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Rheumatology Advance Access originally published online on April 4, 2006
Rheumatology 2006 45(7):792-798; doi:10.1093/rheumatology/kel067
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

REVIEW

Sjögrens syndrome—the non-apoptotic model of glandular hypofunction

L. J. Dawson, P. C. Fox1 and P. M. Smith

Sjögren's Syndrome Research Group, The University of Liverpool School of Dentistry, Liverpool, UK and 1 Visiting Scientist, Department of Oral Medicine, Carolinas Medical Center, Charlotte, North Carolina, USA.

Correspondence to: L. J. Dawson, Lecturer in Oral Surgery, University of Liverpool Dental School, Room 1.10, Edwards Building, Daulby Street, Liverpool L69 3GN, UK. E-mail: ldawson{at}liv.ac.uk

KEY WORDS: Sjögrens syndrome, Glandular hypofunction, Mechanisms, Stimulus-secretion coupling, Antimuscarinic antibodies, Aquaporins, Cytokine


   Introduction
Top
 Introduction
References
 
The ‘classical’ model to explain glandular hypofunction in Sjögrens syndrome (SS) is tissue loss secondary to immune attack mediated by a combination of apoptosis and cytotoxic cell death (reviewed recently by Ramos-Casals and Font [1]). In this model, the process of glandular destruction is made self-sustaining by the continued production of novel ‘self’ antigens, secondary to apoptotic bleb formation or cell-death [2]. Failure of the organ is thought to follow directly from tissue loss. For over six decades, research into SS has been directed towards understanding the mechanisms of destruction of salivary and lacrimal acinar tissue. Over this time, the only role envisaged for salivary glands themselves in the pathological process, has been that of a ‘reactor’ for infiltrating lymphocytes.

Three recent observations cast a serious doubt on the principles upon which the classical model for salivary gland hypofunction in SS is based. Firstly, apoptosis of the epithelial cells in the salivary glands has been shown to be a rare event [3]. Secondly, many patients with SS who have little or no glandular function (as evidenced by markedly diminished or absent saliva output) nevertheless retain large amounts of normal-appearing acinar tissue in their salivary glands [4]. Thirdly, this residual tissue is functional in vitro [5, 6], but with a reduced sensitivity to muscarinic stimulation [5]. The latter is a crucial observation that is reflected in vivo, as many SS patients can be stimulated to secrete using systemic sialogogues [7]. According to the classical model, SS patients with no salivary flow should have no functional salivary tissue. This is clearly not the case.

A ‘non-apoptotic’ model for glandular hypofunction in SS that may accommodate these findings has been proposed [4, 8–10]. In this model, glandular atrophy follows chronic immune-mediated inhibition of acinar secretory function. The many and varied mechanisms of glandular destruction, identified in association with the ‘classical’ model apply equally well to the ‘non-apoptotic’ model. What is different is that the atrophy is a consequence of salivary gland hypofunction and not the cause of it. What is most significant from any clinical perspective is that glandular destruction is clearly an irreversible process, but immune-mediated glandular hypofunction may not be. Within a ‘non-apoptotic’, ‘non-classical’ model of glandular hypofunction in SS, there is a fresh hope for both patients and clinicians because identification of the mechanisms responsible for inhibition of the secretory process may lead to the development of simplified and more sensitive diagnostic tools and ultimately to disease-modifying treatments.

A useful model for stimulus-secretion coupling in salivary acinar cells
One of the keys to unlocking the relationship between the immune response and the secretory process in salivary glands is a detailed understanding of the fluid secretory process itself. The standard ‘simple’ model for the control of fluid secretion in salivary acinar cells is a linear series of steps as follows (Fig. 1):

  1. The ACh binds to type-3 muscarinic acetylcholine receptors (M3R) on the surface of the acinar cells [11, 12].
  2. receptor activation stimulates production of the second messenger inositol 1,4,5-trisphosphate (IP3), which diffuses into the cytoplasm and binds to IP3 receptors (IP3R) on the endoplasmic reticulum causing the release of Ca2+ into the cytoplasm;
  3. increased cytoplasmic Ca2+ activity opens Ca2+-sensitive Cl– channels on the apical membrane of the cell (and the Ca2+-sensitive K+ channels on the basolateral membrane of the cell) and Cl–, which is maintained above electrochemical equilibrium by a Na+-dependent cotransport process, passes from the cell into the duct lumen;
  4. Na+ follows Cl– across the cell in order to maintain electrochemical neutrality and the resulting osmotic gradient drags the water into the duct lumen [13].
This model is accurate, but so simplified that to use it as a guide to understand the pathology of SS is a recipe for confusion. For example, step (ii) of the simple model above is hardly an adequate summary of the dynamic interplay of Ca2+ release and re-uptake mechanisms that underlie fluid secretion, which have been elucidated over many years and detailed in hundreds of publications from different research groups. The only prediction that it is possible to make using the simple model of secretion is that preventing Ca2+ release would prevent secretion. One way to appreciate how misleading and restrictive is this approach, is to expand step (ii) of the simple model into something closer to reality.


Figure 1
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  		FIG. 1. A simple model for secretion. See text for details.

