Pathogenic role of B cells in the development of diffuse alveolar hemorrhage induced by pristane

Barker, Tolga; Lee, Pui Y.; Kelly-Scumpia, Kindra M.; Weinstein, Jason S.; Nacionales, Dina C.; Kumagai, Yutaro; Akira, Shizuo; Croker, Byron P.; Sobel, Eric S.; Reeves, Westley H.; Satoh, Minoru

doi:10.1038/labinvest.2011.108

Cited by 57 publications

(77 citation statements)

References 41 publications

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“…pristane injection [5], whereas B cell-deficient (μMT) mice are resistant [7]. We asked whether this is due to the absence of immunoglobulin or another B cell function.…”

Section: Resultsmentioning

confidence: 99%

Pathogenesis of Diffuse Alveolar Hemorrhage in Murine Lupus

Zhuang

Han

Lee

et al. 2017

Arthritis & Rheumatology

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Objective Diffuse alveolar hemorrhage (DAH) in lupus patients is >50% fatal. The cause is unknown. The pathogenesis of DAH in C57BL/6 mice with pristane-induced lupus, a model of human lupus-associated DAH, was examined. Methods Clinical/pathological and immunological manifestations DAH in pristane-lupus were compared with human DAH. Tissue distribution of pristane was examined by mass spectrometry. Cell types responsible for disease were determined by in vivo depletion using clodronate liposomes (CloLip) and anti-neutrophil monoclonal antibodies (GR1). The effect of complement depletion with cobra venom factor (CVF) was examined. Results After i.p. injection, pristane migrated to the lung, causing cell death, small vessel vasculitis, and alveolar hemorrhage similar to human DAH. B-cell-deficient mice were resistant to induction of DAH, but susceptibility was restored by infusing IgM. C3-deficient and CD18-deficient mice also were resistant and DAH was prevented in wild-type mice by CVF. Induction of DAH was independent of TLRs, inflammasomes, and inducible nitric oxide (iNOS). Mortality was increased in IL-10-deficient mice and pristane treatment decreased IL-10 receptor expression in monocytes and Stat3 phosphorylation in lung macrophages. In vivo neutrophil depletion was not protective, whereas treatment with CloLip prevented DAH, suggesting that macrophage activation is central to DAH pathogenesis. Conclusion The pathogenesis of DAH involves opsonization of dead cells by natural IgM and complement followed by complement receptor-mediated lung inflammation. The disease is macrophage-dependent and IL-10 is protective. Complement inhibition and/or macrophage-targeted therapies may reduce mortality in lupus-associated DAH.

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“…pristane injection [5], whereas B cell-deficient (μMT) mice are resistant [7]. We asked whether this is due to the absence of immunoglobulin or another B cell function.…”

Section: Resultsmentioning

confidence: 99%

Pathogenesis of Diffuse Alveolar Hemorrhage in Murine Lupus

Zhuang

Han

Lee

et al. 2017

Arthritis & Rheumatology

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“…However, the effect of TMPD is strain dependent and most of the murine studies involving TMPD have utilized B6 mice. TMPD-treated B6 mice often develop hemorrhagic lesions in the lung, and exhibit little evidence of glomerulonephritis or other forms of renal disease (33) (34). Moreover, in contrast to spontaneous models of SLE, TMPD-induced autoimmunity was found to be attenuated in Tlr9 −/− B6 mice (18).…”

Section: Discussionmentioning

confidence: 99%

TLR9 Deficiency Leads to Accelerated Renal Disease and Myeloid Lineage Abnormalities in Pristane-Induced Murine Lupus

