Antibodies to the α1-Adrenergic Receptor Cause Vascular Impairments in Rat Brain as Demonstrated by Magnetic Resonance Angiography

Abstract

BackgroundCirculating agonistic autoantibodies acting at G protein-coupled receptors have been associated with numerous sever pathologies in humans. Antibodies directed predominantly against the α1-adrenergig receptor were detected in patients suffering from widespread diseases such as hypertension and type 2 diabetes. Their deleterious action has been demonstrated for peripheral organs. We postulate that antibodies to the α1-adrenergig receptor are relevant pathomolecules in diseases of the central nervous system associated with vascular impairments.Methodology/Principal FindingsUsing a rat model we studied the long-term action of antibodies against the α1-adrenergig receptor either induced by immunization with a receptor peptide or applied by intravenous injection. The vasculature in the rat brains was investigated by time-of-flight magnetic resonance angiography using a 9.4 Tesla small animal MR imaging system. Visual examination of maximum-intensity-projections (MIPs) of brain angiographs revealed the development of vascular defects in antibody- exposed animals between three and eight months of treatment. Relative vascular areas were derived from representative MIP image sections by grayscale analysis and used to form an index of vascular circulation. Animals exposed to the action of α1-adrenergig receptor antibodies showed significantly reduced vascular areas (p<0.05). Calculated index values indicated attenuated blood flow in both antibody-treated cohorts compared to their respective controls reaching with (relative units ± standard error, n = 10) 0.839±0.026 versus 0.919±0.026 statistical significance (p<0.05) for peptide-immunized rats.Conclusion/SignificanceWe present evidence that antibodies to the α1-adrenergig receptor cause cerebrovascular impairments in the rat. Our findings suggest the pathological significance of these antibodies in pathologies of the human central nervous system linked to impairments of brain vasculature such as stroke and dementia.

Cerebral blood volume estimation by ferumoxytol-enhanced steady-state MRI at 9.4 T reveals microvascular impact of α1-adrenergic receptor antibodies

“…Immunohistological analyses confirmed α 1 ‐AR antibody‐induced blood vessel deficiencies. These findings confirm the hypothesis that the α 1 ‐AR antibody has effects reaching beyond previously reported macrovascular impairments in the predominantly extracranial major draining vessels of the rat brain and leads to cerebral microvessel damage throughout the brain. This further underlines the suggested significance of this antibody in brain diseases linked to vasculature impairments, such as dementia.…”

The various faces of autoimmune endocrinopathies: Non-tumoral hypergastrinemia in a patient with lymphocytic colitis and chronic autoimmune gastritis

“…Positive stimulating/agonistic TSH-receptor antibodies are one of the risk factors for developing worsening thyroid eye disease and a drug-like TSH-receptor antagonist inhibits thyrotropin receptor-mediated stimulation of cAMP production in Graves' orbital fibroblasts (Neumann et al, 2012). In analogy, agonistic autoantibodies directed at G protein-coupled receptors such as the TSH-receptor may cause many other (endocrine) disorders including cerebrovascular impairment, stroke, and dementia, as recently shown in a rat model with antibodies against the alpha1-adrenergic receptor (Karczewski et al, 2012). For patients with type 1 (autoimmune) diabetes, a recent proof-of-concept, randomized, controlled clinical trial showed stimulation of the host innate immune response by Bacillus–Calmette–Guerin (BCG) treatment or Epstein Barr virus infection which transiently modified the autoimmunity in these patients (Faustman et al, 2012).…”

Therapeutic Apheresis: Why?

“…More recently, efforts have begun in Alzheimer's patients to giving young blood to older patients and the company Alkahest has designed a randomized, double‐blind, placebo‐controlled, cross‐over trial . Other investigators have identified the presence of specific antibodies, namely alpha 1 adrenergic receptor antibodies (Ab), associated with blood vessel damage in the brain . Grifols International S.A. is working on a trial of therapeutic plasma exchange and therapeutic albumin and immunoglobulin infusion .…”