Sjogren's Syndrome
Abstract # 648 Polymorphism of the Interleukin-10 Promoter in Patients with Primary Sjogren's Syndrome. M Garcia-Carrasco, M Ramos-Casals, A Aldea, R Cervera, M Ingelmo, J Vives, J Yague, J Font. Spain.
The objective was to study IL-10 promoter polymorphisms in patients with primary Sjogrens syndrome (SS) and to evaluate epidemiological, clinical or immunological associations. PCR amplification was used to study the IL-10 gene promoter in 50 consecutive patients meeting 4 or more of the European diagnostic criteria for SS and in 110 healthy volunteer controls.
There was a higher frequency of the G allele at the -1082 position in patients vs. controls (45% vs. 32%, p = 0.02). SS patients with the allele 1082*G showed earlier disease onset (46 years vs. 58 years, p = 0.01) than patients with the allele 1082*A. Patients with the GCC/ATA genotype showed a significantly higher prevalence of pulmonary involvement (42% vs. 5% in non-GCC/ATA patients, p = 0.006), cutaneous vasculitis (33% vs. 8%, p = 0.04), and peripheral neuropathy (33% vs. 5%, p = 0.02) and a higher prevalence of positive immunological markers (100% vs. 74%, p = 0.04). Genotype ACC/ACC patients had later onset of SS (68 years vs. 47 years, p = 0.004) and a lower prevalence of immunological markers (40% vs. 84%, p = 0.04) compared with non-ACC/ACC patients.
This is the first study of IL-10 gene promoter polymorphisms in patients with primary SS. There was a significant difference in the distribution of the 1082 allele between SS patients and controls. Certain genotypes were associated with particular clinical and immunological features. Three new polymorphic sites were also identified, although the investigators found no clinical or immunological associations. The immunosuppressive cytokine IL-10 is produced mainly by T-cells and macrophages. Identification of variations in the gene promoter, and correlation with epidemiological, clinical and immunological associations may advance our understanding of the pathogenesis of primary Sjogrens syndrome.
Abstract #2046 (A) A New Defensive Mechanism to Avoid Apoptosis in Salivary Ductal Cells From Patients with Sjogren's Syndrome: Overexpression of P53 and P21. X Mariette, J Sibilia, A Janin. France.
This study assessed the role of p53 abnormalities, either by mutations leading to proliferation, or by activation of the functional wild-type p53, in the preservation of Sjogren's syndrome (SS) ductal cells (in contrast to the destruction by apoptosis of acinar cells). Labial salivary glands (LSG) from 10 patients primary SS, all with a Chisholm grade 4 LSG biopsy, and from 10 control patients with sicca symptoms or systemic diseases with normal LSG biopsy (grade 0 or 1), were studied. The technique used immunohistochemistry against p53 and its transcription target p21, which is expressed only if p53 is functional and not mutated.
P53 antigen was detected in LSG ductal cells of 9/10 SS patients and only 1/10 controls. P21 antigen was detected in ductal cells of 8/10 LSG from SS patients and 2/10 LSG from controls. P53 and P21 antigens co-localized in the same ductal cells in SS patients and the positive ducts were those located around lymphoid foci.
That p53 and its transcription factor p21 co-localized in salivary ductal cells surrounding lymphoid foci demonstrated that p53 was functional and not mutated. The expression of p53 could represent a new defensive mechanism to provide ductal cells the time to repair DNA damage and to avoid apoptosis. The lack of such p53 and p21 overexpression in acinar cells could be a key component of apoptotic destruction of the acinus in SS. This altered expression could provide a basis for new therapeutic strategies in SS.
Abstract # 2048 Reduced Expression of Salivary Gland Aquaporinם (AQP1) in Patients with Seropositive Primary Sjogren's Syndrome. D Beroukas, B Gannon, M Jonsson, D Wilson, R Jonsson, T Gordon. Saudi Arabia and Norway.
This study compared the expression and localization of aquaporins in labial salivary glands (LSG) from patients with primary SS vs. controls. Following microwave retrieval, sections from paraffin-embedded LSG were incubated with affinity-purified rabbit anti-AQP1 and anti-AQP5 antibodies with good retention of morphology. Bound antibodies were detected with Cy3-conjugated anti-rabbit Ig and slides were viewed by fluorescence and confocal laser microscopy. LSG from 5 patient groups were studied: seropositive primary SS with anti-Ro/La antibodies (n = 8); seronegative primary SS (n = 5); patients with sicca symptoms and normal biopsies or nonspecific sialadenitis (n = 10); patients with normal salivary flow and normal biopsies (n = 5); and normal LSG tissue from surgical specimens (n = 5). Results: Normal glands and residual acinar tissue from SS glands gave a similar pattern of bright AQP5 staining of the apical membranes of mucous acinar cells, with weaker staining of lateral acinar membranes. Basal acinar membranes and ducts were negative. Comparison of SS patients and controls revealed no substantial differences in AQP5 expression or localization. AQP1 membrane staining was evident in the basal aspect of the acini but was markedly decreased in both inflamed and histologically normal LSG tissue from SS patients with anti-Ro/La antibodies. The AQP1 loss was patchy and discontinuous and not observed in biopsies from the seronegative SS or control patients. Nonfenestrated endothelia in venules and capillaries stained brightly for AQP1 in all groups.
Aquaporins are responsible for transporting water across the plasma membrane of absorptive and secretory epithelia. The decreased expression of AQP1 as demonstrated in this study suggests a possible contribution to the impaired saliva production in patients with seropositive SS. The mechanism of sicca symptoms in other subsets of patients remains to be identified.