 
Prolonged cell-wide increases in [Ca2+]i are cytotoxic. Acinar cells survive the high elevated levels of [Ca2+]i necessary for secretion, because the Ca2+ signals are neither prolonged nor cell-wide. Two patterns of Ca2+ signal that are constrained in space and/or time, but capable of supporting fluid secretion have been identified in salivary acinar cells. The first is composed of a series of brief transient increases in [Ca2+]i that are restricted to the apical pole of the cell [14–16]. The second is one or more waves of the increased [Ca2+]i that spread across the cell from the apical pole. Whilst at first seeming quite different, these two patterns of Ca2+ signal depend on the same cellular mechanisms and the cell can easily shift from one pattern to the other. The key mechanism underlying both patterns of Ca2+ signalling in acinar cells is Ca2+-induced-Ca2+ release (CICR), the process whereby the presence of Ca2+ in the cytoplasm causes further release of Ca2+ from the endoplasmic reticulum (Fig. 2).


Figure 2
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  		FIG. 2. Ca2+-induced Ca2+ release. (1) and (2) Both IP3 and Ca2+ increase the open state probability of the IP3R. (3) Increased [Ca2+]i in the vicinity of the IP3R following IP3-stimulated Ca2+ release causes the channel to remain open and thus allows further Ca2+ release. Activation of a single channel also has the effect of making adjacent channels more IP3-sensitive.

 
This positive feedback process gives Ca2+ signals their characteristic rapid kinetics and provides a powerful mechanism for amplification and propagation of the Ca2+ signals. CICR in acinar cells is mediated by both the IP3R and also by the ryanodine receptor (RyR), which is an IP3-independent Ca2+ release channel with similar Ca2+ sensitivities. Together these channels gate Ca2+ release from the endoplasmic reticulum, regulated by the levels of IP3 and cyclic ADP ribose, the natural agonist of the RyR [17–19]. In the absence of the either agonist, there is little or no CICR. Low levels of IP3 or Cyclic adenosine diphosphate ribose (cADPr) permit brief localized CICR-mediated Ca2+ signals and higher levels allow these signals to self-propagate as a Ca2+ wave across the cell (Fig. 3).


Figure 3
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  		FIG. 3. Signal propagation by CICR. In the presence of elevated levels of IP3 and/or cADPr, Ca2+ release at the apical pole (1) of the cell triggers a regenerative wave of Ca2+ release (4) that utilizes both IP3R and RyR to advance through the cell.

 
Simply introducing CICR into the mechanism for Ca2+ signalling has many consequences for the model of secretion, including:
  1. positive feedback mechanisms require very tight regulatory mechanisms to ensure that they do not run out of control. CICR is regulated first by the IP3R and RyR that respond to very high Ca2+ levels by closing [20], second by the Ca2+ buffers and organelles in the cytoplasm that prevent passive spread of Ca2+ within the cell and third by the Ca2+ ATPases that remove Ca2+ from the cytoplasm. Fluid secretion is therefore, critically dependent on any process that modifies Ca2+ buffering or Ca2+ ATPase activity [21].
  2. whilst ACh binding and increased levels of IP3 appear necessary for initiation of the Ca2+ signal, both IP3 and cADPr appear capable of regulating signal amplification and propagation. Cyclic ADPr levels are increased by cGMP-dependent activation of ribosyl cyclase and thus, secretion is also subject to regulation by mechanisms that alter cGMP, for example the cellular levels of nitric oxide (NO). Recent data also suggest a role for cAMP in the control of Ca2+ signalling via regulation of the affinity of the IP3R for IP3 [22].
  3. all Ca2+ signals in acinar cells, whether they propagate across the cell or not, originate at the apical pole of the cell. Ca2+ ‘tunnels’ through the endoplasmic reticulum from the basal pole to be released at the apical pole [23]. Secretion is therefore also subject to regulation via those elements of the cytoskeleton, which maintain the endoplasmic reticulum as a continuous structure within the cell.

One important aspect of this modest expansion of the model of secretion, that has many ramifications for pathological interruption of the secretory process, is recognition that the secretory process involves powerful amplifying mechanisms that are not directly connected to muscarinic ACh receptor activation. For example, reduced levels of cADPr, disruption of the cytoskeleton, increased cellular buffering or reduced ATPase activity would all disrupt CICR and produce acinar cells with an inability to secrete without affecting the ability of the cell to generate IP3 in response to ACh stimulation. In short, simply determining that acinar cells respond to muscarinic receptor activation with increased Phospholipase (PLC) activity [24] and/or increased [Ca2+]i [6] is no guarantee that the cells are functioning ‘normally’. What is important is that the cells generate a Ca2+ signal that is spatially and temporally appropriate to the stimulus [5, 25].

Points 1 (ACh binding to receptor) and 4 (water movement) of the ‘simple model of secretion’ (Fig. 1) also benefit from a closer scrutiny. Salivary fluid secretion is almost entirely regulated by ACh release from parasympathetic nerves, but without the very tight anatomical relationship between nerve ending and effector cell seen in, for example, a neuromuscular junction. ACh must therefore diffuse at least 100 nm in order to bind to the ACh receptors [26]. This ‘epilemmal’ (outside the parenchymal basement membrane) [26] relationship between nerves and cells will make the secretory process vulnerable to disruption between neurotransmitter release and neurotransmitter binding by, for example, acetylcholinesterase [27, 28] or antimuscarinic receptor antibodies [24, 29, 30].

The penultimate step of the secretory process is creation of a trans-acinus osmotic gradient to drag fluid into the ducts. Water movement across the acinus may be either paracellular (between the cells) or transcellular (across the cells). The most straightforward evidence for transcellular water transport is that flow rates are reduced by 65% in knockout mice where aquaporin-5 (AQP-5), the apical membrane water channel, has been eliminated [31]. The rate of fluid secretion will be dependent on both the magnitude of the osmotic gradient, which is controlled ultimately by the Ca2+ signal and also on the water permeability of the acinar cell membrane. This last may also be regulated by ACh binding to muscarinic acetylcholine receptors via ACh-dependent insertion of AQP-5 into the apical membrane [32, 33]. However, these findings are controversial (see subsequently).

