The role of autoantibodies in the syndromes of orthostatic intolerance: a systematic review

Abstract

Orthostatic intolerance is defined as the provocation of symptoms upon standing, commonly caused by neurogenic orthostatic hypotension (OH) and postural tachycardia syndrome (POTS), the etiology for which has not been fully uncovered yet. Many reports have described the occurrence of dysautonomia, orthostatic intolerance and POTS following febrile illness, presumably viral and post-vaccine. Furthermore, patients with dysautonomia have higher rates of autoimmune disorders such as Hashimoto thyroiditis and SLE. Recent evidence has shown the presence of adrenergic and cholinergic receptor antibodies in patients with POTS and orthostatic hypotension. In patients with cholinergic receptor antibodies, higher titers correlate with the disease severity. Few reports have shown that immunomodulation therapy resulted in significant improvement in symptoms. In this article, we review the available literature correlating autoimmunity with orthostatic intolerance syndromes. Future studies are warranted to evaluate the prevalence of such antibodies and examine different treatment modalities in this sub group of patients.

Keywords:

• Adrenergic antibodies
• cholinergic antibodies
• autonomic dysregulation
• POTS

Introduction

Orthostatic intolerance is defined as the provocation of symptoms upon standing, commonly caused by orthostatic hypotension (OH) and postural tachycardia syndrome (POTS). Orthostatic hypotension is further subdivide into neurogenic (for example, in patients who have other neurological manifestations such as autonomic failure, multiple system atrophy or parkinsonism) or non-neurogenic (for example, in patients taking blood pressure lowering medications, or in cases of hypovolemia) [1]. Low effective circulating volume in the central vasculature caused by excess blood pooling is believed to cause these symptoms. Most patients complain of fatigue, inability to concentrate, lightheadedness and in its most severe forms, syncope can follow [2]. In patients with autonomic failure and POTS, etiology has long remained unclear. Evidence has emerged in recent years that a subset of these patients has an autoimmune etiology.

It has been observed that many patients develop orthostatic hypotension or POTS after experiencing a febrile illness, presumably viral. This led to developing the hypothesis of an autoimmune-mediated cause of orthostatic intolerance [2,3]. Other supportive reports demonstrate numerous cases of orthostatic intolerance following immune triggers like vaccines [4,5] or exposure of hidden antigens following cardiac ablation [6]. Furthermore, successful treatment of orthostatic hypotension related acute dysautonomia with intravenous immunoglobulin have been reported [7,8].

In addition, POTS is present in higher frequency in patients with other autoimmune disorders such as multiple sclerosis [9]. In 2015, Blitshteyn reported autoimmune disorders (such as Hashimoto thyroiditis, SLE and celiac disease) in 20% of patients with POTS [10].

These observations have led investigators to seek for autoantibodies that might play a role in the pathogenesis of orthostatic intolerance. The first was identified in 2000, when Vernino et al; found ganglionic-receptor–binding antibodies in 50% of patients with idiopathic autonomic neuropathy, 7% of patients with POTS and none in healthy controls. Higher levels of antibodies were correlated with disease severity [11]. A similar group of ganglionic antibodies were reported by the Mayo Clinic group in 2007 and 2009 in an even greater percent of their patient population [12,13]. Most recently, Cutsforth-Gregory et al revealed ganglionic nicotinic acetylcholine receptor antibodies in patients with orthostatic hypotension and autonomic dysfunction with higher titers present in patients with more severe symptoms [14]. One out of seven patients had increased M3R activity [3]. Six patients had increased autoantibodies against M2/3 [15].

In this article, we have reviewed the available literature correlating autoimmunity with orthostatic intolerance syndromes. A computerized search in the PubMed, Medline and Embase database was performed to retrieve studies with data on orthostatic intolerance and autoantibodies. Subsequently, a manual search of the reference lists from the retrieved articles was done to identify additional articles.

Adrenergic antibodies

The adrenergic receptors for adrenaline and noradrenaline belong to the large multi-genic family of receptors coupled to GTP-binding proteins [16], the α adrenergic and β adrenergic receptor families further subdivided into α1AR, α2AR, β1AR, β2AR and β3AR.

