Identification of antibodies with muscarinic cholinergic activity in human Chagas' disease: pathological implications

doi:10.1016/0165-1838(94)90064-7

Journal of the Autonomic Nervous System

Volume 47, Issues 1–2, April 1994, Pages 45-52

Journal of the Auton...

https://doi.org/10.1016/0165-1838(94)90064-7 Get rights and content

Abstract

We examined the possible role of altered humoral immunity in dysautonomic syndrome in Chagas' disease by analyzing the effect of sera and IgG on the binding of radioligand to heart muscarinic cholinergic receptors and on the contractility of myocardium. Human Chagasic IgG inhibited in a non-competitive manner the binding of [³H]quinuclidinyl benzilate to the cardiac cell membrane. Moreover, human Chagasic IgG behaved as a partial muscarinic cholinergic agonist, reducing heartcontractility and inhibiting the action of pilocarpine. The prevalence of the cholinergic antibody activity was higher in sera from T. cruzi-infected asymptomatic individuals with dysautonomic syndrome than in those without autonomic nervous system alterations. The presence of these antibodies could explain the progressive receptor blockade in the parasympathetic branch of the autonomic nervous system, leading to dysautonomia.

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Cited by (90)

Impairment of agonist-induced M<inf>2</inf> muscarinic receptor activation by autoantibodies from chagasic patients with cardiovascular dysautonomia
2020, Clinical Immunology
Citation Excerpt :
Both frequency and serum reactivity for anti-M2R Ab were higher in DCD patients (n = 15) than in NDCD (n = 15) or control subjects (n = 15), but no statistical differences were found between the two latter groups (Table 1, and Fig. 1A). A strong association between anti-M2R Ab and dysautonomia in chagasic patients was found (Table 1) (p < .0001), in agreement with previous findings [11–13]. In a previous report, anti-M2R Ab from chagasic patients were found to enhance BRET between M2-RLuc and M2R-YFP in live cells, which was interpreted as an enhancement of M2R/M2R interaction [17].
Previous studies showed that circulating autoantibodies against M₂ muscarinic receptors (anti-M₂R Ab) are associated with decreased cardiac parasympathetic modulation in patients with chronic Chagas disease (CD). Here we investigated whether the exposure of M₂R to such antibodies could impair agonist-induced receptor activation, leading to the inhibition of associated signaling pathways. Preincubation of M₂R-expressing HEK 293T cells with serum IgG fractions from chagasic patients with cardiovascular dysautonomia, followed by the addition of carbachol, resulted in the attenuation of agonist-induced G_i protein activation and arrestin-2 recruitment. These effects were not mimicked by the corresponding Fab fractions, suggesting that they occur through receptor crosslinking. IgG autoantibodies did not enhance M₂R/arrestin interaction or promote M₂R internalization, suggesting that their inhibitory effects are not likely a result of short-term receptor regulation. Rather, these immunoglobulins could function as negative allosteric modulators of acetylcholine-mediated responses, thereby contributing to the development of parasympathetic dysfunction in patients with CD.
Molecular mechanisms of cardiac electromechanical remodeling during Chagas disease: Role of TNF and TGF-β
2017, Trends in Cardiovascular Medicine
Chagas disease is caused by the trypanosomatid Trypanosoma cruzi, which chronically causes heart problems in up to 30% of infected patients. Chagas disease was initially restricted to Latin America. However, due to migratory events, this disease may become a serious worldwide health problem. During Chagas disease, many patients die of cardiac arrhythmia despite the apparent benefits of anti-arrhythmic therapy (e.g., amiodarone). Here, we assimilate the cardiac form of Chagas disease to an inflammatory cardiac disease. Evidence from the literature, mostly provided using experimental models, supports this view and argues in favor of new strategies for treating cardiac arrhythmias in Chagas disease by modulating cytokine production and/or action. But the complex nature of myocardial inflammation underlies the need to better understand the molecular mechanisms of the inflammatory response during Chagas disease. Here, particular attention has been paid to tumor necrosis factor alpha (TNF) and transforming growth factor beta (TGF-β) although other cytokines may be involved in the chagasic cardiomyopathy.
Subgroups of Sjögren syndrome patients according to serological profiles
2012, Journal of Autoimmunity
Sjögren Syndrome (SS) is a systemic, autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands. Different clinical associations have been described for each of the diverse autoantibodies found in SS patients. Antibodies directed against the Ro/La ribonucleoprotein complexes have been correlated with younger age, more severe dysfunction of the exocrine glands and a higher prevalence of extraglandular manifestations. Anti-nuclear antibodies and rheumatoid factors have been associated to extraglandular manifestations and an active immunological profile, while cryoglobulins are markers of more severe disease and correlate to lymphoma development and death. Antibodies to cyclic citrullinated peptides are scarce in SS and have been linked in some cases to the development of non-erosive arthritis. Furthermore, the presence of anti-mitochondrial antibodies and anti-smooth muscle antibodies in the sera of primary SS patients is considered indicative of primary biliary cirrhosis and autoimmune hepatitis, respectively. In addition, anti-centromere antibodies have been associated with a clinical phenotype intermediate between primary SS and systemic sclerosis, while antibodies against carbonic anhydrase have been related to renal tubular acidosis. Finally, an association of anti-muscarinic antibodies with cytopenias and a higher disease activity has also been described in primary SS. In conclusion, although not all of the above mentioned antibodies are useful for predicting distinct patient subgroups in SS, knowledge of the clinical associations of the different autoantibody specificities encountered in SS can advance our understanding of the disease and improve patient management.
Enteric Nervous System Structure and Neurochemistry Related to Function and Neuropathology
2012, Physiology of the Gastrointestinal Tract, Two Volume Set
Enteric Nervous System Structure and Neurochemistry Related to Function and Neuropathology
2012, Physiology of the Gastrointestinal Tract
Autoimmunity against the β <inf>2</inf> adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome
2011, Pain
Complex regional pain syndrome (CRPS) is a painful condition affecting one or more extremities of the body, marked by a wide variety of symptoms and signs that are often difficult to manage because the pathophysiology is incompletely understood. Thus, diverse treatments might be ineffective. A recent report revealed the presence of autoantibodies against differentiated autonomic neurons in CRPS patients. However, it remained unclear how the antibodies act in the development of CRPS. We therefore aimed to characterize these antibodies and identify target antigens. Functional properties of affinity-purified immunoglobulin G of control subjects or CRPS patients were assessed using a cardiomyocyte bioassay. Putative corresponding receptors were identified using antagonistic drugs, and synthesized peptide sequences corresponding to segments of these receptors were used to identify the target epitopes. Chinese hamster ovary cells were transfected with putative receptors to ensure observed binding. Further, changes in the intracellular Ca²⁺ concentration induced by agonistic immunoglobulin G were measured using the Ca²⁺-sensitive fluorescent dye fura-2 assay. Herein, we demonstrate the presence of autoantibodies in a subset of CRPS patients with agonistic-like properties on the β₂ adrenergic receptor and/or the muscarinic-2 receptor. We identified these autoantibodies as immunoglobulin G directed against peptide sequences from the second extracellular loop of these receptors. The identification of functionally active autoantibodies in serum samples from CRPS patients supports an autoimmune pathogenesis of CRPS. Thus, our findings contribute to the further understanding of this disease, could help in the diagnosis in future, and encourage new treatment strategies focusing on the immune system.

