Neutrophil-Mediated IFN Activation in the Bone Marrow Alters B Cell Development in Human and Murine Systemic Lupus Erythematosus

Palanichamy, Arumugam; Bauer, JW; Yalavarthi, Srilakshmi; Meednu, Nida; Barnard, Jennifer; Owen, Teresa; Cistrone, Christopher; Bird, Anna; Rabinovich, Alfred; Nevarez, Sarah; Knight, Jason S.; Dedrick, Russell L.; Rosenberg, Alexander F.; Wei, Chungwen; Rangel-Moreno, Javier; Liesveld, Jane L.; Sanz, Iñaki; Baechler, Emily C.; Kaplan, Mariana J.; Anolik, Jennifer H.

doi:10.4049/jimmunol.1302112

Cited by 90 publications

(87 citation statements)

References 72 publications

(90 reference statements)

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“…Neutrophils also accumulate in proliferative lupus nephritis (3), with recent transcriptional profiling of blood from lupus patients showing a gradual enrichment of neutrophil transcripts during progression to active nephritis (57). Reducing the renal burden and cytotoxic function of neutrophils may also preserve long-term kidney function by dampening intrarenal autoimmunity in predisposed individuals (3,58,59). As with other compounds in the Bcr-Abl class of inhibitors, bosutinib can also target other kinases such as salt-inducible kinases and TEC-family kinases (32) and very likely has antiinflammatory effects beyond the inhibition of FcγRIIA and neutrophils (60,61).…”

Section: Methodsmentioning

confidence: 99%

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

Nishi

Furuhashi

Culleré

et al. 2017

Journal of Clinical Investigation

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Section: Methodsmentioning

confidence: 99%

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

Nishi

Furuhashi

Culleré

et al. 2017

Journal of Clinical Investigation

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“…Healthy controls (n = 14) were age matched, and subjects on bisphosphonates were excluded. BMMCs and PBMCs were isolated from heparinized BM aspirate and heparinized PB by Ficoll-Hypaque density gradient centrifugation (Pharmacia Biotech) (60,61). PBMCs and BMMCs were incubated with anti-human CD45 antibody-conjugated microbeads (Miltenyi Biotec).…”

Section: Methodsmentioning

confidence: 99%

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

Zhang¹,

Hilton²,

Anolik³

et al. 2014

J. Clin. Invest.

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NOTCH-dependent signaling pathways are critical for normal bone remodeling; however, it is unclear if dysfunctional NOTCH activation contributes to inflammation-mediated bone loss, as observed in rheumatoid arthritis (RA) patients. We performed RNA sequencing and pathway analyses in mesenchymal stem cells (MSCs) isolated from transgenic TNF-expressing mice, a model of RA, to identify pathways responsible for decreased osteoblast differentiation. 53 pathways were dysregulated in MSCs from RA mice, among which expression of genes encoding NOTCH pathway members and members of the noncanonical NF-κB pathway were markedly elevated. Administration of NOTCH inhibitors to RA mice prevented bone loss and osteoblast inhibition, and CFU-fibroblasts from RA mice treated with NOTCH inhibitors formed more new bone in recipient mice with tibial defects. Overexpression of the noncanonical NF-κB subunit p52 and RELB in a murine pluripotent stem cell line increased NOTCH intracellular domain-dependent (NICD-dependent) activation of an RBPjκ reporter and levels of the transcription factor HES1. TNF promoted p52/RELB binding to NICD, which enhanced binding at the RBPjκ site within the Hes1 promoter. Furthermore, MSC-enriched cells from RA patients exhibited elevated levels of HES1, p52, and RELB. Together, these data indicate that persistent NOTCH activation in MSCs contributes to decreased osteoblast differentiation associated with RA and suggest that NOTCH inhibitors could prevent inflammation-mediated bone loss. IntroductionPatients with chronic inflammatory diseases, such as rheumatoid arthritis (RA), often have severe systemic bone loss and increased risk of fracture due to increased bone resorption and decreased bone formation, partially mediated by elevated TNF levels (1). We (1-4) and others (5, 6) have reported that TNF inhibits bone formation by affecting major osteoblast regulatory pathways, including BMP/SMAD/RUNX2 and WNT-β-catenin, but the role of TNF in osteoblast differentiation from MSCs has not been fully defined. The TNF transgenic (TNF-Tg) mouse model we use, line 3647, represents a good model of RA to study the influence of chronically elevated, but relatively low, levels of TNF and TNF-induced inflammation on bone cell function and MSC differentiation into osteoblasts (7). To attempt to identify molecules responsible for reduced differentiation of MSCs into osteoblasts in RA, we performed genome-wide screening and pathway analyses using data from RNA sequencing (RNA-Seq) of MSCs purified from TNF-Tg mice and WT littermates. We found that genes in the NOTCH and noncanonical NF-κB signaling pathways were markedly upregulated in TNF-Tg mouse MSCs, raising the possibility that NOTCH may interact with noncanonical NF-κB proteins in MSCs to inhibit their osteogenic differentiation.NOTCH is a family of evolutionarily conserved receptors that regulate cell fate. NOTCH receptors are activated following direct contact with their ligands expressed on adjacent cells. In mammals, there are 4 NOTCH receptors (NOTCH1-NOTCH4)...