Table 1 [17–21] summarizes the main cardiovascular effects of these receptors. α2AR exhibits uniquely effect on blood pressure through three subtypes; α2A α2B and α2C [20,21]. β3AR is primarily expressed in adipose tissue and is thought to play a role in the regulation of thermogenesis and lipolysis [17]. Its role on cardiovascular function has not been fully clarified yet [22]. However, it is believed that unlike β1AR and β2AR, it has negative ionotropic effect on the heart [23].

Table 1. Alpha and beta adrenergic receptors and their main physiological effects.

Receptor	Location	Physiological activity upon stimulation
α1A	Blood vessels mainly skin and GI tract	Smooth muscle contraction leading to vasoconstriction
α2A	Brain, presynaptic sympathetic nerves	Decrease blood pressure and lower plasma norepinephrine
α2B	Kidney	Water retention and vasoconstriction
α2C	Skin vasculature	Cold induced vasoconstriction
β1AR	Heart	Increase heart rate and stroke volume
	Juxtaglomerular cells of the kidney	Increase renin release causing fluid retention and water restriction
β2AR	Heart	Increase heart rate and stroke volume
	Blood vessels mainly skeletal muscles	Smooth muscle relaxation leading to vasodilation

Table 2, demonstrates the available evidence of adrenergic antibodies in patients with orthostatic intolerance syndromes. In 2012, Yu et al; used enzyme-linked immunosorbent assay (ELISA) to identify autoantibodies against beta-adrenergic receptors (βAR) in five out of six patients with orthostatic intolerance. These auto-antibodies were able to activate protein kinase A (PKA), demonstrated contractile activity measured by the canine Purkinje fibers and were also able to cause dose dependent vasodilatory effect on rat cremaster arteriolar diameter, supporting their role in βAR function and orthostatic hypotension [15]. Shortly after, the same group used ELISA to demonstrate autoantibodies against β2AR in three out of ten patients with idiopathic orthostatic intolerance and four out of ten patients with diabetes and orthostatic intolerance. Again, these autoantibodies showed dose dependent activity using cAMP Hunter assay and also dose dependent vasodilatation of rat cremaster arteriolar assay, not seen when IgG was taken from healthy controls [24]. In both studies the physiologist effect of activating antibodies was inhibited by the use of nonselective β-blocker; propranolol.

Table 2. Adrenergic antibodies in patients with orthostatic hypotension and POTS.

Author	Year	Group of patients tested	Receptor associated Autoantibodies	No. of patients with positive antibody/No. Of total patients, No. of controls with positive antibodies/No. of total control
Yu et al [15]	2012	Idiopathic OH	(β1/2AR)	5/6, 0/10
Li et al [24]	2012	10 idiopathic OH and 10diabetics with OH	β2AR	7/20, 0/10
Li et al [3]	2014	POTS	β1AR	14/14, 0/10
		POTS	β2AR	7/14, 0/10
		POTS	α1AR	14/14, 0/10
Fedorowski [25]	2016	POTS	α1AR	8/17, 0/11
		POTS	β1AR	11/17, 0/11
		POTS	β2AR	12/17, 0/11

In 2014, Li et al, reported β2AR autoantibodies in seven out of 14 patients with POTS and β1AR in all fourteen patients using cAMP assays with dose dependent activation effect. α1AR autoantibodies were also present in all the fourteen patients causing decrease in cremaster artery diameter that was blocked with prazosin [3].

In 2016, Fedorowski reported that 8, 11, and 12 of 17 POTS patients possessed autoantibodies that activated α1AR, β1AR and β2AR, respectively. Pharmacological blockade suppressed IgG-induced activation of α1AR and β1/2AR. 8 out of the 17 patients had IgG that decreased the α1AR responsiveness to phenylephrine and 13 of them had IgG that increased the β1AR responsiveness to isoproterenol irrespective of their ability to directly activate their receptors. IgG contracted rat cremaster arteriole, which was reversed by α1AR blockade [25].

