Τίτλος:
Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjögren's syndrome
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Introduction: In Sjögren's syndrome, keratoconjunctivitis sicca (dry eye) is associated with infiltration of lacrimal glands by leukocytes and consequent losses of tear-fluid production and the integrity of the ocular surface. We investigated the effect of blockade of the lymphotoxin-beta receptor (LTBR) pathway on lacrimal-gland pathology in the NOD mouse model of Sjögren's syndrome. Methods: Male NOD mice were treated for up to ten weeks with an antagonist, LTBR-Ig, or control mouse antibody MOPC-21. Extra-orbital lacrimal glands were analyzed by immunohistochemistry for high endothelial venules (HEV), by Affymetrix gene-array analysis and real-time PCR for differential gene expression, and by ELISA for CXCL13 protein. Leukocytes from lacrimal glands were analyzed by flow-cytometry. Tear-fluid secretion-rates were measured and the integrity of the ocular surface was scored using slit-lamp microscopy and fluorescein isothiocyanate (FITC) staining. The chemokine CXCL13 was measured by ELISA in sera from Sjögren's syndrome patients (n = 27) and healthy controls (n = 30). Statistical analysis was by the two-tailed, unpaired T-test, or the Mann-Whitney-test for ocular integrity scores. Results: LTBR blockade for eight weeks reduced B-cell accumulation (approximately 5-fold), eliminated HEV in lacrimal glands, and reduced the entry rate of lymphocytes into lacrimal glands. Affymetrix-chip analysis revealed numerous changes in mRNA expression due to LTBR blockade, including reduction of homeostatic chemokine expression. The reduction of CXCL13, CCL21, CCL19 mRNA and the HEV-associated gene GLYCAM-1 was confirmed by PCR analysis. CXCL13 protein increased with disease progression in lacrimal-gland homogenates, but after LTBR blockade for 8 weeks, CXCL13 was reduced approximately 6-fold to 8.4 pg/mg (+/- 2.7) from 51 pg/mg (+/-5.3) in lacrimal glands of 16 week old control mice. Mice given LTBR blockade exhibited an approximately two-fold greater tear-fluid secretion than control mice (P = 0.001), and had a significantly improved ocular surface integrity score (P = 0.005). The mean CXCL13 concentration in sera from Sjögren's patients (n = 27) was 170 pg/ml, compared to 92.0 pg/ml for sera from (n = 30) healthy controls (P = 0.01). Conclusions: Blockade of LTBR pathways may have therapeutic potential for treatment of Sjögren's syndrome. © 2011 Fava et al.
Συγγραφείς:
Fava, R.A.
Kennedy, S.M.
Wood, S.G.
Bolstad, A.I.
Bienkowska, J.
Papandile, A.
Kelly, J.A.
Mavragani, C.P.
Gatumu, M.
Skarstein, K.
Browning, J.L.
Περιοδικό:
Arthritis Research and Therapy
Εκδότης:
BioMed Central Ltd.
Λέξεις-κλειδιά:
CXCL13 chemokine; fluorescein isothiocyanate; lymphotoxin beta receptor; macrophage inflammatory protein 3beta; messenger RNA; CXCL13 chemokine; lymphotoxin beta receptor; monoclonal antibody; mucin; sulfated glycoprotein p50, adult; animal experiment; animal model; animal tissue; Article; B lymphocyte; bioaccumulation; clinical article; controlled study; cornea; disease course; enzyme linked immunosorbent assay; female; flow cytometry; gene; GLYCAM1 gene; high endothelial venule; homogenate; human; immunohistochemistry; lacrimal gland; limit of quantitation; male; mouse; nonhuman; pathogenesis; protein expression; protein function; protein RNA binding; real time polymerase chain reaction; secretion (process); Sjoegren syndrome; slit lamp microscopy; staining; venule; aged; animal; article; drug antagonism; drug effect; fluorescence microscopy; gene expression; gene expression profiling; genetics; immunology; keratoconjunctivitis sicca; lacrimal apparatus; lacrimal fluid; metabolism; middle aged; nonobese diabetic mouse; physiology; reverse transcription polymerase chain reaction; Sjoegren syndrome; vascular endothelium, Adult; Aged; Animals; Antibodies, Monoclonal; Chemokine CXCL13; Cornea; Endothelium, Vascular; Female; Gene Expression; Gene Expression Profiling; Humans; Immunohistochemistry; Keratoconjunctivitis Sicca; Lacrimal Apparatus; Lymphotoxin beta Receptor; Male; Mice; Mice, Inbred NOD; Microscopy, Fluorescence; Middle Aged; Mucins; Reverse Transcriptase Polymerase Chain Reaction; Sjogren's Syndrome; Tears; Venules
