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1.
Arthritis Rheumatol ; 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32293098

RESUMO

Poor outcomes in COVID-19 correlate with clinical and laboratory features of cytokine storm syndrome. Broad screening for cytokine storm and early, targeted antiinflammatory therapy may prevent immunopathology and could help conserve limited health care resources. While studies are ongoing, extrapolating from clinical experience in cytokine storm syndromes may benefit the multidisciplinary teams caring for patients with severe COVID-19.

2.
Clin Immunol ; 215: 108411, 2020 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-32276138

RESUMO

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that predominantly affects medium-sized arteries. With the establishment and refinement of vasculitis nomenclature and diagnostic criteria, clinical findings of PAN and distinguishing features from other vasculitides are now well characterized. Although PAN typically manifests in adulthood, cohort studies in paediatric patients have shaped our understanding of childhood-onset PAN. The paradigm of childhood-onset PAN changed considerably with the landmark discovery of deficiency of ADA2 (DADA2), a monogenic cause of vasculitis that is often indistinguishable from PAN. Testing for DADA2 has provided an explanation to numerous challenging cases of familial PAN and early-onset PAN around the world. The ability to distinguish DADA2 from classic PAN have important therapeutic implications as tumor necrosis factor inhibitors have demonstrated remarkable efficacy in the treatment of DADA2. In this review, we will discuss our current understanding of PAN and DADA2 and highlight similarities and differences between these vasculitides.

3.
JCI Insight ; 5(6)2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32213704

RESUMO

Systemic juvenile idiopathic arthritis (sJIA) begins with fever, rash, and high-grade systemic inflammation but commonly progresses to a persistent afebrile arthritis. The basis for this transition is unknown. To evaluate a role for lymphocyte polarization, we characterized T cells from patients with acute and chronic sJIA using flow cytometry, mass cytometry, and RNA sequencing. Acute and chronic sJIA each featured an expanded population of activated Tregs uncommon in healthy controls or in children with nonsystemic JIA. In acute sJIA, Tregs expressed IL-17A and a gene expression signature reflecting Th17 polarization. In chronic sJIA, the Th17 transcriptional signature was identified in T effector cells (Teffs), although expression of IL-17A at the protein level remained rare. Th17 polarization was abrogated in patients responding to IL-1 blockade. These findings identify evolving Th17 polarization in sJIA that begins in Tregs and progresses to Teffs, likely reflecting the impact of the cytokine milieu and consistent with a biphasic model of disease pathogenesis. The results support T cells as a potential treatment target in sJIA.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31945408

RESUMO

BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is a syndrome with pleiotropic manifestations including vasculitis and hematologic compromise. A systematic definition of the relationship between adenosine deaminase 2 (ADA2) mutations and clinical phenotype remains unavailable. OBJECTIVE: We sought to test whether the impact of ADA2 mutations on enzyme function correlates with clinical presentation. METHODS: Patients with DADA2 with severe hematologic manifestations were compared with vasculitis-predominant patients. Enzymatic activity was assessed using expression constructs reflecting all 53 missense, nonsense, insertion, and deletion genotypes from 152 patients across the DADA2 spectrum. RESULTS: We identified patients with DADA2 presenting with pure red cell aplasia (n = 5) or bone marrow failure (BMF, n = 10) syndrome. Most patients did not exhibit features of vasculitis. Recurrent infection, hepatosplenomegaly, and gingivitis were common in patients with BMF, of whom half died from infection. Unlike patients with DADA2 with vasculitis, patients with pure red cell aplasia and BMF proved largely refractory to TNF inhibitors. ADA2 variants associated with vasculitis predominantly reflected missense mutations with at least 3% residual enzymatic activity. In contrast, pure red cell aplasia and BMF were associated with missense mutations with minimal residual enzyme activity, nonsense variants, and insertions/deletions resulting in complete loss of function. CONCLUSIONS: Functional interrogation of ADA2 mutations reveals an association of subtotal function loss with vasculitis, typically responsive to TNF blockade, whereas more extensive loss is observed in hematologic disease, which may be refractory to treatment. These findings establish a genotype-phenotype spectrum in DADA2.

