Interaction of human chagasic IgG with the second extracellular loop of the human heart muscarinic acetylcholine receptor: functional and pathological implications

Goin, Juan Carlos; Leirós, Claudia Pérez; Borda, Enri; Sterin‐Borda, Leonor

doi:10.1096/fasebj.11.1.9034169

Cited by 90 publications

(84 citation statements)

References 2 publications

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“…Specific antipeptide autoantibodies were then eluted with 3 M KSCN, 1 M NaCl, followed by immediate extensive dialysis against PBS. The IgG concentration of both nonantipeptide Abs and specific antimuscarinic receptor peptide Abs were determined by radial immunodiffusion assay, and their immunological reactivity against the muscarinic receptor peptide was evaluated by ELISA (30).…”

Section: Purification Of Antipeptide Abs By Affinity Chromatographymentioning

confidence: 99%

See 1 more Smart Citation

Antibodies Against Cerebral M1 Cholinergic Muscarinic Receptor from Schizophrenic Patients: Molecular Interaction

Borda

Rivera

Joensen³

et al. 2002

The Journal of Immunology

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We demonstrated the presence of circulating Abs from schizophrenic patients able to interact with cerebral frontal cortex-activating muscarinic acetylcholine receptors (mAChR). Sera and purified IgG from 21 paranoid schizophrenic and 25 age-matched normal subjects were studied by indirect immunofluorescence, flow cytometry, immunoblotting, dot blot, ELISA, and radioligand competition assays. Rat cerebral frontal cortex membranes and/or a synthetic peptide, with an amino acid sequence identical with that of human M1 mAChR, were used as Ags. By indirect immunofluorescence and flow cytometry procedures, we proved that serum-purified IgG fraction from schizophrenic patients reacted to neural cell surfaces from rat cerebral frontal cortex. The same Abs were able to inhibit the binding of the specific M1 mAChR radioligand [3H]pirenzepine. Immunoblotting experiments showed that IgG from schizophrenic patients revealed a band with a molecular mass coincident to that labeled by an anti-M1 mAChR Ab. Using synthetic peptide for dot blot and ELISA, we demonstrated that these Abs reacted against the second extracellular loop of human cerebral M1 mAChR. Also, the corresponding affinity-purified antipeptide Ab displayed an agonistic-like activity associated to specific receptor activation, increasing cyclic GMP production and inositol phosphate accumulation, and protein kinase C translocation. This paper gave support to the participation of an autoimmune process in schizophrenia.

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Section: Purification Of Antipeptide Abs By Affinity Chromatographymentioning

confidence: 99%

“…Rat cerebral frontal cortex membranes were subjected to electrophoresis on 8.5% SDS-polyacrylamide gel as previously described (30). Proteins were transferred to nitrocellulose sheets and revealed with different IgG from schizophrenic or normal individuals.…”

Section: Immunoblotting Assaymentioning

confidence: 99%

Antibodies Against Cerebral M1 Cholinergic Muscarinic Receptor from Schizophrenic Patients: Molecular Interaction

Borda

Rivera

Joensen³

et al. 2002

The Journal of Immunology

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“…The findings of these clinical investigations have been conflicting and controversial. Nonetheless, parasympathetic effects on heart rate are currently considered, by most investigators, as being impaired by cardiac muscarinic auto-antibodies 14,[21][22][23]42,43 . We have postulated, on the contrary, that parasympathetic activity is enhanced by the allosteric effects of the muscarinic cardiac auto-antibodies 11,12 .…”

Section: Discussionmentioning

confidence: 99%

Muscarinic antibodies and heart rate responses to dynamic exercise and to the Valsalva maneuver in chronic chagasic patients