In summary, whilst muscarinic receptor activation and consequent production of IP3 remain at the heart of any model of stimulus secretion coupling in acinar cells, there are many other factors that could contribute to salivary gland hypofunction in SS including antimuscarinic receptor antibody binding [24], cADPr [34], cAMP [22], cGMP [35], ATPase activity [21], mitochondria [36] and anything that affects the cytoskeleton and cellular polarity [37–39].

Mechanisms of immune-induced acinar hypofunction under investigation
With the ‘expanded’ model of stimulus-secretion coupling as a guide, current studies of salivary acinar cell pathology may be divided into three areas: (i) receptor activation, (ii) mobilization of Ca2+ and (iii) fluid movement. Alterations in each may play a role in the exocrine pathology of SS.

Receptor activation
Receptor hypersensitivity followed by cellular atrophy is a well-established consequence of glandular denervation [40] and there is evidence that M3R numbers increase in the labial salivary glands of patients with SS [41]. Hypersensitivity of the lacrimal and submandibular glands to agonist has also been observed in young MRL/lpr mice, an animal model of SS characterized by defects of the Fas receptor [42]. These findings are consistent with a reduction in the amount of ACh reaching the M3R for which possible causes include:

  1. loss of innervation. This most simple explanation of receptor hypersensitivity is not supported by data from either the MRL/lpr mouse model [43] or human SS labial glands [44] that show no reduction in the density of the parasympathetic or neuropeptide neuronal innervation associated with SS.
  2. reduction in ACh release. Data from in vitro experiments using submandibular and lacrimal gland lobules isolated from the MRL/lpr mouse have suggested that the cytokines IL-1{alpha}, IL-1ß and TNF-{alpha} may have a role in impairing the release of ACh from the neurones [45]. However, these findings remain to be confirmed in mice and demonstrated in human salivary glands.
  3. increased breakdown of ACh in the epilemmal space. ACh will be subject to degradation by cholinesterases as part of normal regulatory processes from the point of release by the neurones. Increased levels of cholinesterases in the salivary glands would therefore accelerate ACh breakdown and reduce the amount reaching the acinar cells [28]. We have shown that patients with SS have significantly elevated levels of cholinesterase in saliva, which probably denotes increased levels of cholinesterases in the salivary glands themselves. Cholinesterases are present in both the serum and on the surface of lymphocytes [46]. Cholinesterase could therefore enter the gland within an inflammatory infiltrate or in association with lymphocytic infiltration. This speculative hypothesis also suggests a novel mechanism for the action of hydroxychloroquine, which is an effective cholinesterase inhibitor at therapeutic doses [27] used to treat SS patients.
  4. blockade of M3R by antibodies. Over the last few years, there have been an increasing number of reports detailing autonomic symptoms in patients with SS that could be related to blockade of muscarinic receptors. These symptoms include bladder irritability [29, 47], Aides tonic pupil [48], impaired microvascular responses to cholinergic stimulation [49] and a variable heart rate [50]. All of these symptoms, as well as those of xerostomia and xerophthalmia, could be the result of blockade of M3R by antibodies [24].

Of these four possible mechanisms for acinar cell hypofunction in SS involving a reduction in the amount of ACh reaching the cells, much interest has been focused on a possible role for antimuscarinic auto-antibodies (for detailed review see Dawson et al. [51]). There are three key criteria that must be satisfied in order to give a clear indication of a role for auto-antibodies in the pathology of any disease [52]. These criteria are:

  1. the antibody interferes with the function of the target tissue. SS IgG antibodies are known to be able to bind in vitro to muscarinic receptors present on acinar cell membrane fractions [24, 53]. More importantly, recent in vitro studies demonstrating functional impairment in vital tissue have shown that: SS IgG inhibited the ACh-evoked [Ca2+]i responses in mouse submandibular acinar cells [28] and in a salivary gland cell line [54] as well as perturbing muscarinic receptor-mediated smooth muscle contraction in both bladder and colon [10, 29, 55].
  2. passive transfer of the antibody causes the disease in the recipient. Human SS IgG caused glandular hypofunction when infused into previously healthy animals [56] as did IgG from the non-obese diabetic (NOD) mouse [56] (an animal model of SS [57]).
  3. antibody is present at significant levels only in those individuals who have disease. This is the most difficult criterion to satisfy. Preliminary in vitro data, based on a small number of patients, indicate that SS IgG antibodies capable of causing glandular hypofunction appear with a high frequency in the IgG serum fraction of patients with both primary and secondary SS [24, 29]. Recent data utilizing a novel ELISA show antimuscarinic antibodies in 66/73 (90%) patients with primary SS [58, 59]. However, IgG antibodies with antimuscarinic activity also occur in scleroderma [55]. Antimuscarinic antibodies are difficult to detect using conventional immunological techniques [30, 60] and there is no simple way at present to screen a large number of patients, therefore the true population incidence and the specificity to SS remain unknown.

In summary, there is evidence to support the hypothesis that a reduction in receptor activation, probably mediated by antimuscarinic antibodies (see [51] for review), is at least a contributing factor to the glandular hypofunction seen in SS. However, these data do not exclude supporting roles for increased cholinesterase activity within the salivary glands or cytokine-mediated inhibition of neuronal ACh release.

