Cardiovascular Antibodies and Orthostatic Hypotension

      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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