A Role for Lymphotoxin in Primary Sjögren’s Disease

Shen, Long; Suresh, Lakshmanan; Wu, Jing; Xuan, Jingxiu; Li, Hong; Zhang, Chongjie; Pankewycz, O.; Ambrus, Julian L.

doi:10.4049/jimmunol.1001520

Cited by 52 publications

(85 citation statements)

References 75 publications

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“…IL14aTG mice mimic the features of pSS seen in patients in the same relative time frame (7)(8)(9)(10)(11). The resulting IL14aTG.IFNa/bR 2/2 mice were viable and infection-free.…”

Section: Resultsmentioning

confidence: 86%

“…Tissue sections were prepared and stained by standard histological techniques using H&E as previously described (10).…”

Section: Histological Evaluationmentioning

confidence: 99%

“…Salivary gland secretions were determined in mice after stimulation with pilocarpine as previously described (10). In short, mice were anesthetized with i.p.…”

Section: Measurement Of Salivary Gland Secretionsmentioning

confidence: 99%

“…Studies utilizing IL14aTG mice lacking lymphotoxin a (LTa) demonstrated that LTa is necessary for salivary gland injury, but not for autoantibody production or production of IFN-a (10). In this study, we investigated the role of IFN-a in pSS.…”

mentioning

confidence: 99%

“…In old age, most IL14aTG mice develop B cell lymphomas characteristic of what is seen in patients with pSS. IL14aTG mice, similar to patients with pSS, produce increased amounts of type 1 IFN (IFN-a) (8)(9)(10)(11).…”

mentioning

confidence: 99%

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Different Stages of Primary Sjögren’s Syndrome Involving Lymphotoxin and Type 1 IFN

Shen

Malyavantham

Kowal

et al. 2013

The Journal of Immunology

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Primary Sjögren’s syndrome (pSS) is a complex autoimmune disease starting in the salivary and lacrimal glands and continuing to involve the lungs and kidneys with the eventual development of lymphoma. Many studies have emphasized the role of type 1 IFN (IFN-α) and lymphotoxin α (LTα) in the pathogenesis of the disease. The present studies were designed to delineate the role of IFN-α in pSS using an animal model, the IL-14α (IL14αTG) transgenic mouse. IL14αTG mice lacking the type 1 IFNR (IL14αTG.IFNR−/−) had the same submandibular gland and lacrimal gland injury as did the IL14αTG mice, but they lacked the later parotid gland and lung injury. Development of lymphoma was delayed in IL14αTG.IFNR−/− mice. The switch from IgM to IgG autoantibodies as well as the increase in serum IgG2a seen is IL14αTG mice was inhibited in IL14αTG.IFNR−/− mice. Production of LTα was identified in both IL14αTG mice and IL14αTG.IFNR−/− mice at the time that salivary gland injury was occurring. These and previous studies suggest a model for pSS that separates the disease into several stages: 1) initial injury to the submandibular and lacrimal glands via an environmental insult and LTα; 2) amplification of local injury via the production of type 1 IFN; injury to the parotid glands, lungs, and kidneys is seen; 3) progression of systemic inflammation with the eventual development of large B cell lymphoma. Understanding these different stages will help to develop strategies for treatment of patients with pSS based on the status of their disease.

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“…IL14aTG mice mimic the features of pSS seen in patients in the same relative time frame (7)(8)(9)(10)(11). The resulting IL14aTG.IFNa/bR 2/2 mice were viable and infection-free.…”

Section: Resultsmentioning

confidence: 86%

“…Tissue sections were prepared and stained by standard histological techniques using H&E as previously described (10).…”

Section: Histological Evaluationmentioning

confidence: 99%

“…Salivary gland secretions were determined in mice after stimulation with pilocarpine as previously described (10). In short, mice were anesthetized with i.p.…”

Section: Measurement Of Salivary Gland Secretionsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Different Stages of Primary Sjögren’s Syndrome Involving Lymphotoxin and Type 1 IFN

Shen

Malyavantham

Kowal

et al. 2013

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

159

102

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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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Lymphotoxin targeted to salivary and lacrimal glands induces tertiary lymphoid organs and cervical lymphadenopathy and reduces tear production

2020

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To investigate the role of lymphotoxin (LT) in Sjögren's syndrome (SS) and in mucosal associated lymphoid tissue (MALT)‐lymphoma, we made transgenic mice (Amy1‐LTαβ) that targeted LTα and LTβ to the salivary and lacrimal glands. Amy1‐LTαβ mice developed atrophic salivary and lacrimal glands that contained tertiary lymphoid organs (TLOs) and had reduced tear production. Amy1‐LTαβ mice developed cervical lymphadenopathy but not MALT‐lymphoma. TLO formation in the salivary and lacrimal glands of Amy1‐LTαβ was not sufficient to induce autoimmunity as measured by autoantibody titres.

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A Role for Lymphotoxin in Primary Sjögren’s Disease

Cited by 52 publications

References 75 publications

Different Stages of Primary Sjögren’s Syndrome Involving Lymphotoxin and Type 1 IFN

Different Stages of Primary Sjögren’s Syndrome Involving Lymphotoxin and Type 1 IFN

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

Lymphotoxin targeted to salivary and lacrimal glands induces tertiary lymphoid organs and cervical lymphadenopathy and reduces tear production

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