Mobilization of Ca2+
Despite early work showing that the cytokines INF-{gamma} and TNF-{alpha} were capable of depleting [Ca2+]i stores by interfering with the activity of the Ca2+ ATPase pump in a human salivary ductal cell line [61, 62], no similar phenomenon has been observed in salivary gland acinar cells, where chronic exposure to cytokines was without effect on agonist-stimulated Ca2+ in single cells [5]. However, these findings do not exclude a role for cytokines in perturbation of the intercellular communication necessary for co-operative behaviour between cells of a single acinus [63].

There has been little examination of the pathological potential of disruption of the metabolism of second messengers other than IP3. Nevertheless, changes in intracellular levels of cADPr have profound effects on the ability of acinar cells to respond to secretory stimuli in vitro [34]. There is a clear link between regulation of cADPr production and SS through NO. NO is produced by a number of cell types including macrophages, lymphocytes and salivary acinar cells [44, 64] and increased levels of NO have been demonstrated in both the saliva [44] and expired air from patients with SS [65]. Furthermore, the cytokines TNF-{alpha}, INF-{gamma} and IL-1 as well as SS IgG stimulate nitric oxide synthase (NOS) activity [66–68]. Increased NO levels stimulate cGMP production and cGMP regulates cADPr production [17, 18, 69, 70]. Acute exposure to elevated levels of NO (unpublished data) and cADPr [34] made acinar cells hyper-responsive to ACh stimulation as predicted by the ‘useful’ model of secretion (aforementioned) and consistent with cADPr–mediated enhancement of the contribution of RyR to CICR. Hypersensitivity of acinar cells to stimulation is the opposite of the situation seen in SS, [5] but a chronic exposure to elevated levels of cADPr, as would be the case in SS, could lead to receptor desensitization and hyposensitivity to stimulus. Preliminary data indicate that the responsiveness of acinar cells to ACh falls following chronic exposure to NO (unpublished data). Work is in progress to determine whether this effect is mediated by cADPr.

Fluid movement
Water movement by simple diffusion across the lipid bilayer of the cell membrane is much too slow to support fluid secretion [71]. Instead, water travels via specific water channels known as aquaporins (AQPs) that increase the water permeability of the lipid bilayer by between 10- and 100-fold [71]. To date, ten mammalian AQPs have been identified, each having a unique tissue distribution, and defects in the distribution of these AQPs have been linked with diseases including: nephrogenic diabetes insipidus, pulmonary oedema and hereditary cataracts [72].

Salivary acinar cells express AQP5 on the apical cell membrane and AQP1 on the basolateral membrane [73–79]. Saliva production in AQP5 knockout mice is hypertonic and of increased viscosity and reduced in volume by 65–77% [80], which suggests that AQP5 has some physiological role in salivary secretion. Consistent with this hypothesis is the observation that the salivary acinar cells of knockout mice have significantly reduced water permeability [81].

AQPs could have a role in the pathology of SS if water movement were sufficiently slowed so as to become the rate limiting step of secretion. There are some data that indicate that the expression of AQP5 is reduced at the luminal membrane of salivary acinar cells in patients with SS [77, 78] but evidence from a high-resolution confocal microscopy study indicate that the distribution of AQP5 in SS is unaltered [74]. Assessing the role of AQPs in SS may have been made more difficult because AQP5 expression on the acinar cell luminal membrane had been suggested to be up-regulated by the action of ACh in combination with NO [32, 33]. However, these later in vitro findings have been convincingly challenged by data from a recent electron microscope study performed in intact animals that suggested AQP5 is anchored to the apical acinar cell membrane and does not translocate in response to ACh-stimulation [82].

Overall, the inability to increase water permeability as part of stimulus secretion coupling is a plausible contributing mechanism for glandular hypofunction in SS. If such a mechanism is proved to be important, it could offer an avenue for treatment by localized gene therapy because transfecting the salivary glands of irradiated rats with AQP1 using a recombinant adenovirus has been shown to restore salivary function [83].

The non-apoptotic model of glandular hypofunction
Figure 4 shows possible points of interaction between the immune system and the secretory process that could lead to glandular hypofunction: (i) inhibition of neurotransmitter release by cytokines; (ii) enhanced breakdown of ACh by increased levels of cholinesterase; (iii) blockade of M3R by antimuscarinic autoantibodies; (iv) altered NO production; (v) perturbation of CICR by altered levels of cADPr (possibly as a result of altered NO levels); (vi) altered Ca2+ tunnelling and (vii) altered expression or distribution of AQP5.


Figure 4
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  		FIG. 4. Possible points of interaction between the immune system and the secretory process that could lead to glandular hypofunction. (1) inhibition of neurotransmitter release by cytokines; (2) enhanced breakdown of ACh by increased levels of cholinesterase; (3) blockade of M3R by antimuscarinic autoantibodies; (4) altered NO production; (5) perturbation of CICR by altered levels of cADPr (possibly as a result of altered NO levels); (6) altered Ca2+ tunnelling; and (7) altered expression or distribution of AQP5.

