Although a role for CD4+ T cells in the pathogenesis of Sjögren's syndrome (SS) has been documented, the pathogenic significance of CD8+ T cells is unclear. The aim of this study was to investigate the role of CD8+ T cells in the development of SS. Flow cytometry and immunofluorescence analyses were utilized to detect T cell infiltration within the labial salivary glands of patients with primary SS. In parallel, p40-/- CD25-/- mice were used as a murine model of SS. In addition, mice with genetic knockout of CD4, CD8a, or interferon-γ (IFNγ) were crossed with p40-/- CD25-/- mice to study the pathogenic significance of specific lineage subpopulations, including functional salivary gland tests as well as histopathologic and serologic data. A CD8+ T cell-specific depletion antibody was used in this murine SS model to evaluate its potential as a therapeutic strategy. CD8+ T cells with a tissue-resident memory phenotype outnumbered CD4+ T cells in the labial salivary glands of patients with SS, and were primarily colocalized with salivary duct epithelial cells and acinar cells. Furthermore, infiltrating CD8+ T cells with a CD69+CD103+/- tissue-resident phenotype and with a significant elevation of IFNγ production were dominant in the submandibular glands of mice in this murine SS model. CD8a knockout abrogated the development of SS in these mice. Knockout of IFNγ decreased CD8+ T cell infiltration and gland destruction. More importantly, depletion of CD8+ T cells fully protected mice against the pathologic manifestations of SS, even after the onset of disease. These data reveal the pathogenic significance of CD8+ T cells in the development and progression of SS in the salivary glands. Treatment directed against CD8+ T cells may be a rational therapy for the management of SS in human subjects.

The regenerating gene, Reg, was originally isolated from a rat regenerating islet complementary DNA (cDNA) library, and its human homologue was named REG Iα. Recently, we reported that REG Iα messenger RNA (mRNA), as well as its product, was overexpressed in ductal epithelial cells in the salivary glands of Sjögren's syndrome patients. Furthermore, autoantibodies against REG Iα were found in the sera of Sjögren's syndrome patients, and the patients who were positive for the anti-REG Iα antibody showed significantly lower saliva secretion than antibody-negative patients. We found the mechanism of REG Iα induction in salivary ductal epithelial cells. Reporter plasmid containing REG Iα promoter (-1190/+26) upstream of a luciferase gene was introduced into human NS-SV-DC and rat A5 salivary ductal cells. The cells were treated with several cytokines (interleukin (IL)-6, IL-8, etc.), upregulated in Sjögren's syndrome salivary ducts, and the transcriptional activity was measured. IL-6 stimulation significantly enhanced the REG Iα promoter activity in both cells. Deletion analysis revealed that the -141∼-117 region of the REG Iα gene was responsible for the promoter activation by IL-6, which contains a consensus sequence for signal transducer and activator of transcription (STAT) binding. The introduction of small interfering RNA for human STAT3 abolished IL-6-induced REG Iα transcription. These results indicated that IL-6 stimulation induced REG Iα transcription through STAT3 activation and binding to the REG Iα promoter in salivary ductal cells. This dependence of REG Iα induction upon IL-6/STAT in salivary duct epithelial cells may play an important role in the pathogenesis/progression of Sjögren's syndrome.

Interleukin-6/STAT pathway is responsible for the induction of gene expression of REG Iα, a new auto-antigen in Sjögren׳s syndrome patients, in salivary duct epithelial cells

AB0189 Interleukin-6/Stat Pathway is Responsible for the Induction of REG Iα, A New Auto-Antigen in SjÖGren's Syndrome Patients, in Salivary Duct Epithelial Cells

AB0136 Induction of reg ia, a new auto-antigen in sjögren’s syndrome patients, in salivary duct epithelial cells by interleukin-6 and -11

Xerostomia is a subjective complaint of mouth/oral dryness, caused by a reduction in normal salivary secretion due to different causes. Even though there are many available treatment modalities to enhance salivary flow, the therapy often remains unsatisfactory. The low-level laser therapy (low-level laser irradiation, photo-biomodulation) has been extensively used as a new, non-invasive approach and advantageous tool for reduction of xerostomia. Therefore, the aim of this study is to give a systematic overview on the effects of low-level laser therapy on xerostomia. A systematic review of published articles in PubMed database was carried out using keywords: "low-level laser therapy", "xerostomia", "mouth dryness". In all published articles, which were considered adequate for this overview, positive effects of low-level laser therapy were reported. Low-level laser therapy could significantly enhance salivary secretion and improve antimicrobial characteristics of secreted saliva (increased level of secretory immunoglobulin A; sIgA). Furthermore, low-level laser therapy could improve salivary flow and regeneration of salivary duct epithelial cells. The current literature suggests that low-level laser therapy can be safely and effectively used as an advanced treatment modality for reduction of xerostomia. Further in vivo, in vitro and clinical studies using different irradiation parameters are suggested to determine the best laser parameters to be used.

