The NOD (nonobese diabetic) mouse has been studied as an animal model for autoimmune insulindependent diabetes and Sjögren's syndrome. NOD.Ig null mice, which lack functional B lymphocytes, develop progressive histopathologic lesions of the submandibular and lachrymal glands similar to NOD mice, but in the absence of autoimmune insulitis and diabetes. Despite the focal appearance of T cells in salivary and lachrymal tissues, NOD.Ig null mice fail to lose secretory function as determined by stimulation of the muscarinic͞cholinergic receptor by the agonist pilocarpine, suggesting a role for B cell autoantibodies in mediating exocrine dryness. Infusion of purified serum IgG or F(ab) 2 fragments from parental NOD mice or human primary Sjögren's syndrome patients, but not serum IgG from healthy controls, alters stimulated saliva production, an observation consistent with antibody binding to neural receptors. Furthermore, human patient IgG fractions competitively inhibited the binding of the muscarinic receptor agonist, [ 3 H]quinuclidinyl benzilate, to salivary gland membranes. This autoantibody activity is lost after preadsorption with intact salivary cells. These findings indicate that autoantibodies play an important part in the functional impairment of secretory processes seen in connection with the autoimmune exocrinopathy of Sjögren's syndrome.

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Nonobese diabetic (NOD) mice develop an anti-exocrine gland pathology similar to human Sjögren syndrome. Recently, we demonstrated that NOD-scid mice develop severe loss of submandibular acinar cells with concomitant appearance of abnormal isoforms of salivary proteins suggesting de novo enzymatic cleavage. Because these changes may indicate activation of apoptotic proteases, we examined saliva and salivary tissue for cysteine protease activity. Cysteine protease activities were elevated in saliva and gland lysates from 20-week-old NOD and NOD-scid mice as compared with age-and sex-matched BALB͞c or 8-week-old NOD mice. This activity appeared in the submandibular glands, but not in the parotid glands. Western blot analyses using antibodies directed against specific apoptotic proteases (interleukin 1␤ converting enzyme, Nedd-2, and Apopain͞CPP 32) confirmed these findings. Submandibular glands from NODscid mice exhibited the greatest increase in proteolytic activity, indicating that infiltrating leukocytes are not responsible for these changes. Western blot analyses also failed to reveal changes in the levels of cystatins (saliva proteins that inhibit protease activity). Thus, increased cysteine protease activity appears to be directly related to submandibular acinar cell loss in NOD-scid mice involving the apoptotic pathway. Additional protease activity in saliva and gland lysates of older NOD and NOD-scid mice, apparently mutually distinct from cysteine proteases, generated an enzymatically cleaved parotid secretory protein. We suggest, therefore, that proteolytic enzyme activity contributes to loss of exocrine gland tolerance by generating abnormally processed protein constituents.

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 Sjögren'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 Sjögren's syndrome comprises aberrant immune-mediated neuro-hormonal events.

The number of published cases of adenomatoid odontogenic tumor (AOT) has steadily increased, and about half were reported in Asian populations. Although the clinicopathologic profile of AOT has been extensively reported, factual knowledge of its pathogenesis is rudimentary at best, and there is controversy as to precisely which odontogenic epithelium it arises from. AOT is a successional tooth-associated lesion which develops during the mixed dentition. The permanent successor differs from its deciduous predecessor in that it has an eruptive pathway from the dental follicle to the gingiva, the gubernaculum dentis. With this background in mind, the present review focuses mainly on the early development of AOT. We successfully demonstrated a close spatial relationship between AOT and the gubernaculum dentis in a typical case. From further observations of the same AOT in which an enclosed permanent canine showed enamel hypoplasia, it is possible to pinpoint areas around the crown of a developing successional tooth in continuity with the gubernaculum dentis as starting points. In addition, we discuss the unifying histogenetic concept of three clinical variants, namely, pericoronal (follicular), extracoronal (extrafollicular), (see Article note) and peripheral.

The questionnaires used in this study are useful for measuring patient satisfaction in the dental school hospital setting.

Objective. The appearance of autoimmune diabetes prior to autoimmune exocrinopathy in the NOD mouse suggests that it is an excellent model of secondary , but not primary, autoimmune sicca complications. Since the unique major histocompatibility complex (MHC) I-Ag7 expression in NOD mice is essential for the development of insulitis and diabetes in these animals, we investigated exocrine gland function in NOD.BlOJf2' mice, which have an MHC congenic to NOD, as a potential model for primary Sjogren's syndrome (SS). Methods. Histopathologic manifestations of lym-phocytic infiltrates into the pancreas and exocrine tissues were examined by light microscopy. Sera were evaluated for the presence of antinuclear antibodies. Saliva, tears, and gland lysates were evaluated for total volume and protein concentration, the aberrant expression and processing of parotid secretory protein, and cysteine protease activity. Results. NOD.BlOJf2' mice exhibited the exo-crine gland lymphocytic infiltration typical of the SS-like disease and dysfunction observed in NOD mice, but without the insulitis and diabetes. These mice additionally expressed elevated levels of cysteine protease activ-~~

High Candida CFU, low stimulated saliva flow rate and advanced age were identified as closely associated factors for the risk of development of atrophic tongue.