Adrenergic receptor autoantibodies

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Adrenergic receptor autoantibodies

The adrenergic receptors (or adrenoreceptors) are a class of cell membrane-bound protein receptors throughout the body that are targets of the catecholamines, especially norepinephrine (or noradrenaline) and epinephrine (or adrenaline). The binding to these receptors by catecholamines will generally stimulate the sympathetic nervous system, the arm of the autonomic nervous system responsible for the fight-or-flight response.

Adrenergic receptor autoantibodies are autoantibodies (antibodies directed against a person's own protein) targeting adrenergic receptors.

The mechanism of adrenergic receptors. Adrenaline or noradrenaline are receptor ligands to either a1, a2 or b-adrenergic receptors. a1 couples to Gq, which results in increased intracellular Ca and subsequent smooth muscle contraction. a2, on the other hand, couples to Gi, which causes a decrease in neurotransmitter release, as well as a decrease of cAMP activity resulting in smooth muscle contraction. b receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis. Adrenoceptor-Signal transduktion.PNG
The mechanism of adrenergic receptors. Adrenaline or noradrenaline are receptor ligands to either α1, α2 or β-adrenergic receptors. α1 couples to Gq, which results in increased intracellular Ca and subsequent smooth muscle contraction. α2, on the other hand, couples to Gi, which causes a decrease in neurotransmitter release, as well as a decrease of cAMP activity resulting in smooth muscle contraction. β receptors couple to Gs, and increases intracellular cAMP activity, resulting in e.g. heart muscle contraction, smooth muscle relaxation and glycogenolysis.

The implications of high titers of these circulating antibodies are still being worked out and further investigated. There is compelling evidence that autoimmunity against this class of G protein-coupled receptors results in a variety of pathologies:

Cardiovascular diseases and events:

Circulating autoantibodies to adrenergic receptors have been identified in numerous heart diseases and cardiac symptoms. Laboratory models have revealed a mechanism by which adrenergic autoantibodies accomplish their effects on the cardiovascular system. “Beta1 autoantibodies trigger conformational changes in the receptor, attenuate receptor internalization. The combination of these two properties can result in bimodal effects on receptor activity that are meaningful for basal activity and chronotropic catecholamine responses of human cardiomyocytes.” [1]

Beta-1 adrenergic receptors are the primary receptor of the heart and, therefore, autoantibodies to these receptors have been tied to many different heart diseases.

Autoantibodies to β1-adrenergic receptors are linked to chronic heart failure. [2] However, it has been proposed that both β1-adrenergic receptor polymorphisms and autoantibodies could be working together in the development of chronic heart failure. [3] Cardiomyopathy due to autoimmune dysregulation and production of autoantibodies has been seen in humans and reproduced in animal models. [4] In rabbit models, increased expression of autoantibodies has been directly correlated with induction of atrial fibrillation. [5] [6] In canine models inoculated with adrenergic autoantibodies, it has been shown that beta blockers can negate certain cardiac arrhythmias. [7] Refractory Hypertension associated with autoantibodies to beta1-adrenergic receptors has been documented in diabetic patients. [8]

While the exact pathophysiology of Chagas disease is not completely understood, some models have shown that an overstimulation of the immune system causes production of adrenergic autoantibodies. Current research is trying to determine the exact role of these autoantibodies and whether they correlate with the symptomatology of Chagas disease. [9] [10]

Postural Orthostatic Tachycardia Syndrome

The Heart Rhythm Institute at the University of Oklahoma points to an autoimmune basis in a condition that presents as chronic malfunction of the autonomic nervous system. The work of endocrinology labs have correlated autoantibodies to the beta-adrenergic receptors with postural orthostatic tachycardia syndrome (POTS). [11] [12]

Doctors compare the level of disability seen in POTS to the quality of life experienced in conditions like chronic obstructive pulmonary disease (COPD) or congestive heart failure. With the vast and vague symptomatology, and no previously known etiology, diagnosis and treatment proved elusive and challenging. The identification of these antibodies and the development of better testing provide hope for more targeted therapies and better treatment outcomes.

Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS), a disease characterized by profound fatigue, sleep abnormalities, pain, and other symptoms that are made worse by exertion, is infamous for its confounding etiology. [13] Studies have revealed the specific connection between infection-trigger and disease onset in a cohort of chronic fatigue syndrome patients. These patients showed significantly elevated antibodies to beta2-adrenergic receptors. Future research solidifying this correlation of CFS with autoantibodies to adrenergic receptors would be useful to clinicians tackling this difficult-to-treat condition that affects 200,000 people per year in the US. [14]

Other

Experimental studies observed that activating autoantibodies to the beta1/2-adrenergic and M2 muscarinic receptors are associated with atrial tachyarrhythmias in patients with hyperthyroidism. [15] Additional research into the prevalence of these biomarkers in Grave's disease (grave's hyperthyroidism) showed facilitated triggering of pulmonary veins and atrial fibrillation. [16] [17]

Adrenergic autoantibodies have been linked to Buerger's disease (thromboangiitis obliterans). [18] Buerger's disease is a rare disease in which the arteries and veins in the arms and legs become inflamed, swell and can become blocked with blood clots, also known as thrombi. [19]

Related Research Articles

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Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms (arrhythmia), and to protect the heart from a second heart attack after a first heart attack. They are also widely used to treat high blood pressure, although they are no longer the first choice for initial treatment of most patients.

Atenolol is a beta blocker medication primarily used to treat high blood pressure and heart-associated chest pain. Atenolol, however, does not seem to improve mortality in those with high blood pressure. Other uses include the prevention of migraines and treatment of certain irregular heart beats. It is taken orally or by intravenous injection. It can also be used with other blood pressure medications.

<span class="mw-page-title-main">Metoprolol</span> Medication of the selective β1 receptor blocker type

Metoprolol, sold under the brand name Lopressor among others, is a medication used to treat high blood pressure, chest pain due to poor blood flow to the heart, and a number of conditions involving an abnormally fast heart rate. It is also used to prevent further heart problems after myocardial infarction and to prevent headaches in those with migraines. It is a selective β1 receptor blocker medication. It is taken by mouth or is given intravenously.

<span class="mw-page-title-main">Nadolol</span> Non-selective beta blocker used in the treatment of high blood pressure and chest pain

Nadolol, sold under the brand name Corgard among others, is a medication used to treat high blood pressure, heart pain, atrial fibrillation, and some inherited arrhythmic syndromes. It has also been used to prevent migraine headaches and complications of cirrhosis. It is taken orally.

<span class="mw-page-title-main">Esmolol</span> Class II antiarrhythmic drug

Esmolol, sold under the brand name Brevibloc, is a cardio selective beta1 receptor blocker with rapid onset, a very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilising activity at therapeutic dosages.

<span class="mw-page-title-main">Dobutamine</span> Medication which strengthens heart contractions

Dobutamine is a medication used in the treatment of cardiogenic shock and severe heart failure. It may also be used in certain types of cardiac stress tests. It is given by IV only, as an injection into a vein or intraosseous as a continuous infusion. The amount of medication needs to be adjusted to the desired effect. Onset of effects is generally seen within 2 minutes. It has a half-life of two minutes. This drug is generally only administered short term, although it may be used for longer periods to relieve symptoms of heart failure in patients awaiting heart transplantation.

Tachycardia-induced cardiomyopathy (TIC) is a disease where prolonged tachycardia or arrhythmia causes an impairment of the myocardium, which can result in heart failure. People with TIC may have symptoms associated with heart failure and/or symptoms related to the tachycardia or arrhythmia. Though atrial fibrillation is the most common cause of TIC, several tachycardias and arrhythmias have been associated with the disease.

