Implications of a Vasodilatory Human Monoclonal Autoantibody in Postural Hypotension

Li, Hongliang; Zuccolo, Jonathan; Kem, David C.; Zillner, Caitlin; Smith, Kenneth; James, Judith A.; Cunningham, Madeleine W.; Yu, Xichun

doi:10.1074/jbc.m113.477869

Cited by 12 publications

(5 citation statements)

References 40 publications

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“…16, 18 Briefly, arteriolar segments were microdissected from the cremaster muscle of anesthetized rats and cannulated with glass micropipettes. After equilibration and development of steady-state myogenic tone, the arterioles were perifused with rabbit sera.…”

Section: Methodsmentioning

confidence: 99%

AT2R Autoantibodies Block Angiotensin II and AT1R Autoantibody-Induced Vasoconstriction

Liles

Veitla

et al. 2015

Hypertension

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Activating autoantibodies to the angiotensin type 1 receptor (AT1R) are associated with hypertensive disorders. The angiotensin type 2 receptor (AT2R) is known to counter-regulate the actions of AT1R. We investigated whether AT2R autoantibodies produced in immunized rabbits will activate AT2R and suppress the vasopressor responses to angiotensin II (Ang II) and AT1R-activating autoantibodies. Five rabbits immunized with a peptide corresponding to the second extracellular loop of AT2R developed high AT2R antibody titers. Rabbit anti-AT2R sera failed to directly dilate isolated rat cremaster arterioles; however, when co-perfused with Ang II or AT1R-activating autoantibodies, the anti-AT2R sera significantly inhibited their contractile effects. Rabbit anti-AT2R sera recognized a predominant sequence near the N-terminus of the AT2R second extracellular loop. A decoy peptide based on this sequence effectively reversed the opposing effect of the anti-AT2R sera on Ang II-induced contraction of rat cremaster arterioles. A similar blockade of the anti-AT2R sera effect was observed with the AT2R antagonist PD 123319 and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. Rabbit anti-AT2R sera reacted specifically with AT2R. No cross-reactivity with AT1R was observed. Blood pressure did not change in immunized animals. However, the pressor responses to incremental Ang II infusions were blunted in immunized animals. Thirteen subjects with primary aldosteronism demonstrated increased AT2R autoantibody levels compared to normal controls. In conclusion, AT2R autoantibodies produced in immunized rabbits have the ability to activate AT2R and counteract the AT1R-mediated vasoconstriction. These autoantibodies provide useful and selective tools for study of their roles in blood pressure regulation and possible therapeutic intervention.

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Section: Methodsmentioning

confidence: 99%

AT2R Autoantibodies Block Angiotensin II and AT1R Autoantibody-Induced Vasoconstriction

Liles

Veitla

et al. 2015

Hypertension

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“…Only a few studies have focused on β 2 -AAbs. These studies have indicated that one type of human monoclonal β 2 -AAb against the N terminus of the ECL II peptide displays agonist-like functions in vitro 31 . The activation of β 2 -ARs is likely to have beneficial effects for relieving airflow limitations, although the activation of β 2 -ARs in the absence of pro-inflammatory stimuli has been shown to produce increased IL-1β and IL-6 transcripts in macrophage cell lines 10 .…”

Section: Discussionmentioning

confidence: 99%

Increased circulating β2-adrenergic receptor autoantibodies are associated with smoking-related emphysema

Liu

et al. 2017

Sci Rep

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Smoking is a dominant risk factor for chronic obstructive pulmonary disease (COPD) and emphysema, but not every smoker develops emphysema. Immune responses in smokers vary. Some autoantibodies have been shown to contribute to the development of emphysema in smokers. β2-adrenergic receptors (β2-ARs) are important targets in COPD therapy. β2-adrenergic receptor autoantibodies (β2-AAbs), which may directly affect β2-ARs, were shown to be increased in rats with passive-smoking-induced emphysema in our current preliminary studies. Using cigarette-smoke exposure (CS-exposure) and active-immune (via injections of β2-AR second extracellular loop peptides) rat models, we found that CS-exposed rats showed higher serum β2-AAb levels than control rats before alveolar airspaces became enlarged. Active-immune rats showed increased serum β2-AAb levels, and exhibited alveolar airspace destruction. CS-exposed-active-immune treated rats showed more extensive alveolar airspace destruction than rats undergoing CS-exposure alone. In our current clinical studies, we showed that plasma β2-AAb levels were positively correlated with the RV/TLC (residual volume/total lung capacity) ratio (r = 0.455, p < 0.001) and RV%pred (residual volume/residual volume predicted percentage, r = 0.454, p < 0.001) in 50 smokers; smokers with higher plasma β2-AAb levels exhibited worse alveolar airspace destruction. We suggest that increased circulating β2-AAbs are associated with smoking-related emphysema.

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“…Li et al was able to successfully isolate the human monoclonal antibody that stimulates Beta 2 adrenergic receptors in a patient with orthostatic hypotension and tachyarrhythmias. The effects observed included arteriolar vasodilation, suggesting that the isolated monoclonal antibody has a role in potent vasodilation by altering the normal physiological response to orthostasis [38].…”

Section: Adrenergic Receptorsmentioning

confidence: 97%

Autoimmunity in Syndromes of Orthostatic Intolerance: An Updated Review

Pena,

Moustafa,

Mohamed

et al. 2024

JPM

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Orthostatic intolerance is a broad term that represents a spectrum of dysautonomic disorders, including postural orthostatic tachycardia syndrome (POTS) and orthostatic hypotension (OH), as manifestations of severe autonomic failure. While the etiology of orthostatic intolerance has not yet fully been uncovered, it has been associated with multiple underlying pathological processes, including peripheral neuropathy, altered renin–aldosterone levels, hypovolemia, and autoimmune processes. Studies have implicated adrenergic, cholinergic, and angiotensin II type I autoantibodies in the pathogenesis of orthostatic intolerance. Several case series have demonstrated that immunomodulation therapy resulted in favorable outcomes, improving autonomic symptoms in POTS and OH. In this review, we highlight the contemporary literature detailing the association of autoimmunity with POTS and OH.

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Implications of a Vasodilatory Human Monoclonal Autoantibody in Postural Hypotension

Cited by 12 publications

References 40 publications

AT2R Autoantibodies Block Angiotensin II and AT1R Autoantibody-Induced Vasoconstriction

AT2R Autoantibodies Block Angiotensin II and AT1R Autoantibody-Induced Vasoconstriction

Increased circulating β2-adrenergic receptor autoantibodies are associated with smoking-related emphysema

Autoimmunity in Syndromes of Orthostatic Intolerance: An Updated Review

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