 
A great deal of effort has been expended to map the detailed mechanisms of apoptosis in SS [84]. There can be no doubt that apoptosis occurs in SS, but the significance of apoptosis in the secretory pathophysiology of SS is unclear and there is a growing challenge to the belief that apoptosis is the primary cause of secretory dysfunction [4, 8–10]. Despite much progress towards identifying non-apoptotic antisecretory components of the immune response in SS, the single most convincing argument against glandular hypofunction as a simple consequence of apoptosis and glandular atrophy is the observation that patients have viable glandular tissue and no natural salivary flow. The ‘non-apoptotic’ model of glandular hypofunction is an attempt to gather together the points at which the immune response can inhibit the secretory process, it incorporates possible contributions from B and T lymphocytes, macrophages and acinar cells. No one single factor has yet been discovered that could account for the disruption to the secretory process seen in SS. In fact, the evidence available to date suggests that the causes of salivary gland hypofunction are multifactorial rather than monofactorial. The current challenges are: (i) to determine which of the currently identified possible mechanisms have a genuine role in pathogenesis; (ii) to evaluate additional mechanisms as they are identified and (iii) to create an integrated model that can account for salivary gland hypofunction. A functioning ‘non-apoptotic’ model of glandular hypofunction would provide the first genuine guide towards development of simple diagnostic tests and therapeutic interventions for SS. z
Figure 5

The authors have declared no conflicts of interest.