Cholinergic antibodies

Cholinergic receptors mediate the action of acetylcholine and broadly categorized into muscarinic (mAChR) and nicotinic (nAChR).

Nicotinic receptors are located post-synaptically in all autonomic ganglia and at the neuro-muscular junction. At these junctions, it functions as an excitatory receptor for the postsynaptic cells. Its function includes the release of catecholamines from the adrenal medulla, ganglionic transmission, and transmission of the somatic neuromuscular junction (NMJ). AChRs on autonomic neurons are typically composed of two α3 subunits in combination with three other AChR subunits. Autoimmune dysautonomia caused by nicotinic ganglionic acetylcholine receptors autoantibody (α3-AChR Ab) have different manifestations [11,26,27].

Muscarinic receptors are divided into three main subtypes, M1, M2 and M3. M1 receptors are mainly involved in CNS transmission. On the other hand, M2 and M3 act mainly peripherally on exocrine function, gastrointestinal motility, cardiovascular system and on the airways inducing bronchoconstriction. In the blood vessels, muscarinic receptors are present on the endothelial cells, although these muscarinic receptors are not innervated by cholinergic nerve fibers, they are sensitive to circulating molecules causing vasodilation upon activation. In the heart, these receptors, upon activation, act to decrease heart rate and slow AV conduction.

Table 3 summarizes the main studies that examined the role of cholinergic receptor antibodies in patients with dysautonomia, orthostatic hypotension and POTS.

Table 3. Cholinergic antibodies in patients with dysautonomia.

Author	Year	Receptor	Patient’s population	No. of patients with positive antibody/No. Of total patients, No. of controls with positive antibodies/No. of total control	Comments
Vernino [11]	2000	α3-AChR Ab	POTS	6/67, N/A
Sandroni [28]	2004	ganglionic AChR	Orthostatic intolerance, autonomic neuropathy	Compared 19 seropositive with 87 seronegative patients	Seropositive patients are more likely to have orthostatic hypotension with other cholinergic symptoms like sicca complex or GI symptoms.
Gibbons [42]	2008	AChR	Autoimmune autonomic ganglionopathy	3/3, N/A	Three patients with dysautonomia and nicotine receptor antibody refractory to medical treatment who responded to immunomodulatory therapy
Mckeon [13]	2009	α3-AChR Ab	Paraneoplastic neurological autoimmunity	155/15,000 (1%) with positive titers were examined. 13 had pandysautonomia, 5 had orthostatic hypotension only.	High antibody values ≥1.00 nmol/L, were associated with pandysautonomia
Gibbons [29]	2009	AChR	Autoimmune autonomic ganglionopathy	8/8, N/A	Higher antibody titers were associated with more severe orthostatic hypotension
Yu [15]	2012	M2/M3 receptor Ab	Idiopathic OH	6/6, 0/10	Serum from patients caused dose-dependent vasodilation in rat cremaster arteriole.
Li [24]	2012	M3R	10 idiopathic OH and 10 diabetics with OH	13/20, 0/10	Serum from patients caused vasodilation in rat cremaster arteriole. Their effect was dose-dependent and inhibited by adding atropine

Vernino et al tested 157 patients with various types of dysautonomia and found nicotine receptor antibodies to be positive in six out of 67 patients with postural tachycardia syndrome [11].

Sandroni et al, compared clinical profiles of patients with orthostatic intolerance and seropositive (n = 19) or seronegative (n = 87) ganglionic AChR antibodies. In this study, patients with orthostatic hypotension and prominent cholinergic dysautonomia such as sicca complex, gastrointestinal symptoms, neurogenic bladder, were more likely to be seropositive for ganglionic AChR antibody [28].

Mckeon et at reviewed 155 patients with positive nicotine cholinergic receptor antibodies. 13 patients had pandysautonomia and 5 patients had orthostatic hypotension only. Higher titers were more likely to be associated with pandysautonomia [13]. Patients generally developed profound pandysautonomia with high α3-AChR Ab values (>1.0 nmol/L).

