Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjögren's syndrome in salivary glands of non-obese diabetic mice.
BACKGROUND
The lymphotoxin-beta receptor (LTbetaR) pathway is important in the development and maintenance of lymphoid structures. Blocking this pathway has proven beneficial in murine models of autoimmune diseases such as diabetes and rheumatoid arthritis. The aim of this study was to determine the effects of LTbetaR pathway blockade on Sjögren syndrome (SS)-like salivary gland disease in non-obese diabetic (NOD) mice.


METHODS
The course of SS-like disease was followed in NOD mice that were given lymphotoxin-beta receptor-immunoglobulin fusion protein (LTbetaR-Ig) starting at 9 weeks of age. Treatment was given as a single weekly dose for 3, 7, or 10 weeks. Age-matched NOD mice treated with mouse monoclonal IgG1, or not treated at all, were used as controls. The severity of inflammation, cellular composition, and lymphoid neogenesis in the submandibular glands were determined by immunohistochemistry. Mandibular lymph nodes were also studied. Saliva flow rates were measured, and saliva was analyzed by a multiplex cytokine assay. The salivary glands were analyzed for CXCL13, CCL19, and CCL21 gene expression by quantitative polymerase chain reaction.


RESULTS
Treatment with LTbetaR-Ig prevented the increase in size and number of focal infiltrates normally observed in this SS-like disease. Compared with the controls, the submandibular glands of LTbetaR-Ig-treated mice had fewer and smaller T- and B-cell zones and fewer high endothelial venules per given salivary gland area. Follicular dendritic cell networks were lost in LTbetaR-Ig-treated mice. CCL19 expression was also dramatically inhibited in the salivary gland infiltrates. Draining lymph nodes showed more gradual changes after LTbetaR-Ig treatment. Saliva flow was partially restored in mice treated with 10 LTbetaR-Ig weekly injections, and the saliva cytokine profile of these mice resembled that of mice in the pre-disease state.


CONCLUSIONS
Our findings show that blocking the LTbetaR pathway results in ablation of the lymphoid organization in the NOD salivary glands and thus an improvement in salivary gland function.
Gatumu
Margaret K
MK
Section for Pathology, The Gade Institute, University of Bergen, Haukeland University Hospital, Jonas Lies vei 65, N-5021 Bergen, Norway. margaret.gatumu@gades.uib.no
Skarstein
Kathrine
K
Papandile
Adrian
A
Browning
Jeffrey L
JL
Fava
Roy A
RA
Bolstad
Anne Isine
AI
D000818:Animals; D054415:Chemokine CCL19 / Q000096:biosynthesis; D054421:Chemokine CCL21 / Q000096:biosynthesis; D054382:Chemokine CXCL13 / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D053259:Lymphotoxin beta Receptor / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012469:Salivary Glands / Q000276:immunology* / Q000473:pathology*; D015398:Signal Transduction / Q000276:immunology*; D012859:Sjogren's Syndrome / Q000276:immunology* / Q000473:pathology*
D054415:Chemokine CCL19; D054421:Chemokine CCL21; D054382:Chemokine CXCL13; C505699:Ltbr protein, mouse; D053259:Lymphotoxin beta Receptor