Dysfunction of lacrimal and salivary glands in Sjögren's syndrome: nonimmunologic injury in preinflammatory phase and mouse model

Abstract

Sjögren's syndrome (SjS) is a chronic autoimmune disorder characterized by dry eyes and dry mouth due to dacryoadenitis and sialoadenitis with SS-A/Ro and/or SS-B/La autoantibodies in genetically predisposed individuals. Destruction of lacrimal and salivary glands by autoimmune reactions may lead to clinical manifestation. However, the mechanisms behind the decreased volume of secretions in tears and saliva are complex and are not fully understood. Exocrine gland dysfunction may precede autoimmunity (acquired immunity) or represent a process independent from inflammation in the pathogenesis of SjS. The preceded functional and morphologic changes of those tissues by nonimmunologic injury before the development of inflammation at the sites of target organs have been implicated. This paper focuses on the several factors and components relating to glandular dysfunction and morphologic changes by nonimmunologic injury during the preinflammatory phase in mouse model, including the factors which link between innate immunity and adaptive immunity.

Figure 1

Hypothetical relationship between nonimmune (preinflammatory) phase and immune reaction (acquired immunity). Female B/WF₁ mice, a model for SLE and sSjS, develop several autoantibodies (e.g., anti-dsDNA and antinuclear antibodies: ANA) from younger ages (approximately 12 weeks of age) and thereafter immune-complexes- (ICs-) mediated glomerulonephritis (GN) develops with age, leading to overt disease (renal failure). On the other hand, production of anti-Ro/SS-A antibodies begin at the age of 20 weeks of age and dacryoadenitis and sialoadenitis (SA/DA) may develop in salivary and lacrimal glands. During the nonimmune phase, abnormal function and morphology of these tissues such endothelial cells (Ec) may permit leak of cytokines produced systemically. Dotted line shows hypothetical functional defect. Green lines may indicate clinical manifestation (self-reported symptoms) in human patients with sSjS. In this figure, the regenerative changes of acini components are not shown. T cell (T), B cell (B), and plasma cell (P).

Figure 2

Dysfunction of renal function due to glomerulonephritis may precede glandular dysfunction. Glomerulonephritis in different ages of female B/WF₁ mice. Slight increase of mesangial cells (a), diffuse thickening of basement membranes with segmental proliferation of mesangial cells (b), and sclerosing change (c) in glomeruli are visible. On the other hand, relatively normal structure in submandibular gland is seen (d), but at this time dysfunction of glands is reported [50]. Focal lymphoid cell infiltration (e), and dense infiltration (f) are visible. Samples were obtained survived mice (a, b, d, and e), whereas those were from dead mice (c and f). HE : (a–d). Azan: (e) and (f).

Figure 3

Probable factors and causes (?), which may affect function and structure in lacrimal and salivary glands in nonimmune injury (Hypothesis). Environmental factors (especially viruses and bacteria) may play a role in both nonimmune and immune mechanisms. Self-reporting symptoms in patients with SjS may be the results of cumulative effects of nonimmune and immune mechanisms. Apart from functional changes, the syndrome may be also characterized by structural abnormalities of microenvironmental components (niche) which include endothelial cells (Ec) in capillary, myoepithelium (Me), nervous fibers (An), basement membranes (Bm), tight junction (Tj), duct (De), and secretory acinar epithelial cells. In addition, dendritic cells (Dc), which appear in pSjS patients but not in healthy controls [55], may play an important role in immune attack together with effectors (E). Effect of circulating cytokine* and gene* in nonimmune phase and role of locally produced cytokine** and abnormal gene** being responsible for destruction of self-torerance in immune phase are indicated. In this figure, detailed immune mechanisms including the role of environmental factors are omitted. E: effector cells (e.g., cytotoxic T cell, Th1 cell, B cell, and plasma cell).