Dataset Information

Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjogren's syndrome.

ABSTRACT: 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.

SUBMITTER: Fava RA

PROVIDER: S-EPMC3334628 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjögren's syndrome.

Fava Roy A RA Kennedy Susan M SM Wood Sheryl G SG Bolstad Anne I AI Bienkowska Jadwiga J Papandile Adrian A Kelly John A JA Mavragani Clio P CP Gatumu Margaret M Skarstein Kathrine K Browning Jeffrey L JL

Arthritis research & therapy 20111101 6

<h4>Introduction</h4>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.<h4>Methods</h4>Male NOD mice were treated for up to ten weeks with an antagonist, LTBR-Ig, or control mou ...[more]

PMID: 22044682

Similar Datasets

Project description:The C57BL/6.NOD-Aec1Aec2 mouse has been extensively studied to define the underlying cellular and molecular basis for the onset and development of Sjögren's syndrome (SS), a human systemic autoimmune disease characterized clinically as the loss of normal lacrimal and salivary gland functions leading respectively to dry eye and dry mouth pathologies. While an overwhelming majority of SS studies in both humans and rodent models have long focused primarily on pathophysiological events and the potential role of T lymphocytes in these events, recent studies in our murine models have indicated that marginal zone B (MZB) lymphocytes are critical for both development and onset of SS disease. Although migration and function of MZB cells are difficult to study in vivo and in vitro, we have carried out ex vivo investigations that use temporal global RNA transcriptomic analyses to track early cellular and molecular events in these exocrine glands of C57BL/6.NOD-Aec1Aec2 mice. In the present report, genome-wide transcriptome analyses of lacrimal glands indicate that genes and gene-sets temporally upregulated during early onset of disease define the Notch2/NF-kβ14 and Type1 interferon signal transduction pathways, as well as identify chemokines, especially Cxcl13, and Rho-GTPases, including DOCK molecules, in the cellular migration of immune cells to the lacrimal glands. We discuss how the current results compare with our recently published salivary gland data obtained from similar studies carried out in our C57BL/6.NOD-Aec1Aec2 mice, pointing out both similarities and differences in the etiopathogeneses underlying the autoimmune response within the two glands. Overall, this study uses the power of transcriptomic analyses to identify temporal molecular bioprocesses activated during the preclinical covert pathogenic stage(s) of SS disease and how these findings may impact future intervention therapies as the disease within the two exocrine glands may not be identical.

Project description:Key pointsFew reports have explored the possibility of involvement of non-inflammatory factors in lacrimal hyposecretion in Sjögren's syndrome (SS). RNA-sequencing analysis revealed that only four genes, including arginase 1, were downregulated in the lacrimal gland of SS model male mice (NOD mice) after onset of lacrimal hyposecretion and dacryoadenitis. Even in non-dacryoadenitis-type NOD mice, tear secretion and arginase 1 expression remained low. An arginase 1 inhibitor reduced tear secretion and partially reduced saliva secretion in BALB/c mice. The results indicate that a non-inflammatory factor, arginase 1, is involved in lacrimal hyposecretion in male NOD mice, regardless of dacryoadenitis status.AbstractLacrimal fluid (tears) is important for preservation of the ocular surface, and thus lacrimal hyposecretion in Sjögren's syndrome (SS) leads to reduced quality of life. However, the cause(s) of lacrimal hyposecretion remains unknown, even though many studies have been conducted from the perspective of inflammation. Here, we hypothesized that a non-inflammatory factor induces lacrimal hyposecretion in SS pathology, and to elucidate such a factor, we conducted transcriptome analysis of the lacrimal glands in male non-obese diabetic (NOD) mice as an SS model. The NOD mice showed inflammatory cell infiltration and decreased pilocarpine-induced tear secretion at and after 6 weeks of age compared to age-matched BALB/c mice. RNA-sequencing analysis revealed that only four genes, including arginase 1, were downregulated, whereas many genes relating to inflammation were upregulated, in the lacrimal glands of male NOD mice after onset of lacrimal hyposecretion and dacryoadenitis (lacrimal gland inflammation). Changes in the level of arginase 1 expression were confirmed by real-time RT-PCR and western blot analysis. Furthermore, non-dacryoadenitis-type NOD mice were used to investigate the relationships among arginase 1 expression, lacrimal hyposecretion and dacryoadenitis. Interestingly, these NOD mice retained the phenotype of dacryoadenitis with regard to tear secretion and arginase 1 expression level. An arginase 1 inhibitor reduced tear secretion and partially reduced saliva secretion in BALB/c mice. In conclusion, a non-inflammatory factor, arginase 1, is involved in lacrimal hyposecretion in male NOD mice, regardless of dacryoadenitis status. These results shed light on the pathophysiological role of arginase 1 in SS (dry eye).

Dataset Information

Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjogren's syndrome.

Publications

Lymphotoxin-beta receptor blockade reduces CXCL13 in lacrimal glands and improves corneal integrity in the NOD model of Sjögren's syndrome.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets