Biology: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 α1, α2 or β-adrenergic receptors. α1 couples to Gq, which results in increased intracellular Ca2+ 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 beta1-adrenergic receptors are linked to chronic heart failure.[2] However, it has been proposed that both beta1-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]

References

  1. ↑ Bornholz, Beatrice; Weidtkamp-Peters, Stefanie; Schmitmeier, Stephanie; Seidel, Claus A. M.; Herda, Lars R.; Felix, Stephan B.; Lemoine, Horst; Hescheler, Jürgen et al. (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. 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 et al. (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. 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. et al. (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. PMID 19778674. 
  7. ↑ Yu, Xichun; Patterson, Eugene; Stavrakis, Stavros; Huang, Shijun; Aos, Isabel De; Hamlett, Sean; Cunningham, Madeleine W.; Lazarra, Ralph et al. (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. 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 et al. (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. PMID 22130180. 
  12. ↑ Li, Hongliang; Kem, David C.; Reim, Sean; Khan, Muneer; Vanderlinde-Wood, Megan; Zillner, Caitlin; Collier, Daniel; Liles, Campbell et al. (2012-02-01). "Agonistic Autoantibodies as Vasodilators in Orthostatic Hypotension". Hypertension 59 (2): 402–408. doi:10.1161/HYPERTENSIONAHA.111.184937. ISSN 0194-911X. PMID 22215709. 
  13. ↑ "Chronic fatigue syndrome - Mayo Clinic". http://www.mayoclinic.org/diseases-conditions/chronic-fatigue-syndrome/basics/definition/con-20022009. 
  14. ↑ "Chronic fatigue syndrome - Mayo Clinic". http://www.mayoclinic.org/diseases-conditions/chronic-fatigue-syndrome/basics/definition/con-20022009. 
  15. ↑ Galloway, Allison; Li, Hongliang; Vanderlinde-Wood, Megan; Khan, Muneer; Benbrook, Alexandria; Liles, Campbell; Zillner, Caitlin; Rao, Veitla et al. (2014-12-11). "Activating autoantibodies to the β1/2-adrenergic and M2 muscarinic receptors associate with atrial tachyarrhythmias in patients with hyperthyroidism" (in en). Endocrine 49 (2): 457–463. doi:10.1007/s12020-014-0495-4. ISSN 1355-008X. 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" (in en). Circulation 120 (Suppl 18): S664–S665. doi:10.1161/circ.120.suppl_18.S664-c. ISSN 0009-7322. https://www.ahajournals.org/doi/10.1161/circ.120.suppl_18.S664-c. 
  17. ↑ Stavrakis, Stavros; Yu, Xichun; Patterson, Eugene; Huang, Shijun; Hamlett, Sean R.; Chalmers, Laura; Pappy, Reji; Cunningham, Madeleine W. et al. (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. PMID 19778674. 
  18. ↑ Klein-Weigel, Peter F.; Bimmler, Marion; Hempel, Petra; Schöpp, Sebastian; Dreusicke, Siegrid; Valerius, Jana; Bohlen, Anne; Boehnlein, Joana M. et al. (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". http://www.mayoclinic.org/diseases-conditions/buergers-disease/home/ovc-20179160. 



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