Neves¹,

Bacilio²,

Berrueta

et al. 2013

Rev. Inst. Med. trop. S. Paulo

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SUMMARYWe have studied the cardiac chronotropic responses to the Valsalva maneuver and to dynamic exercise of twenty chronic chagasic patients with normal left ventricular function and no segmental wall abnormalities by two-dimensional echocardiogram. The absolute increase in heart rate of the patients (∆ = 21.5 ± 10 bpm, M±SD) during the maneuver was significantly diminished when compared to controls (∆ = 31.30 ± 70, M±SD, p = 0.03). The minimum heart rate (58.24 ± 8.90 vs. 62.80 ± 10, p = 0.68) and the absolute decrease in heart rate at the end of the maneuver (∆ = 38.30 ± 13 vs. ∆ = 31.47 ± 17, p = 0.10) were not different from controls. The initial heart rate acceleration during dynamic exercise (∆ = 12 ± 7.55 vs. ∆ = 19 ± 7.27, M±SD, p = 0.01) was also diminished, but the heart rate recovery during the first ten seconds was more prominent in the sero-positive patients (Median: 14, Interquartile range: (9.75-17.50 vs. 5(0-8.75, p = 0.001). The serum levels of muscarinic cardiac auto-antibodies were significantly higher in the chagasic patients (Median: 34.58, Interquartile Range: 17-46.5, Optical Density) than in controls (Median: 0, Interquartile Range: 0-22.25, p = 0.001) and correlated significantly and directly (r = 0.68, p = 0.002) with early heart rate recovery during dynamic exercise. The results of this investigation indirectly suggest that, the cardiac muscarinic auto-antibodies may have positive agonist effects on parasympathetic heart rate control of chagasic patients.

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“…In oesophageal and colonic muscle preparations, IgG produced concentration-dependent increases in basal tone which were sensitive to M 2 mAChR antagonism (Goin et al 1999;Sterin-Borda et al 2001). It also acted as a partial agonist, mimicking the effect of the muscarinic agonists carbachol and pilocarpine in a non-competitive manner Goin et al 1997). Radioligand binding assays investigating the interaction of chagasic IgG with the muscarinic receptor indicated chagasic IgG acts as an allosteric antagonist of the muscarinic receptor.…”

Section: Modulation Of Antigen Expression and / Or Functional Effectsmentioning

confidence: 99%

“…To help answer the question of whether the present cohort have autoantibodies which activate muscarinic pathways without binding receptors directly or have another mechanism of action, we proceeded to investigate the functional effects of the sera from our cohort on GI smooth muscle. cholinergic signalling pathway with subsequent end organ effects Goin et al 1997;Sterin-Borda et al 1997;Hernandez et al 2008;Ganzinelli et al 2009) including an increase in GI smooth muscle tone (Goin et al 1999;SterinBorda et al 2001). It should be noted that the majority of these studies originate from a single research group, and all studies have used the same ELISA to detect anti-M 2 mAChR autoantibodies.…”

Section: Significance and Interpretationsmentioning

confidence: 99%

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

Hubball

Martin

Lang

et al. 2009

Progress in Neurobiology

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Dysfunction of the gastrointestinal neuromuscular apparatus (including interstitial cells ofCajal) is presumed to underlie a heterogeneous group of disorders collectively termed gastrointestinal neuromuscular diseases (GINMDs). Humoral (antibody)-mediated autoimmunity directed against ligand-or voltage-gated ion channels or associated proteins involved in neuromuscular transmission is associated with several acquired neuromuscular diseases of the periphery and is now implicated in an increasing number of less well-characterised diseases. Anti-channel antibodies have been reported in small numbers of patients with GINMD, particularly in those with GI dysfunction secondary to an underlying disease such as neoplasia or infection. However, little is known of humoral autoimmunity in primary GINMDs.This thesis investigated the association between anti-channel antibodies and GINMD, and the human GI tract as a potential target of anti-channel antibodies. The presence of antivoltage-and ligand-gated antibodies was investigated in the serum of patients with primary achalasia, enteric dysmotility and intestinal pseudo-obstruction, and in those with GINMD secondary to Chagas' disease. The functional effect of sera from some of these patients on colonic smooth muscle contractility was also characterised. Finally, the distribution of six voltage-gated potassium channels (VGKCs), which serve essential roles in the peripheral and central nervous systems and are known targets of pathological autoantibodies, were investigated in all layers of the human GI tract.Our findings suggest that currently recognised anti-channel antibodies are not a common pathogenic factor in primary GINMDs. Anti-channel antibodies, in particular anti-VGKC antibodies, were however found in a significant number of individuals with Chagas' disease. Furthermore, circulating factors in patients with chagasic GI disease altered GI smooth muscle contractility in vitro which may have pathological relevance to GI

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Interaction of human chagasic IgG with the second extracellular loop of the human heart muscarinic acetylcholine receptor: functional and pathological implications

Cited by 90 publications

References 2 publications

Antibodies Against Cerebral M1 Cholinergic Muscarinic Receptor from Schizophrenic Patients: Molecular Interaction

Antibodies Against Cerebral M1 Cholinergic Muscarinic Receptor from Schizophrenic Patients: Molecular Interaction

Muscarinic antibodies and heart rate responses to dynamic exercise and to the Valsalva maneuver in chronic chagasic patients

The role of humoral autoimmunity in gastrointestinal neuromuscular diseases

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