To determine the prevalence of diffuse infiltrative lymphocytosis syndrome (DILS) in the minor salivary glands of 30 African Cameroonian adults with the acquired immunodeficiency syndrome (AIDS). Salivary gland tissue was analyzed using a modified classification system that was developed to aid the diagnosis of Sjögren syndrome. The advantages and disadvantages of this approach are discussed. Formalin-fixed, paraffin-embedded, hematoxylin-eosin-stained biopsy sections were prepared for 30 patients with AIDS, 26 healthy individuals who declined human immunodeficiency virus (HIV) testing, and 4 seronegative healthy controls. Tissues were immunostained for CD4/CD8+ lymphocytes and cytomegalovirus (CMV), and transmission electron microscopy was performed to locate viral particles. Patients were tested for HIV-1 and HIV-2 by the HIV/Chek System 3 or CAMSTIX-HIV-1 and HIV-2 assay. Severe salivary ductal atypia (96%) was the feature most strongly associated with AIDS, and the lymphocytic focus score was the second histologic feature most strongly correlated with AIDS. Forty-eight percent of patients with HIV-1 infection had more than 1 lymphocytic focus in a minor salivary gland. These lymphocytes were primarily CD8+. We report, to the best of our knowledge, the first case of multinucleated salivary duct epithelial cells in minor salivary glands also containing enveloped virus particles. All cases were negative for CMV. The prevalence of DILS in West Africans with AIDS appears higher than the prevalence reported in whites from the United States and Europe and in blacks from the United States, a group that has been reported to have a greater incidence of DILS than whites. This discrepancy may be related to differences in patient selection criteria. The determination of lymphocytic focus score, as used in the diagnosis of Sjögren syndrome, with the adjunct of ductal atypia is useful for assessing DILS. The impact of patient selection, drug therapy, and parasites on salivary gland pathology is discussed.

c Objective.—To determine the prevalence of diffuse infil- trative lymphocytosis syndrome (DILS) in the minor sali- vary glands of 30 African Cameroonian adults with the ac- quired immunodeficiency syndrome (AIDS). Design.—Salivary gland tissue was analyzed using a modified classification system that was developed to aid the diagnosis of Sjogren syndrome. The advantages and dis- advantages of this approach are discussed. Materials and Methods.—Formalin-fixed, paraffin-em- bedded, hematoxylin-eosin-stained biopsy sections were prepared for 30 patients with AIDS, 26 healthy individuals who declined human immunodeficiency virus (HIV) test- ing, and 4 seronegative healthy controls. Tissues were im- munostained for CD4/CD8 1 lymphocytes and cytomega- lovirus (CMV), and transmission electron microscopy was performed to locate viral particles. Patients were tested for HIV-1 and HIV-2 by the HIV/Chek System 3 or CAMSTIX- HIV-1 and HIV-2 assay. Results.—Severe salivary ductal atypia (96%) was the feature most strongly associated with AIDS, and the lym- phocytic focus score was the second histologic feature most strongly correlated with AIDS. Forty-eight percent of patients with HIV-1 infection had more than 1 lymphocytic focus in a minor salivary gland. These lymphocytes were primarily CD8 1 . We report, to the best of our knowledge, the first case of multinucleated salivary duct epithelial cells in minor salivary glands also containing enveloped virus particles. All cases were negative for CMV. Conclusions.—The prevalence of DILS in West Africans with AIDS appears higher than the prevalence reported in whites from the United States and Europe and in blacks from the United States, a group that has been reported to have a greater incidence of DILS than whites. This discrep- ancy may be related to differences in patient selection cri- teria. The determination of lymphocytic focus score, as used in the diagnosis of Sjogren syndrome, with the ad- junct of ductal atypia is useful for assessing DILS. The im- pact of patient selection, drug therapy, and parasites on salivary gland pathology is discussed. (Arch Pathol Lab Med. 2000;124:1773-1779)