TNFα Inhibition in MRL/lpr Mice Ameliorates Pulmonary but not Renal Disease

Kim, Nahmah; Ussin, LaShon; Cheng, Xin; Murali, Ramachandran; Sullivan, Kathleen E.

doi:10.1006/jaut.2002.0617

Cited by 12 publications

(11 citation statements)

References 55 publications

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“…By contrast, lung disease in MRL lpr mice involves the recruitment of CXCR3 positive T cells via local secretion of CXCL10 [37], and the endothelial expression of selectins [38] and intercellular adhesion molecule (ICAM)-1 [39]. In addition, TNF-α is a crucial mediator of lung injury in experimental lupus [40], [41]. Unspecific immunosuppressants like cyclophosphamide or dihydroorotate dehydrogenase inhibitors suppress pulmonary and renal manifestations in experimental lupus [42], [43].…”

Section: Discussionmentioning

confidence: 99%

“…Unspecific immunosuppressants like cyclophosphamide or dihydroorotate dehydrogenase inhibitors suppress pulmonary and renal manifestations in experimental lupus [42], [43]. However, the aforementioned molecular and cellular pathomechanisms of autoimmune lung injury differ, at least in part, from those of lupus nephritis because Icam-1 -deficiency as well as TNF-α antagonism protects MRL lpr mice from lung but not from kidney disease [39], [41]. Furthermore, P-selectin is only induced in lungs but not in kidneys upon immune stimulation with LPS [38] or, as we found here, in experimental SLE.…”

Section: Discussionmentioning

confidence: 99%

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Lack of the Long Pentraxin PTX3 Promotes Autoimmune Lung Disease but not Glomerulonephritis in Murine Systemic Lupus Erythematosus

Lech¹,

Römmele²,

Kulkarni³

et al. 2011

PLoS ONE

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The long pentraxin PTX3 has multiple roles in innate immunity. For example, PTX3 regulates C1q binding to pathogens and dead cells and regulates their uptake by phagocytes. It also inhibits P-selectin-mediated recruitment of leukocytes. Both of these mechanisms are known to be involved in autoimmunity and autoimmune tissue injury, e.g. in systemic lupus erythematosus, but a contribution of PTX3 is hypothetical. To evaluate a potential immunoregulatory role of PTX3 in autoimmunity we crossed Ptx3-deficient mice with Fas-deficient (lpr) C57BL/6 (B6) mice with mild lupus-like autoimmunity. PTX3 was found to be increasingly expressed in kidneys and lungs of B6lpr along disease progression. Lack of PTX3 impaired the phagocytic uptake of apoptotic T cells into peritoneal macrophages and selectively expanded CD4/CD8 double negative T cells while other immune cell subsets and lupus autoantibody production remained unaffected. Lack of PTX3 also aggravated autoimmune lung disease, i.e. peribronchial and perivascular CD3+ T cell and macrophage infiltrates of B6lpr mice. In contrast, histomorphological and functional parameters of lupus nephritis remained unaffected by the Ptx3 genotype. Together, PTX3 specifically suppresses autoimmune lung disease that is associated with systemic lupus erythematosus. Vice versa, loss-of-function mutations in the Ptx3 gene might represent a genetic risk factor for pulmonary (but not renal) manifestations of systemic lupus or other autoimmune diseases.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lack of the Long Pentraxin PTX3 Promotes Autoimmune Lung Disease but not Glomerulonephritis in Murine Systemic Lupus Erythematosus

Lech¹,

Römmele²,

Kulkarni³

et al. 2011

PLoS ONE

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“…Many cytokine pathways are associated with autoimmune lung disease and include IL‐1β, TNF‐α and IL‐6 (7–9). However, none of these cytokines have been reported to be active exclusively during autoimmunity.…”

Section: Introductionmentioning

confidence: 99%

Anti-Type V Collagen Lymphocytes that Express IL-17 and IL-23 Induce Rejection Pathology in Fresh and Well-Healed Lung Transplants

Yoshida

Haque

Mizobuchi

et al. 2006

American Journal of Transplantation

153

180

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“…For example, MRL/lpr mice massively overexpress TNFα. Treatment of MRL/lpr mice with a TNFα inhibitor ameliorates lung disease and skin disease [9]. Specifically in humans, TNFα is thought to contribute to the dyslipidemia of SLE and glomerular disease [10;11].…”

Section: Introductionmentioning

confidence: 99%

The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

Sullivan

Suriano

Dietzmann

et al. 2007

Clinical Immunology

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In systemic lupus erythematosus, TNFα is elevated in the serum and correlates with disease activity and triglyceride levels. The stimuli that drive TNFα in this setting are incompletely understood. This study was designed to evaluate monocyte chromatin at the TNFα locus to identify semi-permanent changes that might play a role in altered expression of TNFα. SLE patients with relatively quiescent disease (mean Physician Global Assessment=0.6) and healthy controls were recruited for this study. TNFα expression was measured by intracellular cytokine staining of different monocyte subsets in patients (n=24) and controls (n=12). Histone acetylation at the TNFα locus was measured by chromatin immunoprecipitation using a normalized quantitative PCR in patients (n=46) and controls (n=24). There were no differences in the overall fractions of cells expressing CD14 in SLE patients compared to controls, however, the fraction of DR+/CD16+ cells expressing CD14 was slightly higher as was true in the monocyte subset defined by DR+/CD11b+. Within the monocyte population defined by physical characteristics and DR+/CD14+, TNFα expressing cells were more frequent in SLE patients compared to controls. Both the fraction of positive cells and the mean fluorescence intensity were higher in patients than controls. Consistent with this was the finding that monocytes from patients had increased TNFα transcripts and more highly acetylated histones at the TNFα locus compared to controls. Furthermore, patients with the highest levels of TNFα histone acetylation were more likely to have had consistently elevated erythrocyte sedimentation rates, and to have required cytotoxic use. Histone acetylation, associated with increased transcriptional competence of TNFα, may play a role in certain inflammatory aspects of the disease.

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TNFα Inhibition in MRL/lpr Mice Ameliorates Pulmonary but not Renal Disease

Cited by 12 publications

References 55 publications

Lack of the Long Pentraxin PTX3 Promotes Autoimmune Lung Disease but not Glomerulonephritis in Murine Systemic Lupus Erythematosus

Lack of the Long Pentraxin PTX3 Promotes Autoimmune Lung Disease but not Glomerulonephritis in Murine Systemic Lupus Erythematosus

Anti-Type V Collagen Lymphocytes that Express IL-17 and IL-23 Induce Rejection Pathology in Fresh and Well-Healed Lung Transplants

The TNFα locus is altered in monocytes from patients with systemic lupus erythematosus

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