IL-14 alpha, the nexus for primary Sjögren's disease in mice and humans

Shen, Long; Suresh, Lakshmanan; Li, Hong; Zhang, Chongjie; Kumar, Vijay; Pankewycz, O.; Ambrus, Julian L.

doi:10.1016/j.clim.2008.10.006

Cited by 66 publications

(72 citation statements)

References 41 publications

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“…In previous studies, we demonstrated that transgenic mice expressing the B cell growth factor IL-14a develop a disease that reproduces the clinical and immunological changes characteristic of Sjögren's disease. Moreover, these pathological changes occur in IL-14a transgenic (IL14aTG) mice in the same temporal sequence as observed in patients with Sjögren's disease (3)(4)(5)(6). Confirming previous observations in human disease, we demonstrated that in IL-14a mice, the loss of salivary gland secretion precedes lymphocytic infiltration of the salivary glands (4,7,8).…”

supporting

confidence: 88%

“…Moreover, these pathological changes occur in IL-14a transgenic (IL14aTG) mice in the same temporal sequence as observed in patients with Sjögren's disease (3)(4)(5)(6). Confirming previous observations in human disease, we demonstrated that in IL-14a mice, the loss of salivary gland secretion precedes lymphocytic infiltration of the salivary glands (4,7,8). Several possible mechanisms may underlie salivary gland injury independent of cell-mediated destruction including direct cytokine toxicity from IL-12, IFN-a, IFN-g, lymphotoxin a (LTA), or TNF-a (9-11).…”

mentioning

confidence: 68%

“…qPCR was run on an ABI 7900 instrument (Applied Biosystems, Carlsbad, CA) with the following program: 50˚C for 2 min hold, 95˚C for 10 min hold, 40 cycles of 95˚C, 15 s and 60˚C, 60 s. Melting curve analysis was performed as previously described (4). The primers for LTA were forward primer 59-CACGAGGT-CCAGCTCTTTTC-39 and reverse primer 59-AGTGCAAAGGCTCCAAA-GAA-39; for RelA were forward primer 59-GGCCTCATCCACATGAAC-TT-39 and reverse primer 59-CACTGTCACCTGGAAGCAGA-39; for RelB were forward primer 59-GCGGATTTGCCGAATCAACAAGGA-39 and reverse primer 59-AGCTGCTCAACTCTCCAAGGACAT-39; for NF-kB2 were forward primer 59-TGACTGTGGAGCTGAAGTGG-39 and reverse primer 59-GGTGTGTTTCCAGCAAAGGT-39; and for 18S rRNA control were forward primer 59-CGCGGTTCTATTTTGTTGGT-39 and reverse primer 59-AGTCGGCATCGTTTATGGTC-39.…”

Section: Ltamentioning

confidence: 99%

“…The structure of salivary gland tissues was evaluated by standard histological techniques using H&E staining as previously described (3,4). Immunofluorescence studies were performed as previously described using Abs to mouse IgA, IgG, and IgM from Sigma (St. Louis, MO) (4).…”

Section: Histological and Immunofluorescence Evaluation Of Salivary Gmentioning

confidence: 99%

“…The volume of salivary gland secretions was determined as previously described (4). In short, mice were anesthetized with i.p.…”

Section: Determination Of the Volume Of Salivary Gland Secretionsmentioning

confidence: 99%

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A Role for Lymphotoxin in Primary Sjögren’s Disease