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“…No contexto da SAF, também pode ocorrer plaquetopenia. [1][2][3][4][5] Os três componentes do sangue podem ser afetados, isolada ou globalmente. A anemia é a alteração mais comum, embora a leucopenia, a neutropenia, a linfopenia e a trombocitopenia também sejam frequentes.…”

Section: Revisão De Literaturaunclassified

Necrose de medula óssea em paciente portadora de lúpus eritematoso sistêmico

Hilbig

Martinez

2016

Rev. Fac. Ciênc. Méd. Sorocaba

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RESUMOAs manifestações hematológicas do lúpus eritematoso sistêmico (LES) são causas de morbidade e risco aumentado de mortalidade global. Paciente jovem, mulher, com LES e síndrome antifosfolípide (SAF) apresentou pancitopenia severa após infecção urinária. A biópsia de medula óssea (MO) mostrou necrose e fibrose reticulínica. O mecanismo mais comum de pancitopenia é a produção de anticorpos periféricos. No entanto, pode ocorrer raramente com aplasia ou necrose de MO. Necrose de MO é mais frequentemente associada a doenças neoplásicas, infecções severas e anemia falciforme, mas também é descrita em pacientes com LES. Tal necrose é vista, mais raramente, em pacientes com SAF primária. Alterações na microcirculação da MO levam a isquemia necrose. As principais complicações na necrose de MO são pancitopenia e embolia. Poucos estudos da literatura apontam a necrose de medula óssea como causa de pancitopenia em pacientes lúpicos. A necrose de MO é uma entidade relativamente rara e de mau prognóstico. Palavras-chave: lúpus eritematoso sistêmico; pancitopenia; necrose; medula óssea. ABSTRACTThe hematological manifestations of systemic lupus erythematous (SLE) are causes of morbidity and increased risk of mortality. Young patient, female, with SLE and antiphospholipid syndrome (APS) had severe pancytopenia after urinary tract infection. A biopsy of the bone marrow (BM) showed necrosis and fibrosis. The most common pathophysiological mechanism for pancytopenia is the production of peripheral antibodies. However, pancytopenia with BM aplasia or necrosis is rare. BM necrosis is more common with neoplastic diseases, severe infections or sickle cell anemia but is also reported for patients with SLE. It is seen more rarely in patients with primary APS. Changes in the BM microcirculation lead to ischemia and subsequent necrosis. The main complications are pancytopenia and embolism. BM necrosis has been appointed in few clinical studies as a possible cause for pancytopenia in SLE patients. Among the findings, BM necrosis was present in 19% of the patients. BM necrosis is a relatively rare and poor prognosis entity. Keywords: lupus erythematous, systemic; pancytopenia; necrosis; bone marrow. INTRODUÇÃOO lúpus eritematoso sistêmico (LES) é uma doença multissistêmica autoimune. Sua fisiopatologia é baseada na produção de autoanticorpos e imunocomplexos com ativação do sistema complemento. Vários sistemas orgânicos podem ser afetados. Os sintomas podem ser gerais ou específicos, de acordo com os órgãos ou sistemas afetados. São acometidos mais comumente pele, mucosas, serosas, sistema musculoesquelético, rins, sistema nervoso central (SNC), pulmão, coração, trato digestivo e sangue.Este artigo propõe a revisão das manifestações hematológicas do LES , em particular devido à necrose de medula óssea -uma causa rara -, a partir da descrição de um caso específico. RELATO DO CASOO caso se refere a uma paciente do sexo feminino, 28 anos, branca, casada, do lar, natural e procedente de Itapetininga. A paciente foi encaminhada para o hospi...

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Neutrophil-Mediated IFN Activation in the Bone Marrow Alters B Cell Development in Human and Murine Systemic Lupus Erythematosus

Cited by 90 publications

References 72 publications

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

Neutrophil FcγRIIA promotes IgG-mediated glomerular neutrophil capture via Abl/Src kinases

NOTCH inhibits osteoblast formation in inflammatory arthritis via noncanonical NF-κB

Necrose de medula óssea em paciente portadora de lúpus eritematoso sistêmico

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