Antimuscarinic antibodies in Sjögren's syndrome: Where are we, and where are we going?

Dawson, Luke; Tobin, Andrew B.; Smith, Peter M.; Gordon, Tom P.

doi:10.1002/art.21347

Cited by 114 publications

(83 citation statements)

References 79 publications

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“…The specificity for SS remains uncertain, however, because IgG antibodies with antimuscarinic activity have also been detected in association with scleroderma (42) (for review, see ref. 14). Nevertheless, our data do significantly advance the case for a role of anti-M 3 R antibodies in SS, because they provide the first unequivocal demonstration that anti-M 3 R antibodies interfere with the function of the target tissue, salivary gland acinar cells.…”

Section: Discussionsupporting

confidence: 57%

“…14). There is some evidence of passive transfer of disease following infusion of human SS IgG into mice (8,10).…”

Section: Discussionmentioning

confidence: 99%

“…14), and there are few data that provide direct evidence of a role of anti-M 3 R in salivary gland hypofunction. Early reports showing binding of anti-M 3 R to salivary acinar cell membranes (5) have not been substantiated (4).…”

Section: ؉mentioning

confidence: 99%

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Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells

Dawson

Stanbury

Venn

et al. 2006

Arthritis & Rheumatism

153

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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 M 3 receptors (M 3 R), 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-M 3 R. Methods. Microfluorimetric Ca 2؉ imaging and patch clamp electrophysiologic techniques were used to measure the secretagogue-evoked increase in [Ca 2؉] i and consequent activation of Ca 2؉ -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 [Ca 2؉ ] i in both mouse and human acinar cells by ϳ50%. IgG from control subjects had no effect on the Ca 2؉ signal. Furthermore, the inhibitory action of primary SS patient IgG on the Ca 2؉ signal was acutely reversible. We repeated our observations using rabbit serum containing antibodies raised against the second extracellular loop of M 3 R and found an identical pattern of acutely reversible inhibition. Anti-M 3 R-positive serum had no effect on Ca 2؉-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-M 3 autoantibodies is the subject of further research.

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Section: Discussionsupporting

confidence: 57%

“…14). There is some evidence of passive transfer of disease following infusion of human SS IgG into mice (8,10).…”

Section: Discussionmentioning

confidence: 99%

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Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells

Dawson

Stanbury

Venn

et al. 2006

Arthritis & Rheumatism

153

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“…In the present study, we asked whether the Th17/IL-23 system, involving both of the cytokines IL-23 and IL-17, is important in the development of Sjögren's syndrome (SS), an autoimmune disease characterized primarily by destruction of acinar tissue within the salivary and lacrimal glands (14)(15)(16)(17)(18)(19)(20)(21)(22)(23). Using an animal model of SS, we were able to investigate the temporal appearance of both IL-17-and IL-23-positive cells in the targeted glandular tissues, as well as the correlation between these cell populations and the presence of lymphocytic foci.…”

Section: Conclusion These Results Suggest That the Th17/ Il-23 Systementioning

confidence: 99%

Salivary gland tissue expression of interleukin‐23 and interleukin‐17 in Sjögren's syndrome: Findings in humans and mice