Shen

Suresh

et al. 2010

The Journal of Immunology

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The etiology of salivary gland injury in primary Sjögren’s disease is not well understood. We have previously described a mouse model of Sjögren’s disease, IL-14α transgenic (IL14αTG) mice, which reproduces many of the features of the human disease. We now demonstrate a critical role for lymphotoxin α (LTA) in the pathogenesis of Sjögren’s disease in IL14αTG mice. IL14αTG mice express LTA mRNA in their salivary glands and spleen and produce soluble LTA protein in their salivary secretions. When IL14αTG mice were crossed with LTA−/− mice, the IL14αTG.LTA−/− mice retained normal salivary gland secretions and did not develop either lymphocytic infiltration of their salivary glands or secondary lymphomas. However, both IL14αTG and IL14αTG.LTA−/− mice produced similar amounts of IFN-α and had similar deposition of autoantibodies in their salivary glands. Both IL14α and IL14α/LTA−/− mice had similar B cell responses to T-dependent and T-independent Ags, L-selectin expression, and expression of RelA, RelB, and NF-κB2 in their spleens. These studies suggest that LTA plays a critical role in the local rather than systemic inflammatory process of Sjögren’s disease. Furthermore, local production of soluble LTA in the salivary glands of IL14αTG mice is necessary for the development of overt Sjögren’s disease. Autoantibody deposition alone is not sufficient to produce salivary gland dysfunction. We also demonstrate that LTA is increased in the salivary gland secretions and sera of patients with Sjögren’s disease, further strengthening the biological relevance of the IL14αTG model to understanding the pathogenesis of human disease.

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supporting

confidence: 88%

mentioning

confidence: 68%

Section: Ltamentioning

confidence: 99%

Section: Histological and Immunofluorescence Evaluation Of Salivary Gmentioning

confidence: 99%

“…The volume of salivary gland secretions was determined as previously described (4). In short, mice were anesthetized with i.p.…”

Section: Determination Of the Volume Of Salivary Gland Secretionsmentioning

confidence: 99%

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A Role for Lymphotoxin in Primary Sjögren’s Disease

Shen

Suresh

et al. 2010

The Journal of Immunology

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Genome‐Wide DNA Methylation Patterns in Naive CD4+ T Cells From Patients With Primary Sjögren's Syndrome

Altorok

Coit

Hughes

et al. 2014

Arthritis & Rheumatology

155

101

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Objective Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease with incompletely understood etiology. Very little is known about the role of epigenetic dysregulation in the pathogenesis of pSS. Methods We performed a genome-wide DNA methylation study in naïve CD4+ T cells in eleven pSS patients compared to age-, sex-, and ethnicity-matched healthy controls. Cytosine methylation was quantified using the Illumina Infinium HumanMethylation450 BeadChip array and validated using bisulfite sequencing. Results We identified 553 hypomethylated and 200 hypermethylated CpG sites in naïve CD4+ T cells from pSS patients compared to healthy matched controls, representing 311 hypomethylated and 115 hypermethylated gene regions. Hypomethylated genes in pSS include LTA, coding for Lymphotoxin α. Other relevant genes such as CD247, TNFRSF25, PTPRC, GSTM1 and PDCD1 were also hypomethylated. The interferon signature pathway was represented by hypomethylation of STAT1, IFI44L, USP18 and IFITM1. A group of genes encoding for members of the solute carrier proteins were differentially methylated. In addition, the transcription factor RUNX1 was hypermethylated in patients, suggesting a possible connection to lymphoma predisposition. Gene ontology (GO) analysis of hypomethylated genes demonstrated enrichment of genes involved in lymphocyte activation and immune response. GO terms for hypermethylated genes included antigen processing and presentation. Conclusion This is the first epigenome-wide DNA methylation study in pSS. Our data highlight a role for DNA methylation in pSS and identify disease-associated DNA methylation changes in several genes and pathways in naïve CD4+ T cells in pSS that may be involved in the pathogenesis of this disease.

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Positive Findings on an Early Autoantibody Panel in Sjögren's Syndrome Often Predate Positive Findings on Classic Tests: Comment on the Article by Theander et al

Lichtbroun

2016

Arthritis & Rheumatology

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IL-14 alpha, the nexus for primary Sjögren's disease in mice and humans

Cited by 66 publications

References 41 publications

A Role for Lymphotoxin in Primary Sjögren’s Disease

A Role for Lymphotoxin in Primary Sjögren’s Disease

Genome‐Wide DNA Methylation Patterns in Naive CD4+ T Cells From Patients With Primary Sjögren's Syndrome

Positive Findings on an Early Autoantibody Panel in Sjögren's Syndrome Often Predate Positive Findings on Classic Tests: Comment on the Article by Theander et al

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