Bossaller

Christ

Pelka

et al. 2016

The Journal of Immunology

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Systemic lupus erythematosus (SLE) is a chronic, life threatening autoimmune disorder, leading to multiple organ pathologies and kidney destruction. Analyses of numerous murine models of spontaneous SLE have revealed a critical role for endosomal Toll-like receptors (TLRs) in the production of autoantibodies and development of other clinical disease manifestations. Nevertheless, the corresponding TLR9-deficient autoimmune-prone strains consistently develop more severe disease pathology. Injection of BALB/c mice with 2,6,10,14-tetramethylpentadecane (TMPD), commonly known as pristane, also results in the development of SLE-like disease. We now show that Tlr9−/− BALB/c mice injected intraperitoneally with TMPD develop more severe autoimmunity than their TLR-sufficient cohorts. Early indications include an increased accumulation of TLR7-expressing Ly6Chi inflammatory monocytes at the site of injection, upregulation of interferon regulated gene expression in the peritoneal cavity, and an increased production of myeloid lineage precursors (CMP and GMP) in the bone marrow. TMPD-injected Tlr9−/− BALB/c mice develop higher autoantibody titers against RNA, neutrophil cytoplasmic antigens (ANCA), and myeloperoxidase (MPO) than TMPD-injected WT BALB/c mice. The TMP-injected Tlr9−/− mice, and not the WT mice, also develop a marked increase in glomerular IgG deposition and infiltrating granulocytes, much more severe glomerulonephritis, and a reduced lifespan. Together the data point to a major role for TLR7 in the response to self-antigens in this model of experimental autoimmunity. Therefore the BALB/c pristane model recapitulates other TLR7-driven spontaneous models of SLE and is negatively regulated by TLR9.

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“…In addition, Th1 cells were downregulated, and CD4+CD25+Foxp3+ Treg cells were elevated by MSCT in ALI mice [24]. Animal experiments exhibited that recruitment of macrophages and neutrophils preceded the hemorrhage by several days in DAH [29]. Thus, MSCs may also play an important role in the macrophage-and neutrophil-infiltrated lungs in SLE-associated DAH, which might explain the amelioration of the lung exudations.…”

Section: Improvement Of the Infiltrates On Chest Radiographsmentioning

confidence: 99%

Allogeneic transplantation of umbilical cord-derived mesenchymal stem cells for diffuse alveolar hemorrhage in systemic lupus erythematosus

Shi

Wang

et al. 2012

Clin Rheumatol

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Umbilical cord-derived mesenchymal stem cell transplantation (UC-MSCT) has been proved to be effective in the treatment of systemic lupus erythematosus (SLE), based on animal experiments and clinical trials. Diffuse alveolar hemorrhage (DAH) is a rare complication of SLE with a high mortality usually over 50%. This study aimed to assess the efficacy of UC-MSCT in the treatment of SLE-associated DAH. Four SLE patients complicated with DAH, who underwent UC-MSCT, were included. Clinical changes before and after transplantation were assessed by measurements of hemoglobin, platelet level, oxygen saturation, and serological factors. High-resolution CT (HRCT) scans of the chest were performed to evaluate pulmonary manifestation. All the four patients showed dramatic improvements of their clinical manifestations. Hemoglobin was elevated after UC-MSCT and was sustained at a normal level 6 months after UC-MSCT in the four patients. Platelet level was upregulated in two patients who had thrombocytopenia at baseline. Oxygen saturation appeared to be normal at 1 month after UC-MSCT, and this result was confirmed by the HRCT scan of the chest. Serum albumin elevated to 3.5 g/dl 6 months after transplantation. Our findings suggest that UC-MSCT results in amelioration of oxygen saturation as well as hematological and serologic changes, which revealed that UC-MSCT could be applied as a salvage strategy for DAH patients.

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Pathogenic role of B cells in the development of diffuse alveolar hemorrhage induced by pristane

Cited by 57 publications

References 41 publications

Pathogenesis of Diffuse Alveolar Hemorrhage in Murine Lupus

Pathogenesis of Diffuse Alveolar Hemorrhage in Murine Lupus

TLR9 Deficiency Leads to Accelerated Renal Disease and Myeloid Lineage Abnormalities in Pristane-Induced Murine Lupus

Allogeneic transplantation of umbilical cord-derived mesenchymal stem cells for diffuse alveolar hemorrhage in systemic lupus erythematosus

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