<span class="mw-page-title-main">Bisoprolol</span> Beta-1 selective adrenenergic blocker medication used to treat cardiovascular diseases

Bisoprolol, sold under the brand name Zebeta among others, is a beta blocker medication used for heart diseases. This includes tachyarrhythmias, high blood pressure, chest pain from not enough blood flow to the heart, and heart failure. It is taken by mouth.

<span class="mw-page-title-main">Penbutolol</span> Chemical compound

Penbutolol is a medication in the class of beta blockers, used in the treatment of high blood pressure. Penbutolol is able to bind to both beta-1 adrenergic receptors and beta-2 adrenergic receptors, thus making it a non-selective β blocker. Penbutolol is a sympathomimetic drug with properties allowing it to act as a partial agonist at β adrenergic receptors.

<span class="mw-page-title-main">Levosalbutamol</span> Chemical compound

Levosalbutamol, also known as levalbuterol, is a short-acting β2 adrenergic receptor agonist used in the treatment of asthma and chronic obstructive pulmonary disease (COPD). Evidence is inconclusive regarding the efficacy of levosalbutamol versus salbutamol or salbutamol-levosalbutamol combinations, though levosalbutamol is believed to have a better safety profile due to its more selective binding to β2 receptors versus β1.

<span class="mw-page-title-main">Beta-1 adrenergic receptor</span> Protein-coding gene in the species Homo sapiens

The beta-1 adrenergic receptor, also known as ADRB1, can refer to either the protein-encoding gene or one of the four adrenergic receptors. It is a G-protein coupled receptor associated with the Gs heterotrimeric G-protein that is expressed predominantly in cardiac tissue. In addition to cardiac tissue, beta-1 adrenergic receptors are also expressed in the cerebral cortex.

<span class="mw-page-title-main">Nebivolol</span> Chemical compound

Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. It is taken by mouth.

<span class="mw-page-title-main">Beta-adrenergic agonist</span> Medications that relax muscles of the airways

Beta adrenergic agonists or beta agonists are medications that relax muscles of the airways, causing widening of the airways and resulting in easier breathing. They are a class of sympathomimetic agents, each acting upon the beta adrenoceptors. In general, pure beta-adrenergic agonists have the opposite function of beta blockers: beta-adrenoreceptor agonist ligands mimic the actions of both epinephrine- and norepinephrine- signaling, in the heart and lungs, and in smooth muscle tissue; epinephrine expresses the higher affinity. The activation of β1, β2 and β3 activates the enzyme, adenylate cyclase. This, in turn, leads to the activation of the secondary messenger cyclic adenosine monophosphate (cAMP); cAMP then activates protein kinase A (PKA) which phosphorylates target proteins, ultimately inducing smooth muscle relaxation and contraction of the cardiac tissue.

Beta1-adrenergic agonists, also known as Beta1-adrenergic receptor agonists, are a class of drugs that bind selectively to the beta-1 adrenergic receptor. As a result, they act more selectively upon the heart. Beta-adrenoceptors typically bind to norepinephrine release by sympathetic adrenergic nerves and to circulating epinephrine. The effect of B-adrenoceptors is cardiac stimulation, such as increased heart rate, heart contractility, heart conduction velocity and heart relaxation.

<span class="mw-page-title-main">Landiolol</span> Chemical compound

Landiolol (INN) is an ultra short-acting, β1-superselective intravenous adrenergic antagonist, which decreases the heart rate effectively with less negative effect on blood pressure or myocardial contractility. In comparison to other beta blockers, landiolol has the shortest elimination half-life, ultra-rapid onset of effect, and predictable effectiveness with inactive metabolites. The pure S-enantiomer structure of landiolol is believed to develop less hypotensive side effects in comparison to other β-blockers. This has a positive impact on the treatment of patients when reduction of heart rate without decrease in arterial blood pressure is desired. Landiolol was developed by modifying the chemical structure of esmolol to produce a compound with a higher rate of cardioselectivity and a greater potency without increasing its duration of action. It is sold as landiolol hydrochloride. Based on its positive benefit risk profile, landiolol has been granted the marketing authorization and introduced to the European markets under the brand names Rapibloc, Raploc, Runrapiq, Landibloc mid 2016. Landiolol is available in Japan under the brand names Onoact (50 mg) and Corbeta.