   References
Top
 Introduction
 References
 

  1. Ramos-Casals M, Font J. Primary Sjögren's syndrome: current and emergent aetiopathogenic concepts. Rheumatology, 2005;44:1354–67.[Free Full Text]
  2. Nagaraju K, Cox A, Casciola-Rosen L, Rosen A. Novel fragments of the Sjögren's syndrome autoantigens alpha-fodrin and type 3 muscarinic acetylcholine receptor generated during cytotoxic lymphocyte granule-induced cell death. Arthritis Rheum 2001;44:2376–86.[CrossRef][Medline]
  3. Ohlsson M, Skarstein K, Bolstad AI, Johannessen AC, Jonsson R. Fas-induced apoptosis is a rare event in Sjögren's syndrome. Lab Invest 2001;81:95–105.
  4. Fox RI, Maruyama T. Pathogenesis and treatment of Sjögren's syndrome. Curr Opin Rheumatol 1997;9:393–9.[Medline]
  5. Dawson LJ, Field EA, Harmer AR, Smith PM. Acetylcholine-evoked calcium mobilization and ion channel activation in human labial gland acinar cells from patients with primary Sjögren's syndrome. Clin Exp Immunol 2001;124:480–5.[Medline]
  6. Pedersen AM, Dissing S, Fahrenkrug J, Hannibal J, Reibel J, Nauntofte B. Innervation pattern and Ca2+ signalling in labial salivary glands of healthy individuals and patients with primary Sjögren's syndrome (pSS). J Oral Pathol Med 2000;29:97–109.[CrossRef][Medline]
  7. Rhodus NL. Oral pilocarpine HCl stimulates labial (minor) salivary gland flow in patients with Sjögren's syndrome. Oral Dis 1997;3:93–8.[Medline]
  8. Dawson LJ, Smith PM, Moots RJ, Field EA. Sjögren's syndrome-time for a new approach. Rheumatology 2000;39:234–7.[Free Full Text]
  9. Humphreys-Beher MG, Brayer J, Yamachika S, Peck AB, Jonsson R. An alternative perspective to the immune response in autoimmune exocrinopathy: induction of functional quiescence rather than destructive autoaggression. Scand J Immunol 1999;49:7–10.[CrossRef][Medline]
  10. Gordon TP, Bolstad AI, Rischmueller M, Jonsson R, Waterman SA. Autoantibodies in primary Sjögren's syndrome: new insights into mechanisms of autoantibody diversification and disease pathogenesis. Autoimmunity 2001;34:123–32.[ISI][Medline]
  11. Nakamura T, Matsui M, Uchida K et al. M(3) muscarinic acetylcholine receptor plays a critical role in parasympathetic control of salivation in mice. J Physiol 2004;558:561–75.[Abstract/Free Full Text]
  12. Matsui M, Motomura D, Karasawa H et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci USA 2000;97:9579–84.[Abstract/Free Full Text]
  13. Smith PM. Mechanisms of secretion by salivary glands, In: Edgar WM, O'Mullane D, eds, Saliva and Oral Health. London: BDJ, 1996;9–25.
  14. Thorn P, Lawrie AM, Smith PM, Gallacher DV, Petersen OH. Local and global cytosolic Ca2+ oscillations in exocrine cells evoked by agonists and inositol trisphosphate. Cell 1993;74:661–8.[CrossRef][ISI][Medline]
  15. Zhuge R, Fogarty KE, Tuft RA, Walsh JV Jr. Spontaneous transient outward currents arise from microdomains where BK channels are exposed to a mean Ca(2+) concentration on the order of 10 microM during a Ca(2+) spark. J Gen Physiol 2002;120:15–27.[Abstract/Free Full Text]
  16. Marchant, JS, Ramos V, Parker I. Structural and functional relationships between Ca2+ puffs and mitochondria in Xenopus oocytes. Am J Physiol Cell Physiol 2002;282:C1374–86.[Abstract/Free Full Text]
  17. Galione A, McDougall A, Busa WB, Willmott N, Gillot I, Whitaker M. Redundant mechanisms of calcium-induced calcium release underlying calcium waves during fertilization of sea urchin eggs. Science 1993;261:348–52.[Abstract/Free Full Text]
  18. Galione, A, White A, Willmott N, Turner M, Potter BV, Watson SP. cGMP mobilizes intracellular Ca2+ in sea urchin eggs by stimulating cyclic ADP-ribose synthesis. Nature 1993;365:456–9.[CrossRef][Medline]
  19. Berridge, MJ. Elementary and global aspects of calcium signalling. J Exp Biol 1997;200:315–9.[Abstract]
  20. Bezprozvanny, I, Watras J, Ehrlich BE. Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 1991;351:751–4.[CrossRef][Medline]
  21. Smith, PM, Reed HE. Amplification of the thapsigargin-evoked increase in the cytosolic free Ca2+ concentration by acetylcholine in acutely isolated mouse submandibular acinar cells. Biochem J 1996;317:779–83.[Medline]
  22. Straub, SV, Wagner LE2nd, Bruce JI, Yule DI. Modulation of cytosolic calcium signaling by protein kinase A-mediated phosphorylation of inositol 1,4,5-trisphosphate receptors. Biol Res 2004;37:593–602.[ISI][Medline]
  23. Mogami H, Nakano K, Tepikin AV, Petersen OH. Ca2+ flow via tunnels in polarized cells: recharging of apical Ca2+ stores by focal Ca2+ entry through basal membrane patch. Cell 1997;88:49–55.[CrossRef][ISI][Medline]
  24. Bacman S, Sterin-Borda L, Camusso JJ, Arana R, Hubscher O, Borda E. Circulating antibodies against rat parotid gland M3 muscarinic receptors in primary Sjögren's syndrome. Clin Exp Immunol 1996;104:454–9.[CrossRef][ISI][Medline]
  25. Harmer AR, Smith PM, Gallacher DV. Local and global calcium signals and fluid and electrolyte secretion in mouse submandibular acinar cells. Am J Physiol Gastrointest Liver Physiol 2005;288:G118–24.[Abstract/Free Full Text]
  26. Garrett JR, Kidd A. The innervation of salivary glands as revealed by morphological methods. Microsc Res Tech 1993;26:75–91.[Medline]
  27. Dawson LJ, Caulfield VL, Stanbury JB, Field AE, Christmas SE, Smith PM. Hydroxychloroquine therapy in patients with primary Sjögren's syndrome may improve salivary gland hypofunction by inhibition of glandular cholinesterase. Rheumatology 2005;44:449–55.[Abstract/Free Full Text]
  28. Dawson LJ, Christmas SE, Smith PM. An investigation of interactions between the immune system and stimulus-secretion coupling in mouse submandibular acinar cells. A possible mechanism to account for reduced salivary flow rates associated with the onset of Sjögren's syndrome. Rheumatology 2000;39:1226–33.[Abstract/Free Full Text]
