptor. They are a target for the development of a new class of drugs as well as for new diagnostic tools for the personalized medicine.