In 2009, Gibbons and Freeman, reported nicotinic acetylcholine receptor antibodies in 8 patients with higher titers correlated with disease activity [29].

In 2012, Yu et al and Li et al; identified a group of in vitro antibodies capable of activating muscarinic M2/3 receptors [15,24]. Unlike other receptor agonists, these antibodies did not lead to desensitization of their receptor with continuous exposure [24]. These autoantibodies, when added to rat cremaster arteriole assay, caused dose dependent vasodilation that was inhibited with atropine, indicating their role in the complex pathophysiology of orthostatic hypotension [24].

Aadditional antibodies

An additional set of autoantibodies were revealed by Wang et al in 2012. These antibodies were IgGs that interacted with many cardiac proteins such as mimecan, myozenin, periostin, desmin, desmoplakin, and laminin, and subsequently altered their function. They were present in a higher frequency in patients with POTS [30].

Discussion

The available literature supports the hypothesis that autoimmunity, mainly adrenergic and cholinergic autoantibodies may play a major role in the pathogenesis of orthostatic intolerance syndromes. These circulating antibodies were found in a subset of patients with orthostatic hypotension and POTS and exert different changes in the cardiovascular system including tachycardia and vasodilatation.

The control of blood pressure and heart rate is multifactorial and requires integration of multiple organs coordinated by the autonomic system. The displacement of blood caused by gravity upon standing triggers rapid vasoconstriction and an increase in cardiac output that prevents a decline in blood pressure in order to maintain blood flow to vital organs, mainly the brain. This pathophysiological response is altered in patients with orthostatic intolerance partly due autoantibodies as previously explained.

The interaction of autoantibodies and their target receptor is complex and the change in receptor activity and its second messenger is not consistent across patients. Recently, authors have demonstrated how autoantibodies can cause vasodilatation and tachycardia responsible for the symptoms in patients with orthostatic intolerance [3,15,24]. However, it has long been established that similar adrenergic and muscarinic antibodies can lead to dilated cardiomyopathy and tachyarrhythmia [31–35] or more unexpectedly, resistant hypertension [36,37].

The presence of multiple autoantibodies in patients with orthostatic intolerance is consistent with the pattern found in other autoimmune disorders. For example, numerous antibodies can be detected in patients with SLE years before the onset of the disease. In addition, patients with different antibodies have diverse but predictable disease courses with organ involvement dependent on which antibodies are present [38,39]. In patients with orthostatic hypotension, the presence of other cholinergic symptoms was shown to be associated with higher rates of positive cholinergic antibody titers [28].

So far, no controlled trials have examined the treatment modalities in such patients and only few case reports exist [40,41]. Gibbons et al, reported three patients with nicotinic acetylcholine receptor and refractory symptoms of syncope and orthostatic intolerance despite conventional medical therapy who responded to immunomodulatory therapy [42].

These autoantibodies do not explain the complex pathophysiology of orthostatic intolerance syndromes. Nonetheless, their cardiovascular effects improve our insight of the disease and provide a new hope for both patients and physicians for a better understanding of the disease and consequently targets for pharmacological therapy. These discoveries warrant further research to investigate whether the symptoms of orthostatic intolerance and response to treatment correlate with the type of autoantibodies present in each patient. For instance, it would be useful to know if patients with ganglionic receptor antibodies experience more muscle weakness that may be treated with Pyridostigmine compared to their counterparts without these antibodies, and whether patients with β1/β2-adrenergic receptors antibodies demonstrate more tachycardia responsive to Beta-blockers.

Conclusion

This review summarizes the available evidence correlating orthostatic intolerance syndromes with autoimmunity. While large controlled studies are lacking, the results among current reports have been consistent. Adrenergic and cholinergic receptor antibodies were found in higher proportions in patients with orthostatic intolerance compared with controls. With their cardiovascular effects, these antibodies explain some of the complex pathophysiology of orthostatic intolerance. Case reports and small series have suggested immunomodulation as a potential treatment strategy for severe cases unresponsive to conventional therapy. Further larger scale studies are warranted in this field.

Disclosure

No potential conflict of interest was reported by the author(s).