Impaired microvascular response to cholinergic stimuli in primary Sjogren's syndrome

Kovács, László; Török, Tamás L.; Bari, Ferenc; Kéri, Zsuzsanna; Kovács, Attila; Morava, Éva; Pokorny, G.

doi:10.1136/ard.59.1.48

Cited by 45 publications

(30 citation statements)

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“…In the SS-I patients, the chronic presence of inflammation caused by the lymphocytic infiltration of the lachrymal gland reduces tear secretion and corneal sensitivity, 31 as also found by others 32 and supported by morphological findings. 33 A reduced tear secretion, consequent to reduced corneal sensitivity, could also be in relation with an impairment in the parasympathetic control of lachrymal gland, as demonstrated in other exocrine gland, 34,35 as a consequence of the presence of anti M3 muscarinic receptors 36 independently from the concurrent presence of anti-SSA and anti-SSB, 37 as it has been demonstrated in an animal model. 38 A reduced tear clearance rate results in accumulation of corneal metabolism products, including the inflammatory cytokines present in the tear fluid of SS-I patients 39,40 maintaining the ocular surface inflammation within a vicious circle.…”

Section: Eyementioning

confidence: 90%

Diagnostic performance of tear function tests in Sjogren's syndrome patients

Versura

Frigato

Cellini

et al. 2006

Eye

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Objective To evaluate the diagnostic performance of the tests included in primary Sjogren's syndrome (SS-I) diagnostic criteria (Schirmer I, break-up time, vital dye staining) and to compare them with other examinations related to the ocular surface status. Methods Clinical and cytological data were collected from 177 patients (62 SS-1, 56 non-SS autoimmune diseases, 59 Sicca syndrome). Tear tests included: a validated questionnaire on symptoms, Schirmer I, Jones test, Ferning test, BUT, corneal aesthesiometry, tear clearance test, lissamine green staining, impression conjunctival cytology. Data were statistically evaluated and sensitivity, specificity, likelihood ratio (LR þ ), receiveroperating characteristics (ROC) curves were calculated for each test. Results Data showed a poor diagnostic performance of Schirmer test I (sensitivity 0.42; specificity 0.76; LR þ 1.75) and BUT (sensitivity 0.92; specificity 0.17; LR þ 1.11) (area under the curve in ROC analysis o0.58). Validated subjective symptoms questionnaire (sensitivity 0.89; specificity 0.72; LR þ 3.18), Jones test (sensitivity 0.60; specificity 0.88; LR þ 5), corneal aesthesiometry (sensitivity 0.80; specificity 0.67; LR þ 2.42), and tear clearance test (sensitivity 0.63; specificity 0.84; LR þ 3.93), all exhibited a high diagnostic performance (area under the curve in the ROC analysis always 40.70). Lissamine green staining exhibited the best performance (sensitivity 0.63; specificity 0.89; LR þ 5.72) but the result could be distorted by an incorporation bias. Conclusions Our data suggest to implement the items for ocular signs and symptoms contained in many SS-I diagnostic criteria with the use of a validated questionnaire, performance of Jones test, corneal aesthesiometry measurement, and tear clearance rate evaluation.

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Section: Eyementioning

confidence: 90%

Diagnostic performance of tear function tests in Sjogren's syndrome patients

Versura

Frigato

Cellini

et al. 2006

Eye

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“…Salivary secretion by salivary acinar cells follows cholinergic stimulation of muscarinic type 3 receptors (M 3 R) (1)(2)(3). Recent data have suggested that putative antibodies directed against M 3 R (anti-M 3 R), present in the IgG serum fraction of patients with primary SS, may contribute to the hypofunction of the salivary glands (4)(5)(6)(7)(8) and be responsible for a host of extraglandular features, such as bladder (9,10) and colon (11) irritability, Adie tonic pupil (12), and altered microvascular responses (13).…”

Section: ؉mentioning

confidence: 99%

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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“…In SS patients, isolated salivary acinar cells remain functional in vitro [92,93], but with a reduced sensitivity to threshold levels of muscarinic stimulation [93], suggesting that the lack of glandular function in many patients with SS is the result of a perturbation of acinar function [94,95]. In addition, perturbation of muscarinic receptor function by the presence of antimuscarinic antibodies would account, in large part, for some of the reported extraglandular features of SS, such as bladder irritability [90,96,97], impairment of esophageal motor function [98], and microvascular responses to cholinergic stimulation [99], Adie pupil [100], and variable heart rate [101]. In one study, the antibody levels against the 213-228aa peptide of M3R correlated positively with the number of extraglandular organ manifestations [87].…”

Section: Autoantibodies Associated With Particular Disease Manifestatmentioning

confidence: 99%

Sjögren’s Syndrome—Study of Autoantigens and Autoantibodies

Routsias

Tzioufas

2007

Clinic Rev Allerg Immunol

110

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The presence of autoantibodies is the hallmark of systemic autoimmune diseases. During the past 30 years, intense clinical and basic research have dissected the clinical value of autoantibodies in many autoimmune diseases and offered new insights into a better understanding of the molecular and functional properties of the targeted autoantigens. Unraveling the immunologic mechanisms underlying the autoimmune tissue injury, provided useful conclusions on the generation of autoantibodies and the perpetuation of the autoimmune response. Primary Sjögren's syndrome (pSS) is characterized by the presence of autoantibodies binding on a vast array of organ and non-organ specific autoantigens. The most common autoantibodies are those targeting the Ro/La RNP complex, and they serve as disease markers, as they are included in the European-American Diagnostic Criteria for pSS. Other autoantibodies are associated with particular disease manifestations, such as anti-centromere antibodies with Raynaud's phenomenon, anti-carbonic anhydrase II with distal renal tubular acidosis, anti-mitochondrial antibodies with liver pathology, and cryoglobulins with the evolution to non-Hodgkin's lymphoma. Finally, autoantibodies against autoantigens such as alpha- and beta-fodrin, islet cell autoantigen, poly(ADP)ribose polymerase (PARP), NuMA, Golgins, and NOR-90 are found in a subpopulation of SS patients without disease specificity, and their utility remains to be elucidated. In this review, the molecular and clinical characteristics (divided according to their clinical utility) of the autoantigens and autoantibodies associated with pSS are discussed.

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Impaired microvascular response to cholinergic stimuli in primary Sjogren's syndrome

Abstract: Unresponsiveness to cholinergic stimuli may contribute to exocrine insuYciency.

Cited by 45 publications

References 20 publications

Diagnostic performance of tear function tests in Sjogren's syndrome patients

Diagnostic performance of tear function tests in Sjogren's syndrome patients

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

Sjögren’s Syndrome—Study of Autoantigens and Autoantibodies

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