Destruction of salivary and lacrimal glands by Th1-polarized reaction in a model of secondary Sjögren's syndrome in lupus-prone female NZB × NZWF(1) mice.
ABSTRACT T helper (Th)1/Th2 balance determines the direction of some kinds of autoimmune diseases. The involvement of acini areas by CD4(+) helper T(Th) cell subset in submandibular and lacrimal glands are largely unknown in secondary Sjögren's syndrome (sSjS) with systemic lupus erythematosus (SLE). Submandibular and lacrimal glands were examined immunopathologically in lupus-prone female NZB × NZW(B/W)F(1) mice, model for human sSjS with SLE. Dacryoadenitis and sialoadenitis with renal failure developed with age. Infiltration of lymphoid cells (lymphocytes and plasma cells) expanded from the periductal areas in striated ducts to the acini, and the isolated foci in the acini were observed in those organs. The destruction of duct and acini epithelium, including the myoepithelium, was induced by interferon (IFN)-γ(+) and IgG2a(+) lymphoid cells, but not by interleukin(IL)-4(+), IL-5(+), IL-13(+), and IgG1(+) lymphoid cells. Compared with IL-5 and IL-13, high values of IFN-γ were produced systemically at various ages. Also local expression of IFN-γ mRNA was higher than that of IL-4 mRNA. The result suggests that the acini destruction in submandibular and lacrimal glands may be induced by systemic and local Th1 cell dominant reactions in lupus-prone B/WF(1) mice with sSjS.
- SourceAvailable from: ncbi.nlm.nih.gov[show abstract] [hide abstract]
ABSTRACT: Recently, the Th1/Th2 paradigm has been expanded by the discovery of Th17 cells, a subset of CD4+ memory T cells characterized by their unique ability to secrete interleukin-17 (IL-17) family cytokines. Importantly, Th17 cells appear to be intimately involved in autoimmunity. We undertook the present study to investigate whether the Th17/IL-23 system is up-regulated in Sjögren's syndrome (SS). Sera, saliva, and salivary glands from C57BL/6.NOD-Aec1Aec2 mice (a model for primary SS), as well as sera, saliva, and salivary gland biopsy specimens obtained from patients with primary SS, were evaluated for IL-17 and IL-23 expression by immunohistochemistry, real-time polymerase chain reaction, and the Luminex system. Immunohistochemical stainings of submandibular glands from C57BL/6.NOD-Aec1Aec2 mice and of salivary gland biopsy specimens from SS patients revealed strong positive staining for both IL-17 and IL-23 within lymphocytic foci and diffuse staining on epithelial tissues. Temporal expression of IL-17 and IL-23 in submandibular glands of C57BL/6.NOD-Aec1Aec2 mice correlated with expression of retinoic acid-related orphan receptor gammat, the Th17 cell master control gene. While IL-17 could not be detected in saliva from 4-20-week-old C57BL/6.NOD-Aec1Aec2 mice, this cytokine was present in the blood of mice up to age 16 weeks. This contrasted with sera and saliva from SS patients, in which IL-17 and IL-6 were present at varying levels. These results suggest that the Th17/IL-23 system is up-regulated in C57BL/6.NOD-Aec1Aec2 mice and SS patients at the time of disease. A correlation between up-regulated IL-17/IL-23 expression and specific clinical manifestations of SS has yet to be identified.Arthritis & Rheumatology 04/2008; 58(3):734-43. · 7.48 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Sjögren's syndrome is a human autoimmune disease characterized by lymphocytic infiltration of salivary and lacrimal glands, hypergammaglobulinemia, and specific autoantibodies. The accessibility of the salivary gland to biopsy provides an opportunity to study cytokine mRNA expression at the site of organ-specific immune damage. Using reverse transcriptase and a quantitative PCR to measure cytokine mRNA, we found Sjögren's syndrome: 1) salivary gland CD4+ T cells produce over 40-fold more IL-2, IFN-gamma, and IL-10 mRNA than peripheral blood CD4+ T cells from the same patient or from normal controls; 2) salivary gland CD4+ T cells produced little IL-4 and IL-5 mRNA immediately after elution from the salivary gland, although these mRNAs could be induced by mitogen stimulation of Sjögren's syndrome salivary gland lymphocytes in vitro; 3) salivary gland epithelial cells produced over 40-fold more IL-1 alpha, IL-6, and TNF-alpha mRNA than epithelial cells from individuals with histologically normal salivary glands. Increased levels of IL-1 alpha, IL-6, IL-10, TNF-alpha, and IFN-gamma cytokines were found by ELISA assay in the saliva of Sjögren's syndrome patients, indicating that the elevated mRNA levels detected in their glandular tissue by PCR correlate with local protein synthesis. Our results demonstrate that CD4+ cells in the salivary glands of Sjögren's syndrome patients exhibit mRNA expression that is distinct from previously described Th1 and Th2 lymphocytes in mice or cytokines reported in other human autoimmune or allergic diseases. Also, we found that salivary gland epithelial cells may participate in the pathogenesis of Sjögren's syndrome biopsy by producing cytokines (IL-1 alpha, IL-6, and TNF-alpha).The Journal of Immunology 07/1994; 152(11):5532-9. · 5.52 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Sjögren's syndrome (SS) is an autoimmune disorder characterized by ocular and oral dryness as well as systemic manifestations. The immunopathogenesis of SS is complex with different intricate factors. Because of the delay in the appearance of symptoms and due to ethical issues it is very difficult to study the wide array of factors intervening in the pathogenesis of SS in human patients. To circumvent this problem, different animal models have been elaborated for studying the different subsets of the aspects of the physiopathology of this disease. In this review, we focus on the mouse models that have been established to deepen our insight into the immunopathogenesis of SS.Oral Diseases 08/2007; 13(4):366-75. · 2.38 Impact Factor