We previously demonstrated that the cells expressed by activation antigens were increased in several T cell subsets from the peripheral blood (PB) and joint fluid (JF) of patients with Sjögren's syndrome (SS) or rheumatoid arthritis (RA). In the present report, we further determined by three-color flow cytometry the homing receptors (Leu8) for peripheral lymph nodes expressed on naive (CD45RA+) or memory (CD45RA-) CD4+ cells and on the two subsets of CD8+ cells (CD11b+ and CD11b-) in the PB and JF from SS and RA patients. In addition, the activation antigens (HLA-DR) and two adhesion molecules, including the alpha-chain of the leukocyte function associated antigen-1 (LFA 1 alpha: CD11a) and its ligand (intercellular adhesion molecule-1: ICAM-1: CD54) expressed on T cells, were compared. We found that CD45RA-CD4+ cells were markedly increased in JF, while CD45RA+CD4+ cells were almost absent. Leu8+ cells were decreased in both CD45RA-CD4+ and CD8+CD11b-cells (cytotoxic T cells) in the JF, and were also decreased in the CD8+CD11b-subset in the patients' PB. Furthermore, activated (DR+) T cells were markedly increased in JF, and the cells expressed more adhesion molecules in both the PB and JF from patients, compared with the DR-T cells. The DR+ T cells therefore are considered to be memory T cells, which are more efficient for cell-to-cell interactions. These observations also suggest that the Leu8- and DR+ T cells with increased adhesion molecules might preferentially migrate into inflammatory tissues, and that naive T cells are being further converted to to memory T cells by in vivo stimulation within the tissues.

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Serum thrombomodulin and anticardiolipin antibodies in patients with systemic lupus erythematosus.

Since thrombomodulin (TM) is a specific cell surface glycoprotein for vascular endothelial cells, serum TM (s-TM) might be a useful marker of endothelial cell damage. Antiphospholipid antibodies (aPL) frequently detected in systemic lupus erythematosus (SLE) have been associated with vascular occlusive diseases. Therefore we measured the s-TM in 60 patients with SLE, in 23 patients with other diseases including aPL (disease control group) and in 26 healthy subjects, by means of an enzyme immunoassay using monoclonal antibodies to human TM. A significant positive correlation was found between s-TM and serum creatinine levels in SLE patients (r = 0.813, p less than 0.001). When the s-TM level was divided by the serum creatinine level (TM/Cr) to exclude the effect of renal clearance, the TM/Cr ratios were significantly increased in SLE patients with active lupus nephritis (LN) compared to those without LN (p less than 0.05). The ratios did not correlate with the presence of aPL or antiphospholipid antibody syndrome (APLS) in SLE patients or in the disease control group, although a weak correlation between the TM/Cr ratios and IgG-anticardiolipin antibody titers was found in the SLE patients without LN (r = 0.449, p less than 0.01). The present results suggest that elevated TM/Cr ratios reflect renal and possibly extra-renal endothelial cell damage in SLE patients with active LN, but that s-TM levels do not associate with the presence of aPL or a history of APLS.

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T cells bearing gamma/delta T cell receptor and their expression of activation antigen in peripheral blood from patients with Sjögren's syndrome.

T cells bearing gamma/delta T cell receptor (gamma/delta + T cells) and their expression of activation antigen (HLA-DR) or the marker of natural killer (NK) cells (CD56), were examined in the peripheral blood lymphocytes (PBL) from twenty-two patients with Sjögren's syndrome (SS) by three-color flowcytometry to elucidate possible pathological roles of the T cell subset in SS. The frequency of gamma/delta + T cells in PBL was not elevated in SS patients, while that of gamma/delta - T cells, which are T cells bearing the alpha/beta T cell receptor (alpha/beta + T cells), was significantly low in the patients, as compared with 22 healthy controls. We found that the proportions of activated cells (HLA-DR+) in both the gamma/delta + and alpha/beta+T cell subsets were significantly higher in the patients than in the controls. The proportions of HLA-DR+ cells in cells in both patients and controls. Furthermore, the frequency of activated cells in both T cell subsets correlated with the duration of disease in SS patients. However, no difference was found in the percentages of total CD56+ cells, CD56+CD3- cells (true NK cells), CD56+CD3+T cells, CD56+gamma/delta+T cells, or CD56-gamma/delta+T cells between the patients and controls. The above results indicate that immunologic activation in SS patients is progressive and involves both alpha/beta+ and gamma/delta+ T cell subsets.

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Lupus cystitis and performation of the small bowel in a patient with systemic lupus erythematosus and overlapping syndrome.

We describe a patient with systemic lupus erythematosus (SLE) and overlapping syndrome who had repeated gastrointestinal (GI) symptoms such as nausea, vomiting and malabsorption. With a subacute process, she developed paralytic ileus and contracted bladder, and died of perforation of the ileum. When 13 reported cases with lupus cystitis were reviewed, an extremely strong correlation between GI and urinary tract symptoms was observed, indicating the presence of a unique subgroup of SLE.

