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Scand. J. Immunol. 49, 7–10, 1999

FRONTLINES REVIEW

An Alternative Perspective to the Immune Response in Autoimmune Exocrinopathy: Induction of Functional Quiescence Rather Than Destructive Autoaggression M. G. HUMPHREYS-BEHER*†, J. BRAYER*, S. YAMACHIKA*, A. B. PECK*† & R. JONSSON‡ *Departments of Oral Biology, Pharmacology, Pathology and Laboratory Medicine, †The Center for Orphaned Autoimmune Diseases, University of Florida, Gainesville, FL, USA; and ‡Broegelmann Research Laboratory, University of Bergen, Bergen, Norway

(Received 21 August 1998; Revised version accepted 6 October 1998)

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 Sjo¨gren’s syndrome is characterized by dryness of the eyes and the mouth due to mononuclear cell infiltration of the lacrimal and salivary glands. The aetiology is unknown but autoimmunity is considered to play a significant role in the pathogenesis. Recent studies have focused on the fact that tear and salivary flow involves an entire functional system that includes the mucosal surfaces with adnexes (the site of inflammation), efferent nerve signals sent to the midbrain (lacrimal and salivary response region), and afferent neural signals from the brain to the acinar/ductal epithelial structures in the gland. Mononuclear cell infiltration in exocrine glands can lead to glandular destruction, suggested to be mediated through apoptosis. However, the functional impairment of exocrine glands could be regulated by cytokines and/or antibodies against the muscarinic M3 receptor by inhibiting the neural stimulation of the residual glands. This review discusses the possibility that the pathogenesis of Sjo¨gren’s syndrome comprises aberrant immune-mediated neuro-hormonal events. Michael G. Humphreys-Beher PhD, Department of Oral Biology, PO Box 100424, University of Florida, Gainesville, FL 32610, USA

INTRODUCTION Our present interpretation of the role of activated lymphocytes and cytokines in chronic inflammatory autoimmune diseases is one of aberrant immune system aggression against the target tissues. Similarities in aspects of the proinflammatory cytokine profiles, observed in both acute and chronic inflammation, may allow us to examine the immune response from an alternative interpretation. Observation of the target organs at the end stage of clinical presentation does provide us with substantial evidence for destructive autoaggression as evidenced by in situ studies indicating an inability to regulate or turn off the immune response. On the other hand, if we view the initial immune system activation as a normal response to dysfunctional physiological events in the target organ of some of these diseases, then we may approach our understanding of autoimmunity as a benign process at the onset; one that may offer new avenues to therapeutic strategies. An example of this interpretation may be derived from recent studies on autoimmune exocrinopathy (Sjo¨gren’s syndrome). q 1999 Blackwell Science Ltd

Sjo¨gren’s syndrome, a disorder of unknown aetiology primarily targeting the salivary and lacrimal glands, has recently received a high level of attention among the rheumatic diseases. It is considered a complication of chronic lymphocytic inflammation and can exist as a primary condition or in association with other autoimmune disorders. Differences in diagnostic criteria have led to confusion in the research literature and in clinical practice [1]. ¨ GREN’S SYNDROME PATHOGENESIS OF SJO The reasons behind the decreased volume of secretions in tears and saliva are complex and not fully understood. Even though biopsies show lymphocytic infiltrates with atrophy of secreting acinar epithelium, morphometric analyses of the glands indicate a decrease of only < 50% in the number of acinar structures [2]. The remaining epithelium, including both acinar and ductal epithelium, might thus be functioning at a suboptimal level. Moreover, even though a connection between the decreased salivary flow and focal sialadenitis often exists [3], the decrease in flow does not parallel the increased focal sialadenitis [4].

