Antimuscarinic antibodies in primary Sjögrens syndrome Reversibly Inhibit Fluid Secretion by Human Submandibular Salivary Acinar Cells

L. Dawson, J. Stanbury, N. Venn, B. Hasdimir, S. Rogers, P. Smith

Research output: Contribution to journalArticle

111 Citations (Scopus)

Abstract

Objective Sjögren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M3 receptors (M3R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M3R. Methods Microfluorimetric Ca2+ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca2+]i and consequent activation of Ca2+-dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity. Results IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca2+]i in both mouse and human acinar cells by ∼50%. IgG from control subjects had no effect on the Ca2+ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca2+ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M3R and found an identical pattern of acutely reversible inhibition. Anti-M3R–positive serum had no effect on Ca2+-dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate. Conclusion These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M3 autoantibodies is the subject of further research.
Original languageEnglish
Pages (from-to)1165-1173
JournalArthritis & Rheumatism
Volume54
Issue number4
DOIs
Publication statusPublished - Apr 2006

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Fluids and Secretions
Muscarinic Antagonists
Acinar Cells
Autoantibodies
Immunoglobulin G
Antibodies
Salivary Glands
Ion Channels
Muscarinic M3 Receptors
Xerostomia
Inositol 1,4,5-Trisphosphate
Carbachol
Patch-Clamp Techniques
Serum
Saliva
Biological Assay
Rabbits
Research

Cite this

Dawson, L. ; Stanbury, J. ; Venn, N. ; Hasdimir, B. ; Rogers, S. ; Smith, P. / Antimuscarinic antibodies in primary Sjögrens syndrome Reversibly Inhibit Fluid Secretion by Human Submandibular Salivary Acinar Cells. In: Arthritis & Rheumatism. 2006 ; Vol. 54, No. 4. pp. 1165-1173.
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title = "Antimuscarinic antibodies in primary Sj{\"o}grens syndrome Reversibly Inhibit Fluid Secretion by Human Submandibular Salivary Acinar Cells",
abstract = "Objective Sj{\"o}gren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M3 receptors (M3R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M3R. Methods Microfluorimetric Ca2+ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca2+]i and consequent activation of Ca2+-dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity. Results IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca2+]i in both mouse and human acinar cells by ∼50{\%}. IgG from control subjects had no effect on the Ca2+ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca2+ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M3R and found an identical pattern of acutely reversible inhibition. Anti-M3R–positive serum had no effect on Ca2+-dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate. Conclusion These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M3 autoantibodies is the subject of further research.",
author = "L. Dawson and J. Stanbury and N. Venn and B. Hasdimir and S. Rogers and P. Smith",
year = "2006",
month = "4",
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Antimuscarinic antibodies in primary Sjögrens syndrome Reversibly Inhibit Fluid Secretion by Human Submandibular Salivary Acinar Cells. / Dawson, L.; Stanbury, J.; Venn, N.; Hasdimir, B.; Rogers, S.; Smith, P.

In: Arthritis & Rheumatism, Vol. 54, No. 4, 04.2006, p. 1165-1173.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Antimuscarinic antibodies in primary Sjögrens syndrome Reversibly Inhibit Fluid Secretion by Human Submandibular Salivary Acinar Cells

AU - Dawson, L.

AU - Stanbury, J.

AU - Venn, N.

AU - Hasdimir, B.

AU - Rogers, S.

AU - Smith, P.

PY - 2006/4

Y1 - 2006/4

N2 - Objective Sjögren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M3 receptors (M3R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M3R. Methods Microfluorimetric Ca2+ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca2+]i and consequent activation of Ca2+-dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity. Results IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca2+]i in both mouse and human acinar cells by ∼50%. IgG from control subjects had no effect on the Ca2+ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca2+ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M3R and found an identical pattern of acutely reversible inhibition. Anti-M3R–positive serum had no effect on Ca2+-dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate. Conclusion These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M3 autoantibodies is the subject of further research.

AB - Objective Sjögren's syndrome (SS) is an autoimmune condition affecting salivary glands, for which a clearly defined pathogenic autoantibody has yet to be identified. Autoantibodies that bind to the muscarinic M3 receptors (M3R), which regulate fluid secretion in salivary glands, have been proposed in this context. However, there are no previous data that directly show antisecretory activity. This study was undertaken to investigate and characterize the antisecretory activity of anti-M3R. Methods Microfluorimetric Ca2+ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca2+]i and consequent activation of Ca2+-dependent ion channels in individual mouse and human submandibular acinar cells. Together, these techniques form a sensitive bioassay that was used to determine whether IgG isolated from patients with primary SS and from control subjects has antisecretory activity. Results IgG (2 mg/ml) from patients with primary SS reduced the carbachol-evoked increase in [Ca2+]i in both mouse and human acinar cells by ∼50%. IgG from control subjects had no effect on the Ca2+ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca2+ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M3R and found an identical pattern of acutely reversible inhibition. Anti-M3R–positive serum had no effect on Ca2+-dependent ion channel activation evoked by the direct intracellular infusion of inositol 1,4,5-triphosphate. Conclusion These observations show for the first time that IgG from patients with primary SS contains autoantibodies capable of damaging saliva production and contributing to xerostomia. The unusual but not unprecedented acute reversibility of the effects of anti-M3 autoantibodies is the subject of further research.

U2 - 10.1002/art.21764

DO - 10.1002/art.21764

M3 - Article

VL - 54

SP - 1165

EP - 1173

JO - Arthritis and Rheumatology

JF - Arthritis and Rheumatology

SN - 2326-5191

IS - 4

ER -