  29. Waterman SA, Gordon TP, Rischmueller M. Inhibitory effects of muscarinic receptor autoantibodies on parasympathetic neurotransmission in Sjögren's syndrome. Arthritis Rheum 2000;43:1647–54.[CrossRef][ISI][Medline]
  30. Dawson LJ, Allison HE, Stanbury J, Fitzgerald D, Smith PM. Putative anti-muscarinic antibodies cannot be detected in patients with primary Sjögren's syndrome using conventional immunological approaches. Rheumatology 2004;43:1488–95.[Abstract/Free Full Text]
  31. Song Y, Verkman AS. Aquaporin-5 dependent fluid secretion in airway submucosal glands. J Biol Chem 2001;276:41288–92.[Abstract/Free Full Text]
  32. Ishikawa Y, Eguchi T, Skowronski MT, Ishida H. Acetylcholine acts on M3 muscarinic receptors and induces the translocation of aquaporin5 water channel via cytosolic Ca2+ elevation in rat parotid glands. Biochem Biophys Res Commun 1998;245:835–40.[CrossRef][ISI][Medline]
  33. Ishikawa, Y, Iida H, Ishida H. The muscarinic acetylcholine receptor-stimulated increase in aquaporin-5 levels in the apical plasma membrane in rat parotid acinar cells is coupled with activation of nitric oxide/cGMP signal transduction. Mol Pharmacol 2002;61:1423–34.[Abstract/Free Full Text]
  34. Harmer AR, Gallacher DV, Smith PM. Role of Ins(1,4,5)P3, cADP-ribose and nicotinic acid-adenine dinucleotide phosphate in Ca2+ signalling in mouse submandibular acinar cells. Biochem J 2001;353:555–60.[CrossRef][Medline]
  35. Looms D, Tritsaris K, Pedersen AM, Nauntofte B, Dissing S. Nitric oxide signalling in salivary glands. J Oral Pathol Med 2002;31:569–84.[CrossRef][ISI][Medline]
  36. Tinel H, Cancela JM, Mogami H et al. Active mitochondria surrounding the pancreatic acinar granule region prevent spreading of inositol trisphosphate-evoked local cytosolic Ca(2+) signals. EMBO J 1999;18:4999–5008.[CrossRef][ISI][Medline]
  37. Harmer AR, Gallacher DV, Smith PM. Correlations between the functional integrity of the endoplasmic reticulum and polarized Ca2+ signalling in mouse lacrimal acinar cells: a role for inositol 1,3,4,5-tetrakisphosphate. Biochem J 2002;367:137–43.[CrossRef][ISI][Medline]
  38. Turvey MR, Fogarty KE, Thorn P. Inositol (1,4,5)-trisphosphate receptor links to filamentous actin are important for generating local Ca2+ signals in pancreatic acinar cells. J Cell Sci 2005;118:971–80.[Abstract/Free Full Text]
  39. Fogarty KE, Kidd JF, Turner A, Skepper JN, Carmichael J, Thorn P. Microtubules regulate local Ca2+ spiking in secretory epithelial cells. J Biol Chem 2000;275:22487–94.[Abstract/Free Full Text]
  40. Emmelin N. ‘Paralytic’ secretion of saliva. An example of supersensitivity after denervation. Physiol Rev 1952;32:21–46.[Free Full Text]
  41. Beroukas D, Goodfellow R, Hiscock J, Jonsson R, Gordon TP, Waterman SA. Up-regulation of M3-muscarinic receptors in labial salivary gland acini in primary Sjögren's syndrome. Lab Invest 2002;82:203–10.
  42. Zoukhri D, Hodges RR, Rawe IM, Dartt DA. Ca2+ signaling by cholinergic and alpha1-adrenergic agonists is up-regulated in lacrimal and submandibular glands in a murine model of Sjögren's syndrome. Clin Immunol Immunopathol 1998;89:134–40.[CrossRef][ISI][Medline]
  43. Zoukhri D, Hodges RR, Dartt DA. Lacrimal gland innervation is not altered with the onset and progression of disease in a murine model of Sjögren's syndrome. Clin Immunol Immunopathol 1998;89:126–33.[CrossRef][ISI][Medline]
  44. Konttinen YT, Platts LA, Tuominen S et al. Role of nitric oxide in Sjögren's syndrome. Arthritis Rheum 1997;40:875–83.[ISI][Medline]
  45. Zoukhri D, Kublin CL. Impaired neurotransmitter release from lacrimal and salivary gland nerves of a murine model of Sjögren's syndrome. Invest Ophthalmol Vis Sci 2001;42:925–32.[Abstract/Free Full Text]
  46. Szelenyi JG, Bartha E, Hollan SR. Acetylcholinesterase activity of lymphocytes: an enzyme characteristic of T-cells. Br J Haematol 1982;50:241–5.[Medline]
  47. Walker J, Gordon T, Lester S et al. Increased severity of lower urinary tract symptoms and daytime somnolence in primary Sjögren's syndrome. J Rheumatol 2003;30:2406–12.[Medline]
  48. Bachmeyer C, Zuber M, Dupont S, Blanche P, Dhote R, Mas JL. Adie syndrome as the initial sign of primary Sjögren syndrome. Am J Ophthalmol 1997;123:691–2.[Medline]
  49. Kovacs L, Torok T, Bari F et al. Impaired microvascular response to cholinergic stimuli in primary Sjögren's syndrome. Ann Rheum Dis 2000;59:48–53.[Abstract/Free Full Text]
  50. Tumiati B, Perazzoli F, Negro A, Pantaleoni M, Regolisti G. Heart rate variability in patients with Sjögren's syndrome. Clin Rheumatol 2000;19:477–80.[CrossRef][Medline]
  51. Dawson L, Tobin A, Smith P, Gordon T. Antimuscarinic antibodies in Sjögren's syndrome: where are we, and where are we going? Arthritis Rheum 2005;52:2984–95.[Medline]
  52. Drachman DB. Autonomic "myasthenia": the case for an autoimmune pathogenesis. J Clin Invest 2003;111:797–9.[CrossRef][ISI][Medline]
  53. Bacman S, Perez Leiros C, Sterin-Borda L, Hubscher O, Arana R, Borda E. Autoantibodies against lacrimal gland M3 muscarinic acetylcholine receptors in patients with primary Sjögren's syndrome. Invest Ophthalmol Vis Sci 1998;39:151–6.[Abstract/Free Full Text]
  54. Li J, Ha YM, Ku NY et al. Inhibitory effects of autoantibodies on the muscarinic receptors in Sjögren's syndrome. Lab Invest 2004;84:1430–8.[ISI][Medline]
  55. Goldblatt F, Gordon TP, Waterman SA. Antibody-mediated gastrointestinal dysmotility in scleroderma. Gastroenterology 2002;123:1144–50.
  56. Robinson CP, Brayer J, Yamachika S et al. Transfer of human serum IgG to nonobese diabetic Igµ null mice reveals a role for autoantibodies in the loss of secretory function of exocrine tissues in Sjögren's syndrome. Proc Natl Acad Sci USA 1998;95:7538–43.[Abstract/Free Full Text]
  57. van Blokland SC, Versnel MA. Pathogenesis of Sjögren's syndrome: characteristics of different mouse models for autoimmune exocrinopathy. Clin Immunol 2002;103:111–24.[CrossRef][ISI][Medline]
  58. Marczinovits I, Kovacs L, Gyorgy A et al. A peptide of human muscarinic acetylcholine receptor 3 is antigenic in primary Sjögren's syndrome. J Autoimmun 2005;24:47–54.[ISI][Medline]
  59. Kovacs L, Marczinovits I, Gyorgy A et al. Clinical associations of autoantibodies to human muscarinic acetylcholine receptor 3213–228 in primary Sjögren's syndrome. Rheumatology 2005;8:1021–5.
  60. Cavill D, Waterman SA, Gordon TP. Failure to detect antibodies to extracellular loop peptides of the muscarinic M3 receptor in primary Sjögren's syndrome. J Rheumatol 2002;29:1342–4.[Medline]
  61. Wu AJ, Kurrasch RH, Katz J, Fox PC, Baum BJ, Atkinson JC. Effect of tumor necrosis factor-alpha and interferon-gamma on the growth of a human salivary gland cell line. J Cell Physiol 1994;161:217–26.[CrossRef][ISI][Medline]
  62. Wu AJ, Chen ZJ, Tsokos M, O'Connell BC, Ambudkar IS, Baum BJ. Interferon-gamma induced cell death in a cultured human salivary gland cell line. J Cell Physiol 1996;167:297–304.[CrossRef][ISI][Medline]
  63. Rottingen J, Iversen JG. Ruled by waves? Intracellular and intercellular calcium signalling. Acta Physiol Scand 2000;169:203–19.[CrossRef][ISI][Medline]
  64. Forstermann U, Gath I, Schwarz P, Closs EI, Kleinert H. Isoforms of nitric oxide synthase. Properties, cellular distribution and expressional control. Biochem Pharmacol 1995;50:1321–32.[CrossRef][ISI][Medline]
  65. Ludviksdottir D, Janson C, Hogman M et al. Increased nitric oxide in expired air in patients with Sjögren's syndrome. BHR study group. Bronchial hyperresponsiveness. Eur Respir J 1999;13:739–43.[Abstract]
  66. Bacman SR, Berra A, Sterin-Borda L, Borda ES. Human primary Sjögren's syndrome autoantibodies as mediators of nitric oxide release coupled to lacrimal gland muscarinic acetylcholine receptors. Curr Eye Res 1998;17:1135–42.[CrossRef][ISI][Medline]
  67. Bacman S, Berra A, Sterin-Borda L, Borda E. Muscarinic acetylcholine receptor antibodies as a new marker of dry eye Sjögren syndrome. Invest Ophthalmol Vis Sci 2001;42:321–7.[Abstract/Free Full Text]
  68. Perez Leiros C, Sterin-Borda L, Hubscher O, Arana R, Borda ES. Activation of nitric oxide signaling through muscarinic receptors in submandibular glands by primary Sjögren syndrome antibodies. Clin Immunol 1999;90:190–5.[CrossRef][ISI][Medline]
  69. Looms DK, Tritsaris K, Nauntofte B, Dissing S. Nitric oxide and cGMP activate Ca2+-release processes in rat parotid acinar cells. Biochem J 2001;355:87–95.[CrossRef][ISI][Medline]
  70. Denninger JW, Marletta MA. Guanylate cyclase and the NO/cGMP signaling pathway. Biochim Biophys Acta 1999;1411:334–50.[Medline]
  71. Agre P, King LS, Yasui M et al. Aquaporin water channels – from atomic structure to clinical medicine. J Physiol 2002;542:3–16.[Abstract/Free Full Text]
  72. King LS, Yasui M, Agre P. Aquaporins in health and disease. Mol Med Today 2000;6:60–5.[CrossRef][ISI][Medline]
  73. Raina S, Preston GM, Guggino WB, Agre P. Molecular cloning and characterization of an aquaporin cDNA from salivary, lacrimal, and respiratory tissues. J Biol Chem 1995;270:1908–12.[Abstract/Free Full Text]
  74. Beroukas D, Hiscock J, Jonsson R, Waterman SA, Gordon TP. Subcellular distribution of aquaporin 5 in salivary glands in primary Sjögren's syndrome. Lancet 2001;358:1875–6.[ISI][Medline]
  75. Beroukas D, Hiscock J, Gannon BJ, Jonsson R, Gordon TP, Waterman SA. Selective down-regulation of aquaporin-1 in salivary glands in primary Sjögren's syndrome. Lab Invest 2002;82:1547–52.[ISI][Medline]
  76. Nielsen S, King LS, Christensen BM, Agre P. Aquaporins in complex tissues. II. Subcellular distribution in respiratory and glandular tissues of rat. Am J Physiol 1997;273:C1549–61.[ISI][Medline]
  77. Tsubota K, Hirai S, King LS, Agre P, Ishida N. Defective cellular trafficking of lacrimal gland aquaporin-5 in Sjögren's syndrome. Lancet 2001;357:688–9.[CrossRef][ISI][Medline]
  78. Steinfeld S, Cogan E, King LS, Agre P, Kiss R, Delporte C. Abnormal distribution of aquaporin-5 water channel protein in salivary glands from Sjögren's syndrome patients. Lab Invest 2001;81:143–8.[ISI]
  79. Gresz V, Burghardt B, Ferguson CJ et al. Expression of aquaporin 1 (AQP1) water channels in human labial salivary glands. Arch Oral Biol 1999;44 (Suppl 1):S53–7.
  80. Ma T, Song Y, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS. Defective secretion of saliva in transgenic mice lacking aquaporin-5 water channels. J Biol Chem 1999;274:20071–4.[Abstract/Free Full Text]
  81. Krane CM, Melvin JE, Nguyen HV et al. Salivary acinar cells from aquaporin 5-deficient mice have decreased membrane water permeability and altered cell volume regulation. J Biol Chem 2001;276:23413–20.[Abstract/Free Full Text]
  82. Gresz V, Kwon TH, Gong H et al. Immunolocalization of AQP-5 in rat parotid and submandibular salivary glands after stimulation or inhibition of secretion in vivo. Am J Physiol Gastrointest Liver Physiol 2004;287:G151–61.[Abstract/Free Full Text]
  83. Delporte C, O'Connell BC, He X et al. Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. Proc Natl Acad Sci USA 1997;94:3268–73.[Abstract/Free Full Text]
  84. Manganelli P, Fietta P. Apoptosis and Sjögren syndrome. Semin Arthritis Rheum 2003;33:49–65.[CrossRef][ISI][Medline]
Submitted 30 November 2005; revised version accepted 3 February 2006.
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T. Mandl, V. Granberg, J. Apelqvist, P. Wollmer, R. Manthorpe, and L. T. H. Jacobsson
Autonomic nervous symptoms in primary Sjogren's; syndrome
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