Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjögren's syndrome in salivary glands of non-obese diabetic mice

Gatumu, Margaret Karimi; Skarstein, Kathrine; Papandile, Adrian; Browning, Jeffrey L.; Fava, Roy A.; Bolstad, Anne Isine

doi:10.1186/ar2617

Cited by 114 publications

(88 citation statements)

References 42 publications

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“…3). Similar discordance has been noted in the NOD mouse when analyzing diabetes and salivary gland injury (46,65). Although this suggests that the mechanism of injury in these two organs may be different, it must also be considered that the mechanism of lung injury in IL14aTG mice is different from the mechanism of lung injury in IL14aTG.LTA 2/2 mice.…”

Section: Discussionmentioning

confidence: 51%

“…A recent study examining LTBR-Ig in NOD mice, an animal model for both diabetes and Sjögren's syndrome, confirmed that it blocked both the development of diabetes and sialitis. However, LTBR-Ig provided incomplete protection in maintaining normal salivary gland secretions (46). In contrast, a more recent study examining collagen-induced arthritis found that soluble LTBR-Ig had no influence on the disease, whereas Abs to LTA blocked disease induction and the aberrant production of cytokines associated with it (47).…”

Section: Discussionmentioning

confidence: 97%

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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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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 97%

A Role for Lymphotoxin in Primary Sjögren’s Disease

Shen

Suresh

et al. 2010

The Journal of Immunology

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“…baminercept and pateclizumab) may prove effective in blocking ELF activity. Although clinically untested for ELF‐associated inflammation, targeting LT β has shown promise in pre‐clinical experimental models of disease 126, 127, 128, 129. Similarly, CXCL13 blockade has shown some promise in pre‐clinical studies for the treatment of experimental inflammatory arthritis, diabetes and Sjögren syndrome 130, 131, 132.…”

Section: Concluding Remarks and Future Perspectives On The Therapeutimentioning

confidence: 99%

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

2015

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SummaryLymphoid neogenesis is traditionally viewed as a pre‐programmed process that promotes the formation of lymphoid organs during development. Here, the spatial organization of T and B cells in lymph nodes and spleen into discrete structures regulates antigen‐specific responses and adaptive immunity following immune challenge. However, lymphoid neogenesis is also triggered by chronic or persistent inflammation. Here, ectopic (or tertiary) lymphoid organs frequently develop in inflamed tissues as a response to infection, auto‐immunity, transplantation, cancer or environmental irritants. Although these structures affect local immune responses, the contribution of these lymphoid aggregates to the underlining pathology are highly context dependent and can elicit either protective or deleterious outcomes. Here we review the cellular and molecular mechanisms responsible for ectopic lymphoid neogenesis and consider the relevance of these structures in human disease.

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“…NOD H-2 h4 mice also develop a Sj€ ogren's Syndrome-like disease with infiltration of lymphocytes into the salivary gland of older female mice [40]. Treatment of NOD mice with LTbR-Fc for long periods of time reduces these structures [39]. Neutralization of CXCL13 IHC of frozen-spleen sections from mice treated with indicated molecules 9-11 days after immunization (similar splenic structure was noted for all groups 3-5 days after 2nd challenge).…”

Section: Cxcl13 Inhibition Alters Follicular Architecturementioning

confidence: 80%

Effects of CXCL13 inhibition on lymphoid follicles in models of autoimmune disease

Finch

Ettinger²,

Karnell³

et al. 2013

Eur J Clin Investigation

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The chemokine CXCL13 has a key role in secondary lymphoid tissue orchestration and lymphoid neogenesis. Transgenic mice deficient in CXCL13 or its receptor CXCR5 have severely impaired lymph node development, lack peritoneal B-lymphocytes and are deficient in circulating antibodies to common bacterial antigens. However, total circulating numbers of B-lymphocytes are slightly elevated and humoral responses to T-dependent or blood-borne antigens are relatively normal. Lymphoid neogenesis is an aberrant process that occurs in chronically inflamed tissue and provides a microenvironment supportive of pathogenic B-cell survival and activation. Here, we describe the impact of therapeutic dosing of a CXCL13 antibody in a mouse model of arthritis, and detail the contribution CXCL13 makes to lymphoid follicle microenvironment, without affecting humoral immune responses.

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Blockade of lymphotoxin-beta receptor signaling reduces aspects of Sjögren's syndrome in salivary glands of non-obese diabetic mice

Cited by 114 publications

References 42 publications

A Role for Lymphotoxin in Primary Sjögren’s Disease

A Role for Lymphotoxin in Primary Sjögren’s Disease

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

Effects of CXCL13 inhibition on lymphoid follicles in models of autoimmune disease

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