<span class="mw-page-title-main">Celivarone</span> Experimental drug being tested for use in pharmacological antiarrhythmic therapy

Celivarone is an experimental drug being tested for use in pharmacological antiarrhythmic therapy. Cardiac arrhythmia is any abnormality in the electrical activity of the heart. Arrhythmias range from mild to severe, sometimes causing symptoms like palpitations, dizziness, fainting, and even death. They can manifest as slow (bradycardia) or fast (tachycardia) heart rate, and may have a regular or irregular rhythm.

<span class="mw-page-title-main">Discovery and development of beta-blockers</span>

β adrenergic receptor antagonists were initially developed in the 1960s, for the treatment of angina pectoris but are now also used for hypertension, congestive heart failure and certain arrhythmias. In the 1950s, dichloroisoproterenol (DCI) was discovered to be a β-antagonist that blocked the effects of sympathomimetic amines on bronchodilation, uterine relaxation and heart stimulation. Although DCI had no clinical utility, a change in the compound did provide a clinical candidate, pronethalol, which was introduced in 1962.

<span class="mw-page-title-main">Automatic tachycardia</span> Medical condition

An automatic tachycardia is a cardiac arrhythmia which involves an area of the heart generating an abnormally fast rhythm, sometimes also called enhanced automaticity. These tachycardias, or fast heart rhythms, differ from reentrant tachycardias in which there is an abnormal electrical pathway which gives rise to the pathology. Most automatic tachycardias are supraventricular tachycardias (SVT). It is important to recognize an automatic tachycardia because the treatment will be different to that for a reentrant tachycardia. The most useful clue will be the presence of 'warm up' and 'cool down'. This means that whereas a reentrant tachycardia will both begin and end abruptly as cardiac conduction uses then ceases to use the accessory pathway, an automatic tachycardia will rise and fall gradually in rate as the automatic focus increases and decreases its automatic rate of electrical discharge.

Autonomic drugs can either inhibit or enhance the functions of the parasympathetic and sympathetic nervous systems. This type of drug can be used to treat a wide range of diseases, such as glaucoma, asthma, urinary, gastrointestinal and cardiopulmonary disorders.

<span class="mw-page-title-main">BC-007</span> DNA-based experimental drug

BC-007 is an oligonucleotide aptamer, a synthetic DNA compound designed to bind other chemicals. BC-007 is in early-stage clinical trials as a lead compound intended for the potential treatment of heart failure or long COVID. The international nonproprietary name is rovunaptabin.