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Lymphocyte subsets of the peripheral blood in Sjögren's syndrome and rheumatoid arthritis.

Lymphocyte subsets were determined in the peripheral blood from twenty-three patients with primary Sjögren's syndrome (SS) and sixteen patients with clinically active rheumatoid arthritis (RA) by two-color flowcytometry using various monoclonal antibodies. In both diseases, T-cells (CD3+), suppressor/cytotoxic cells (CD8+) and their cytotoxic subset (CD8+CD11-) were decreased, as compared with thirty-one healthy controls. B-cells (CD 21+ and CD 3-DR+) and activated T-cells (CD 3+DR+) were increased in SS patients. Helper T-cells (CD 4+Leu8-), suppressor-inducer T-cells (CD4+Leu8+), suppressor T-cells (CD8+Leu 15+) and three natural killer (NK) cell subsets determined by both CD16 and Leu7 antibodies did not differ between controls and SS or RA, although Leu7+NK cells were significantly increased in SS patients. In addition, we found that the treatment with low-dose prednisolone decreased B-cells and suppressor-inducer T cells, and increased suppressor T-cells, cytotoxic T-cells and Leu7+NK cells. The results indicate similar changes in the proportion of lymphocyte subsets and suggest immunologically activated and deficient conditions in both diseases. Immunomodulating effects of the treatment with low-dose prednisolone on some of the lymphocyte subsets in patients with these diseases were also supported by the study.

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Familial Sjögren's syndrome in the Japanese: immunogenetic and serological studies.

Serological abnormalities and HLA haplotypes were studied in a Japanese family of two patients with Sjögren's syndrome (SS) associated with other autoimmune diseases. In contrast to the reports in the U.S.A. and Europe, we found a significant excess of HLA-DRw53 antigen in the family members. Two family members, mother and niece of the probands, had suffered from other connective tissue diseases. Although none of the siblings of probands had manifestations of connective tissue diseases, two siblings had several autoantibodies. No consistent segregation, however, was found between the HLA haplotypes and the serological abnormalities in the relatives. Therefore, HLA alone can not explain the familial clustering of autoimmune diseases including SS and of autoantibodies.

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T lymphocyte subsets of the infiltrating cells in the salivary gland and kidney of a patient with Sjögren's syndrome associated with interstitial nephritis.

Lymphocyte subsets in the salivary gland and kidney were examined in a 38 years-old female patient with Sjögren's syndrome associated with interstitial nephritis by PAP immunoperoxidase method using monoclonal antibodies. Predominant cells of the infiltrating cells in both tissues were T lymphocytes and most of them were Ia+, OKT4+ cells (activated helper/inducer T lymphocytes). A small number of T lymphocytes were OKT8+ (suppressor/cytotoxic T lymphocytes). Moreover, we found the OKT8+ cells invading the salivary duct epithelial cells. There was no difference in the proportion of lymphocyte subsets of the infiltrating cells between the salivary gland and kidney. A similar pathologic mechanism of tissue damage, therefore, was suggested in both tissues.

Acidosis, Renal Tubular↗

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Abnormal expression of apoptosis-related antigens, Fas and bcl-2, on circulating T-lymphocyte subsets in primary Sjögren's syndrome.

OBJECTIVE: To clarify the pathological role of the apoptosis-related molecules expressed on peripheral blood (PB) lymphocyte subsets in primary Sjögren's syndrome (SS). METHODS: The levels of apoptosis-regulating proteins, Fas and bcl-2, were determined in the PB lymphocyte subsets from 21 patients with SS and 14 healthy controls by 2-color flow cytometry. RESULTS: In the PB from SS patients, lymphocytopenia, especially CD4+ cell-lymphocytopenia, was prominent. As observed in previous studies, the percentages of CD4+ CD45RA+ cells were lower in the SS patients than in the controls, while activated (DR+) cells were increased in CD4+ cells from the patients. Fas+ cells were also increased in the patients' CD4+ cells and CD8+ cells, but not in their B cells or natural killer cells. Furthermore, we observed several positive correlations among the percentages of activated cells (DR+ cells or CD45RA-cells) and Fas+ cells recognized in the CD4+ and/or CD8+ cells from the patients. On the other hand, intra-cellular bcl-2 proteins measured as mean fluorescence intensity were significantly diminished in the CD4+ cells, CD8+ cells, CD19+ cells, CD45RO+ cells and Fas+ cells from 14 SS patients compared with 12 healthy controls. In addition, the numbers and/or percentages of CD4+ cells and Fas+ cells positively correlated with their expression of bcl-2 in SS patients. CONCLUSION: The abnormal balance between Fas and bcl-2 expression detected in the PB lymphocyte subsets from SS patients relates, at least partially, to the lymphocytopenia observed in the patients.

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