8 M. G. Humphreys-Beher et al. There are several immunological factors that can influence the decreased salivary and tear flow. Among these are cytokines such as interleukin (IL)-1 and tumour necrosis factor (TNF)-a, which have been shown to inhibit the basal and stimulated tear response [5–7]. In addition, interferon (IFN)-g can alter the physiological responses of a human salivary gland cell line, HSG. Treatment of cells with IFN-g and TNF-a produces a response similar to the induction of programmed cell death [8–10]. Interestingly, an autoimmune response against the rodent muscarinic M3 receptor has been detected in the sera of patients with Sjo¨gren’s syndrome [11–14]. Experimental evidence disclosed that these antibodies could prevent an adequate response of the glands to neural stimulation in the same way as previously demonstrated in the nonobese diabetic (NOD) mouse [15,16]. A logical extension of these studies will now be to determine if Sjo¨gren’s sera react with human M3 receptors. If such studies are extended to show a primary role for antibody directed against the human M3 receptor, which is the receptor in lacrimal and salivary glands regulating fluid secretion, then Sjo¨gren’s syndrome may be considered an immune-mediated neuro-hormonal disorder with features analogous to some of the autoimmune neurological disorders. FUNCTION AND REGULATION OF EXOCRINE SECRETION The main function of the secretions of exocrine organs is to protect mucosal surfaces in direct contact with the external environment [17,18]. Thus, a number of the protein components from the different secretions share biological function. High molecular weight mucinous glycoproteins provide a thin hypersaturated film that coats the mucosal surfaces and prevents dessication of the underlying cell layers. This layer, along with other proteins such as lysozyme, lactoferrin and calprotectin, also provides a protective nonimmune barrier against bacterial and viral infection through direct bacteriocidal properties or indirectly through aggregation interactions with glycoprotein carbohydrate moieties and microbial receptors. The release of these protein products and the accompanying fluid phase of exocrine secretions are regulated by neural input to the tissues. In the case of saliva production, norepinephrine and acetylcholine are released by the sympathetic and parasympathetic nervous system, respectively, following masticatory and/or gustatory stimulation [19, 20]. Interaction with cell-surface receptors of the exocrine tissues induces internal second-messenger signalling pathways. Stimulation of the muscarinic/cholinergic receptors by acetylcholine results in increased levels of membrane inositol phosphate with the generation of second-messenger molecules IP3 and diacylglycerol [19]. The activation of protein kinase C isoforms by diacylglycerol can influence cell fate as it relates to proliferation or survival [21, 22]. Inositol trisphosphate alters intracellular calcium levels, and, along with other ion movements across the membrane, leads to generation of a chemiosmotic gradient and movement of fluid from the basolateral surfaces of epithelial acinar cells to the ductal lumen of the salivary glands.

¨ GREN’S ANTINEURAL RESPONSE IN SJO SYNDROME – OBSERVATIONS Recent analyses of serum IgG both from Sjo¨gren’s syndrome patients and from an animal model for autoimmune exocrinopathy have identified the presence of a population of autoantibodies targeting the muscarinic receptor [14]. These studies have indicated that the antibodies are directed at the agonist binding site of the molecule on the cell surface and interfere with subsequent ability of muscarinic receptor agonists, such as pilocarpine or carbachol, to activate inositol phosphate metabolism (Fig. 1). The presence of this antineural receptor response has obvious implications for the ability of the exocrine tissues to carry out their biological function. Furthermore, introduction of patient IgG fractions, in vivo, does not lead to (as might be suspected) an increase in epithelial cell damage through apoptosis. Consequently, the interaction of autoantibody with neural receptor function has the appearance of inducing functional quiescense of the exocrine tissues. Withdrawal of antibody treatment in congenic NOD mice lacking B-cells results in recovery of secretory function [14]. The most direct mechanism to influence the signal response is through receptor desensitization [23]. Inactivation of cell-surface receptor by repeat ligand binding can be accomplished by intracellular sequestration of receptor. In this context, decreased receptor density has been noted for salivary glands of older NOD mice (Fig. 2) [15, 16]. CELL PROLIFERATION AND APOPTOSIS Intracellular second-messenger signalling pathways often have overlapping activation capacity. This is clearly the case for

Fig. 1. IP3 Metabolism induced by serum treatment in vitro. Histogram of inositol phosphate metabolism following treatment of freshly isolated mouse submandibular acinar cells with carbachol and/or the IgG fraction isolated from normal or Sjo¨gren’s syndrome patient sera. All assays were performed as described previously (14, 15). Inositol phosphate metabolites (IP1 þ IP2 þ IP3) are reported as mean percentage increase over basal levels 6 SE for three experimental determinations performed in duplicate. The stimulating or inhibiting IgG fractions from Sjo¨gren’s syndrome patients presented here were previously reported in (14). q 1999 Blackwell Science Ltd, Scandinavian Journal of Immunology, 49, 7–10