References

  1. ↑ Bornholz, Beatrice; Weidtkamp-Peters, Stefanie; Schmitmeier, Stephanie; Seidel, Claus A. M.; Herda, Lars R.; Felix, Stephan B.; Lemoine, Horst; Hescheler, Jürgen; Nguemo, Filomain (2013-03-01). "Impact of human autoantibodies on β1-adrenergic receptor conformation, activity, and internalization". Cardiovascular Research. 97 (3): 472–480. doi:10.1093/cvr/cvs350. ISSN   0008-6363. PMC   3567785 . PMID   23208588.
  2. ↑ Jahns, R.; Boivin, V.; Siegmund, C.; Inselmann, G.; Lohse, M. J.; Boege, F. (1999-02-09). "Autoantibodies activating human beta1-adrenergic receptors are associated with reduced cardiac function in chronic heart failure". Circulation. 99 (5): 649–654. doi: 10.1161/01.CIR.99.5.649 . ISSN   0009-7322. PMID   9950662.
  3. ↑ Bornholz, Beatrice; Hanzen, Birgit; Reinke, Yvonne; Felix, Stephan B.; Boege, Fritz (July 2016). "Impact of common β1-adrenergic receptor polymorphisms on the interaction with agonistic autoantibodies in dilated cardiomyopathy". International Journal of Cardiology. 214: 83–85. doi:10.1016/j.ijcard.2016.03.032. PMID   27057984.
  4. ↑ Yu, Xichun; Patterson, Eugene; Stavrakis, Stavros; Huang, Shijun; De Aos, Isabel; Hamlett, Sean; Cunningham, Madeleine W.; Lazarra, Ralph; Kem, David C. (2009-01-01). "Development of cardiomyopathy and atrial tachyarrhythmias associated with activating autoantibodies to beta-adrenergic and muscarinic receptors". Journal of the American Society of Hypertension. 3 (2): 133–140. doi:10.1016/j.jash.2008.10.004. ISSN   1933-1711. PMC   3116651 . PMID   20409953.
  5. ↑ Li, Hongliang; Murphy, Taylor; Zhang, Ling; Huang, Bing; Veitla, Vineet; Scherlag, Benjamin J.; Kem, David C.; Yu, Xichun (2015-10-30). "β1-Adrenergic and M2 Muscarinic Autoantibodies and Thyroid Hormone Facilitate Induction of Atrial Fibrillation in Male Rabbits". Endocrinology. 157 (1): 16–22. doi: 10.1210/en.2015-1655 . ISSN   0013-7227. PMID   26517045.
  6. ↑ Stavrakis, Stavros; Yu, Xichun; Patterson, Eugene; Huang, Shijun; Hamlett, Sean R.; Chalmers, Laura; Pappy, Reji; Cunningham, Madeleine W.; Morshed, Syed A. (2009-09-29). "Activating autoantibodies to the beta1-adrenergic and M2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism". Journal of the American College of Cardiology. 54 (14): 1309–1316. doi:10.1016/j.jacc.2009.07.015. ISSN   0735-1097. PMC   2801559 . PMID   19778674.
  7. ↑ Yu, Xichun; Patterson, Eugene; Stavrakis, Stavros; Huang, Shijun; Aos, Isabel De; Hamlett, Sean; Cunningham, Madeleine W.; Lazarra, Ralph; Kem, David C. (March 2009). "Development of cardiomyopathy and atrial tachyarrhythmias associated with activating autoantibodies to beta-adrenergic and muscarinic receptors". Journal of the American Society of Hypertension. 3 (2): 133–140. doi:10.1016/j.jash.2008.10.004. PMC   3116651 . PMID   20409953.
  8. ↑ Zhao, Lin-shuang; Liao, Yu-hua; Xiang, Guang-da; Wang, Min; Zhou, Zi-hua; Hou, Jie; Le, Ling; Xu, Lin (2006-05-01). "[Autoantibodies against beta1 and M2 receptor in diabetic patients with refractory hypertension]". Zhonghua Xin Xue Guan Bing Za Zhi. 34 (5): 407–410. ISSN   0253-3758. PMID   16776952.
  9. ↑ Soares, Milena B. P.; Pontes-De-Carvalho, Lain; Ribeiro-Dos-Santos, Ricardo (December 2001). "The pathogenesis of Chagas' disease: when autoimmune and parasite-specific immune responses meet". Anais da Academia Brasileira de Ciências. 73 (4): 547–559. doi: 10.1590/S0001-37652001000400008 . ISSN   0001-3765. PMID   11743602.
