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CXCL13 is elevated in Sjogren's syndrome in mice and humans and is implicated in disease pathogenesis.

ABSTRACT: SS is an autoimmune disease. pSS affects exocrine glands predominantly, whereas sSS occurs with other autoimmune connective tissue disorders. Currently, care for patients with SS is palliative, as no established therapeutics target the disease directly, and its pathogenetic mechanisms remain uncertain. B-cell abnormalities have been identified in SS. CXCL13 directs B-cell chemotaxis and is elevated in several autoimmune diseases. In this study, we tested the hypothesis that CXCL13 is elevated in SS in mice and humans and that neutralization of the chemokine ameliorates disease in a murine model. We assayed CXCL13 in mouse models and human subjects with SS to determine whether CXCL13 is elevated both locally and systemically during SS progression and whether CXCL13 may play a role in and be a biomarker for the disease. Cxcl13 expression in salivary tissue increases with disease progression, and its blockade resulted in a modest reduction in glandular inflammation in an SS model. We demonstrate that in humans CXCL13 is elevated in serum and saliva, and an elevated salivary CXCL13 level distinguishes patients with xerostomia. These data suggest a role for CXCL13 as a valuable biomarker in SS, as 74% of patients with SS displayed elevated CXCL13 in sera, saliva, or both. Thus, CXCL13 may be pathogenically involved in SS and may serve as a new marker and a potential therapeutic target.

SUBMITTER: Kramer JM

PROVIDER: S-EPMC3800060 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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CXCL13 is elevated in Sjögren's syndrome in mice and humans and is implicated in disease pathogenesis.

Kramer Jill M JM Klimatcheva Ekaterina E Rothstein Thomas L TL

Journal of leukocyte biology 20130731 5

SS is an autoimmune disease. pSS affects exocrine glands predominantly, whereas sSS occurs with other autoimmune connective tissue disorders. Currently, care for patients with SS is palliative, as no established therapeutics target the disease directly, and its pathogenetic mechanisms remain uncertain. B-cell abnormalities have been identified in SS. CXCL13 directs B-cell chemotaxis and is elevated in several autoimmune diseases. In this study, we tested the hypothesis that CXCL13 is elevated in ...[more]

PMID: 23904442

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Project description:ObjectiveThe objective of this study was to determine the effect of epithelial barrier disruption, caused by deficiency of the membrane-anchored serine protease, matriptase, on salivary gland function and the induction of autoimmunity in an animal model.MethodsEmbryonic and acute ablation of matriptase expression in the salivary glands of mice was induced, leading to decreased epithelial barrier function. Mice were characterized for secretory epithelial function and the induction of autoimmunity including salivary and lacrimal gland dysfunction, lymphocytic infiltration, serum anti-Ro/SSA, anti-La/SSB and antinuclear antibodies. Salivary glands immune activation/regulation, barrier function as well as tight junction proteins expression also were determined. Expression of matriptase in minor salivary gland biopsies was compared among pSS patients and healthy volunteers.ResultsEmbryonic ablation of matriptase expression in mice resulted in the loss of secretory epithelial cell function and the induction of autoimmunity similar to that observed in primary Sjögren's syndrome. Phenotypic changes included exocrine gland dysfunction, lymphocytic infiltrates, production of Sjögren's syndrome-specific autoantibodies, and overall activation of the immune system. Acute ablation of matriptase expression resulted in significant salivary gland dysfunction in the absence of overt immune activation. Analysis of the salivary glands indicates a loss of electrical potential across the epithelial layer as well as altered distribution of a tight junction protein. Moreover, a significant decrease in matriptase gene expression was detected in the minor salivary glands of pSS patients compared with healthy volunteers.ConclusionsOur findings demonstrate that local impairment of epithelial barrier function can lead to loss of exocrine gland function [corrected] in the absence of inflammation while systemic deletion can induce a primary Sjögren's syndrome like phenotype with autoimmunity and loss of gland function.

Project description:Sjögren's Syndrome (SS) is a chronic autoimmune disorder characterized by focal mononuclear cell infiltrates that surround the ducts of the exocrine glands, impairing the function of their secretory units. Compared to other autoimmune disorders, SS is associated with a notably high incidence of non-Hodgkin lymphoma (NHL) and more frequently mucosa associated lymphoid tissue (MALT) lymphoma, leading to increased morbidity and mortality rates. High risk features of lymphoma development include systemic extraepithelial manifestations, low serum levels of complement component C4 and mixed type II cryoglobulinemia. The discrimination between reactive and neoplastic lymphoepithelial lesion (LEL) is challenging, probably reflecting a continuum in the evolution from purely inflammatory lymphoid infiltration to the clonal neoplastic evolution. Early lesions display a predominance of activated T cells, while B cells prevail in severe histologic lesions. This strong B cell infiltration is not only a morphologic phenomenon, but it is also progressively associated with the presence of ectopic germinal centers (GCs). Ectopic formation of GCs in SS represents a complex process regulated by an array of cytokines, adhesion molecules and chemokines. Chronic antigenic stimulation is the major driver of specific B cell proliferation and increases the frequency of their transformation in the ectopic GCs and marginal zone (MZ) equivalents. B cells expressing cell surface rheumatoid factor (RF) are frequently detected in the salivary glands, suggesting that clonal expansion might arise from antigen selection of RF-expressing B cells. Abnormal stimulation and incomplete control mechanisms within ectopic lymphoid structures predispose RF MZ like cells to lymphoma development. Immunoglobulin recombination, somatic mutation and isotype switching during B cell development are events that may increase the translocation of oncogenes to immunoglobulin loci or tumor suppressor gene inactivation, leading to monoclonal B cell proliferation and lymphoma development. Concerning chronic antigenic stimulation, conclusive data is so far lacking. However immune complexes containing DNA or RNA are the most likely candidates. Whether additional molecular oncogenic events contribute to the malignant overgrowth remains to be proved.

Dataset Information

CXCL13 is elevated in Sjogren's syndrome in mice and humans and is implicated in disease pathogenesis.

Publications

CXCL13 is elevated in Sjögren's syndrome in mice and humans and is implicated in disease pathogenesis.

Similar Datasets

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