Anti-Neural Receptor Response in Sjo¨gren’s Syndrome 9 repeated treatment of animals with secretory agonists such as isoproterenol or the overexpression of recombinant muscarinic receptors. In these situations, pathway crosstalk leads to activation of signalling components of the phosphotyrosine proliferation pathway. It is now becoming clear that components of cell proliferation pathways can influence signals leading to activation or down-regulation of apoptosis. Typically, this involves members of the BCL superfamily of proteins, which may inhibit or promote programmed cell death. Chronic muscarinic receptor stimulation in a neuroblastoma cell line has been shown to increase the expression of the antiapoptotic bcl-2 protein [24]. Different isoforms of protein kinase C (activated by diacylglycerol) are capable of promoting or inhibiting programmed cell death [21, 22]. Thus, differential patterns of isoform activation could provide a mechanism for the induction of functional quiescense in acinar cells of NOD mice treated with antimuscarinic receptor autoantibodies isolated from Sjo¨gren’s syndrome patients. In this instance, inactivation of receptor by phosphorylation could provide the mechanism for secretory dysfunction through disruption of the intracellular signalling pathway (Fig. 2). Changes in glandular neural innervation and intracellular signalling components in primary Sjo¨gren’s syndrome patients have previously been reported [25–27]. Previous observations in immunodeficient NOD-scid (lacking both B- and T-lymphocytes) mice have indicated that, as the animal matures, differentiated gene expression and glandular homeostasis begin to fail at about 10–12 weeks of age [28, 29]. The loss of differentiated function is accompanied by elevated caspace activity which, in part, may be responsible for the generation of autoantigens during the process of programmed cell death. The appearance of autoantibodies directed against the signalling receptors may act to establish a functional «time-out» of the target organ in an attempt to allow epithelial cells the chance to correct functional deficiencies by inducing a period of rest. In the salivary glands, functional stress can be artificially inhibited by decreasing neural input to the gland through a reduction in mastication. The validity of this approach might be assessed using the Sjo¨gren’s syndrome-like pathophysiology of the NOD mouse model.

Fig. 2. Model of functional quiescence. Schematic representation of the muscarinic/ cholinergic signal transduction pathway present in rodent salivary glands. The sites of autoantibody interaction with receptor and desensitization of the signal are indicated by number and include intracellular second messenger protein isoforms that may potentially induce functional quiescense or modulate rates of epithelial cell apoptosis. q 1999 Blackwell Science Ltd, Scandinavian Journal of Immunology, 49, 7–10

PROSPECTS FOR THERAPEUTIC INTERVENTION If the antineural immune response is viewed as providing a beneficial boost to the prospects of exocrine gland survival, then efforts at therapeutic interventions that stimulate glandular function so as to increase fluid output may only serve to hasten its demise. With improved sensitivity to early detection of autoimmune exocrinopathy it may be possible to supersede the immune response through the placement of patients on dietary and activity regimens that reduce glandular innervation and accomplish the same goals as the production of autoantibodies to the signalling receptors. This type of strategy is presently under investigation for treatment of individuals susceptible to autoimmune diabetes [30]. The prophylactic introduction of insulin into this population may provide a period of rest for the islet cells of the pancreas, thus delaying immune system aggression. A second approach to therapeutic intervention may be provided through induction of oral tolerance [31] by specific ingestion of muscarinic receptor. Clearly the immune cell response could be one of clonal anergy or clonal deletion at the site of the lymphocytic lesion. Here again, the respite from autoimmune aggression directed against the tissue may be sufficient to allow functional recovery of exocrine tissue dynamics. ACKNOWLEDGMENTS MH-B was supported by a visiting scientist grant from the International Office, University of Bergen, and R01 grant DE10515 from NIH/NIDR. RJ was supported by the Norwegian Research Council project no. 115563/320 and EU Biomed 2 contract BMH4-CT96–0595. ABP was supported by Juvenile Diabetes Foundation International grant I96091. JB was supported by NIDR training grant DE 7200. REFERENCES 1 Fox RI, Tornwall J, Maruyami T, Stern M. Sjo¨gren’s syndrome: evolving concepts of diagnosis, pathogenesis and therapy. Current Opinion Rheumatol 1998 (in press).

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q 1999 Blackwell Science Ltd, Scandinavian Journal of Immunology, 49, 7–10