Autoantibodies (AAb) which activate GPCR were first identified for the TSH receptor
and are acknowledged as causative of Graves’. Cardiovascular autonomic GPCR were identified
in the 1990s. Their etiology remains unclear but evidence supports their impact on
autonomic CV and CNS function. Several laboratories have provided circumstantial and
direct evidence for involvement in pathophysiology of a number of diseases. The co-presence
of AAb for the B2 and M3 adrenergic receptors has been reported in a high proportion
of subjects we studied with idiopathic orthostatic hypotension (IOH) and more recently
for alpha1AR and B1/2AR in postural tachycardia syndrome (POTS). There is increasing
evidence these and other AAbs play a role in the variable accompanying symptomatology
including gastroparesis, constipation and for CNS manifestations such as obsessive
behavior and involuntary motion (tic) disorders (AAbs directed toward D1/2R). This
wide spectrum of activity has been documented by both in vivo and in vitro testing.
These effects result from the allosteric consequences of AAb interactions with epitope-specific
sites on the receptor extracellular loops. Some AAbs act as partial agonists (i.e.
AAbs to the alpha1AR in POTS) while others appear as pure agonists (AAbs to B1/2AR
in POTS). This variety of effects demonstrates the complexity for assigning causality
by AAb ELISA studies; and even using activity assays. Proof of causality will depend
on eliminating or markedly suppressing the AAb using highly selective modalities.
In limited testing some AAb generated CV manifestations such as hypertension can be
successfully reversed using AAb-specific decoy peptides.
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© 2015 Published by Elsevier Inc.