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Journal of the Autonomic Nervous System

Abstract

References (29)

Chagas' cardiomyopathy: effect of ganglioside treatment in chronic dysautonomic patients

Am. Heart J.

Chagasic IgG modifies the activity of sarcolemmal ATPases through a beta-adrenergic mechanism

Life Sci.

Modification of sarcolemmal enzymes of chagasic IgG and its effect on cardiac contractility

Biochem. Pharmacol.

Chagasic sera alter the effect of ouabain on isolated rat atria

Eur. J. Pharmacol.

Chagasic IgG binds and interacts with cardiac beta adrenoceptor coupled adenylate cyclase system

Int. J. Immunopharmacol.

Elevated cerebroside antibody levels in human visceral and cutaneous leishmaniasis, T. rangeli infection and chronic Chagas disease

Am. J. Trop. Med. Hyg.

A circulating IgG in Chagas' disease which binds to beta adrenoceptor of myocardium and modulates its activity

Clin. exp. Immunol.

Chagasic cardiopathy: demonstration of a serum globulin factor which binds with endocardium and vascular structures

Circulation

Distribution of antibodies against beta-adrenoceptors in the course of huamn T. cruzi infection

L3T4 T cells able to mediate parasite-specific delayed-type hypersensitivity play a role in the pathology of experimental Chagas disease

Eur. J. Immunol.

Pathogenesis of cardiac neuromyopathy in Chagas disease and the role of the autonomic nervous system

J. Auton. Nerv. Syst.

Circulating antibodies to peripheral nerve in American trypanosomiasis

Clin. exp. Immunol.

Pathology and pathological anatomy of Chagas disease

Bol. O.P.S.

Pathogenesis of Chagas disease

Cited by (90)

Impairment of agonist-induced M<inf>2</inf> muscarinic receptor activation by autoantibodies from chagasic patients with cardiovascular dysautonomia

Molecular mechanisms of cardiac electromechanical remodeling during Chagas disease: Role of TNF and TGF-β

Subgroups of Sjögren syndrome patients according to serological profiles

Enteric Nervous System Structure and Neurochemistry Related to Function and Neuropathology

Enteric Nervous System Structure and Neurochemistry Related to Function and Neuropathology

Autoimmunity against the β <inf>2</inf> adrenergic receptor and muscarinic-2 receptor in complex regional pain syndrome

Research paperIdentification of antibodies with muscarinic cholinergic activity in human Chagas' disease: pathological implications

Abstract

Am. Heart J.

Life Sci.

Biochem. Pharmacol.

Eur. J. Pharmacol.

Int. J. Immunopharmacol.

Elevated cerebroside antibody levels in human visceral and cutaneous leishmaniasis, T. rangeli infection and chronic Chagas disease

Am. J. Trop. Med. Hyg.

A circulating IgG in Chagas' disease which binds to beta adrenoceptor of myocardium and modulates its activity

Clin. exp. Immunol.

Chagasic cardiopathy: demonstration of a serum globulin factor which binds with endocardium and vascular structures

Circulation

Distribution of antibodies against beta-adrenoceptors in the course of huamn T. cruzi infection

L3T4 T cells able to mediate parasite-specific delayed-type hypersensitivity play a role in the pathology of experimental Chagas disease

Eur. J. Immunol.

Pathogenesis of cardiac neuromyopathy in Chagas disease and the role of the autonomic nervous system

J. Auton. Nerv. Syst.

Circulating antibodies to peripheral nerve in American trypanosomiasis

Clin. exp. Immunol.

Pathology and pathological anatomy of Chagas disease

Bol. O.P.S.

Pathogenesis of Chagas disease

Research paper
Identification of antibodies with muscarinic cholinergic activity in human Chagas' disease: pathological implications