Nguyen

et al. 2008

Arthritis & Rheumatism

264

228

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Objective. Recently, the Th1/Th2 paradigm has been expanded by the discovery of Th17 cells, a subset of CD4؉ memory T cells characterized by their unique ability to secrete interleukin-17 (IL-17) family cytokines. Importantly, Th17 cells appear to be intimately involved in autoimmunity. We undertook the present study to investigate whether the Th17/IL-23 system is up-regulated in Sjögren's syndrome (SS).Methods. Sera, saliva, and salivary glands from C57BL/6.NOD-Aec1Aec2 mice (a model for primary SS), as well as sera, saliva, and salivary gland biopsy specimens obtained from patients with primary SS, were evaluated for IL-17 and IL-23 expression by immunohistochemistry, real-time polymerase chain reaction, and the Luminex system.Results. Immunohistochemical stainings of submandibular glands from C57BL/6.NOD-Aec1Aec2 mice and of salivary gland biopsy specimens from SS patients revealed strong positive staining for both IL-17 and IL-23 within lymphocytic foci and diffuse staining on epithelial tissues. Temporal expression of IL-17 and IL-23 in submandibular glands of C57BL/6.NODAec1Aec2 mice correlated with expression of retinoic acid-related orphan receptor ␥t, the Th17 cell master control gene. While IL-17 could not be detected in saliva from 4-20-week-old C57BL/6.NOD-Aec1Aec2 mice, this cytokine was present in the blood of mice up to age 16 weeks. This contrasted with sera and saliva from SS patients, in which IL-17 and IL-6 were present at varying levels.Conclusion. These results suggest that the Th17/ IL-23 system is up-regulated in C57BL/6.NOD-Aec1Aec2 mice and SS patients at the time of disease. A correlation between up-regulated IL-17/IL-23 expression and specific clinical manifestations of SS has yet to be identified.

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“…Onset of clinical symptoms of SjS is highly dependent on the activity of B lymphocytes, including the well-documented hyperreactivity of B cells, extreme hypergammaglobulinemia, production of numerous autoantibodies, and eventually glandular dysfunction (1,2,(5)(6)(7)(8)(9)(10)(11)(12). One mechanism known to control survival, activation, and proliferation of B cells is through cross-linking of their Ag receptors (BCR) and their coreceptors, especially CD19 and CD21.…”

Section: S Jögren's Syndrome (Sjs)mentioning

confidence: 99%

Development of Sjögren’s Syndrome in Nonobese Diabetic-Derived Autoimmune-Prone C57BL/6.NOD-Aec1Aec2 Mice Is Dependent on Complement Component-3

Nguyen

Kim

Cornelius

et al. 2007

The Journal of Immunology

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The role of complement in the etiology of Sjögren’s syndrome (SjS), a human autoimmune disease manifested primarily by salivary and lacrimal gland dysfunction resulting in dry mouth/dry eye syndrome, remains ill-defined. In the present study, we examined the role of complement component-3 (C3) using a newly constructed C3-gene knockout mouse, C57BL/6.NOD-Aec1Aec2.C3−/−. Inactivation of C3 in the parental C57BL/6.NOD-Aec1Aec2 strain, a model of primary SjS, resulted in a diminished or total absence of both preclinical and clinical manifestations during development and onset of disease, including reduced acinar cell apoptosis, reduced levels of caspase-3, lack of leukocyte infiltration of submandibular glands, reduced synthesis of disease-associated autoantibodies, maintenance of normal glandular architecture, and retention of normal saliva secretion. In addition, C57BL/6-NOD.Aec1Aec2.C3−/− mice did not exhibit increased numbers of marginal zone B cells, a feature of SjS-prone C57BL/6-NOD.Aec1Aec2 mice. Interestingly, C57BL/6-NOD.Aec1Aec2.C3−/− mice retained some early pathological manifestations, including activation of serine kinases with proteolytic activity for parotid secretory protein. This improvement in the clinical manifestations of SjS-like disease in C57BL/6.NOD-Aec1Aec2.C3−/− mice, apparently a direct consequence of C3 deficiency, supports a much more important role for complement in the adaptive autoimmune response than previously recognized, possibly implicating an essential role for innate immunity.

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Antimuscarinic antibodies in Sjögren's syndrome: Where are we, and where are we going?

Cited by 114 publications

References 79 publications

Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells

Antimuscarinic antibodies in primary Sjögren's syndrome reversibly inhibit the mechanism of fluid secretion by human submandibular salivary acinar cells

Salivary gland tissue expression of interleukin‐23 and interleukin‐17 in Sjögren's syndrome: Findings in humans and mice

Development of Sjögren’s Syndrome in Nonobese Diabetic-Derived Autoimmune-Prone C57BL/6.NOD-Aec1Aec2 Mice Is Dependent on Complement Component-3

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