  10. ↑ Talvani, Andre; Rocha, Manoel O. C.; Ribeiro, Antonio L.; Borda, Enri; Sterin-Borda, Leonor; Teixeira, Mauro M. (2006-08-01). "Levels of anti-M2 and anti-β1 autoantibodies do not correlate with the degree of heart dysfunction in Chagas' heart disease". Microbes and Infection. 8 (9–10): 2459–2464. doi:10.1016/j.micinf.2006.06.006. PMID   16963301.
  11. ↑ Yu, Xichun; Stavrakis, Stavros; Hill, Michael A.; Huang, Shijun; Reim, Sean; Li, Hongliang; Khan, Muneer; Hamlett, Sean; Cunningham, Madeleine W. (2012-01-01). "Autoantibody Activation of Beta-Adrenergic and Muscarinic Receptors Contributes to an "Autoimmune" Orthostatic Hypotension". Journal of the American Society of Hypertension. 6 (1): 40–47. doi:10.1016/j.jash.2011.10.003. ISSN   1933-1711. PMC   3259269 . PMID   22130180.
  12. ↑ Li, Hongliang; Kem, David C.; Reim, Sean; Khan, Muneer; Vanderlinde-Wood, Megan; Zillner, Caitlin; Collier, Daniel; Liles, Campbell; Hill, Michael A. (2012-02-01). "Agonistic Autoantibodies as Vasodilators in Orthostatic Hypotension". Hypertension. 59 (2): 402–408. doi:10.1161/HYPERTENSIONAHA.111.184937. ISSN   0194-911X. PMC   3275920 . PMID   22215709.
  13. ↑ "Chronic fatigue syndrome - Mayo Clinic". www.mayoclinic.org. Retrieved 2016-09-24.
  14. ↑ "Chronic fatigue syndrome - Mayo Clinic". www.mayoclinic.org. Retrieved 2016-09-24.
  15. ↑ Galloway, Allison; Li, Hongliang; Vanderlinde-Wood, Megan; Khan, Muneer; Benbrook, Alexandria; Liles, Campbell; Zillner, Caitlin; Rao, Veitla; Cunningham, Madeleine W. (2014-12-11). "Activating autoantibodies to the β1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism". Endocrine. 49 (2): 457–463. doi:10.1007/s12020-014-0495-4. ISSN   1355-008X. PMC   5810549 . PMID   25500789.
  16. ↑ Stavrakis, Stavros; Yu, Xichun; Huang, Shijun; Cunningham, Madeleine W.; Kem, David C.; Patterson, Eugene (2009-11-03). "Abstract 2616: Facilitation of Triggered Firing in Superfused Canine Pulmonary Veins by Activating Antibodies to Beta Adrenergic and Muscarinic Receptors in Serum From Patients With Graves' Disease". Circulation. 120 (Suppl 18): S664–S665. doi:10.1161/circ.120.suppl_18.S664-c (inactive 31 January 2024). ISSN   0009-7322.{{cite journal}}: CS1 maint: DOI inactive as of January 2024 (link)
  17. ↑ Stavrakis, Stavros; Yu, Xichun; Patterson, Eugene; Huang, Shijun; Hamlett, Sean R.; Chalmers, Laura; Pappy, Reji; Cunningham, Madeleine W.; Morshed, Syed A. (2009-09-29). "Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism". Journal of the American College of Cardiology. 54 (14): 1309–1316. doi:10.1016/j.jacc.2009.07.015. ISSN   1558-3597. PMC   2801559 . PMID   19778674.
  18. ↑ Klein-Weigel, Peter F.; Bimmler, Marion; Hempel, Petra; Schöpp, Sebastian; Dreusicke, Siegrid; Valerius, Jana; Bohlen, Anne; Boehnlein, Joana M.; Bestler, Daniel (2014-09-01). "G-protein coupled receptor auto-antibodies in thromboangiitis obliterans (Buerger's disease) and their removal by immunoadsorption". VASA. Zeitschrift für Gefässkrankheiten. 43 (5): 347–352. doi:10.1024/0301-1526/a000372. ISSN   0301-1526. PMID   25147011.
  19. ↑ "Overview - Buerger's disease - Mayo Clinic". www.mayoclinic.org. Retrieved 2016-09-24.
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