6.
Arthritis Rheumatol ; 72(1): 100-113, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31390156

RESUMO

OBJECTIVE: Peripheral blood mononuclear cells (PBMCs) in systemic lupus erythematosus (SLE) patients exhibit a gene expression program (interferon [IFN] signature) that is attributed to overproduction of type I IFNs by plasmacytoid dendritic cells. Type I IFNs have been thought to play a role in the pathogenesis of SLE. This study was undertaken to examine an unexpected influence of monocyte/macrophages on the IFN signature. METHODS: Proinflammatory (classic) and antiinflammatory (nonclassic) monocyte/macrophages were sorted from mice and analyzed by RNA sequencing and quantitative polymerase chain reaction (qPCR). Type I IFN-α/ß/ω receptor (IFNAR-1) expression was determined by qPCR and flow cytometry. Macrophages were stimulated in vitro with IFNα, and pSTAT1was measured. RESULTS: Transcriptional profiling of peritoneal macrophages from mice with pristane-induced SLE unexpectedly indicated a strong IFN signature in classic, but not nonclassic, monocyte/macrophages exposed to the same type I IFN concentrations. Ifnar1 messenger RNA and IFNAR surface staining were higher in classic monocyte/macrophages versus nonclassic monocyte/macrophages (P < 0.0001 and P < 0.05, respectively, by Student's t-test). Nonclassic monocyte/macrophages were also relatively insensitive to IFNα-driven STAT1 phosphorylation. Humans exhibited a similar pattern: higher IFNAR expression (P < 0.0001 by Student's t-test) and IFNα-stimulated gene expression (P < 0.01 by paired Wilcoxon's rank sum test) in classic monocyte/macrophages and lower levels in nonclassic monocyte/macrophages. CONCLUSION: This study revealed that the relative abundance of different monocyte/macrophage subsets helps determine the magnitude of the IFN signature. Responsiveness to IFNα signaling reflects differences in IFNAR expression in classic (high IFNAR) compared to nonclassic (low IFNAR) monocyte/macrophages. Thus, the IFN signature depends on both type I IFN production and the responsiveness of monocyte/macrophages to IFNAR signaling.

7.
Ann Rheum Dis ; 79(2): 225-231, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31707357

RESUMO

OBJECTIVE: Macrophage activation syndrome (MAS) is a life-threatening complication of systemic juvenile idiopathic arthritis (sJIA) characterised by a vicious cycle of immune amplification that can culminate in overwhelming inflammation and multiorgan failure. The clinical features of MAS overlap with those of active sJIA, complicating early diagnosis and treatment. We evaluated adenosine deaminase 2 (ADA2), a protein of unknown function released principally by monocytes and macrophages, as a novel biomarker of MAS. METHODS: We established age-based normal ranges of peripheral blood ADA2 activity in 324 healthy children and adults. We compared these ranges with 173 children with inflammatory and immune-mediated diseases, including systemic and non-systemic JIA, Kawasaki disease, paediatric systemic lupus erythematosus and juvenile dermatomyositis. RESULTS: ADA2 elevation beyond the upper limit of normal in children was largely restricted to sJIA with concomitant MAS, a finding confirmed in a validation cohort of sJIA patients with inactive disease, active sJIA without MAS or sJIA with MAS. ADA2 activity strongly correlated with MAS biomarkers including ferritin, interleukin (IL)-18 and the interferon (IFN)-γ-inducible chemokine CXCL9 but displayed minimal association with the inflammatory markers C reactive protein and erythrocyte sedimentation rate. Correspondingly, ADA2 paralleled disease activity based on serial measurements in patients with recurrent MAS episodes. IL-18 and IFN-γ elicited ADA2 production by peripheral blood mononuclear cells, and ADA2 was abundant in MAS haemophagocytes. CONCLUSIONS: These findings collectively identify the utility of plasma ADA2 activity as a biomarker of MAS and lend further support to a pivotal role of macrophage activation in this condition.

8.
Nature ; 577(7788): 109-114, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31827280

RESUMO

Activation of RIPK1 controls TNF-mediated apoptosis, necroptosis and inflammatory pathways1. Cleavage of human and mouse RIPK1 after residues D324 and D325, respectively, by caspase-8 separates the RIPK1 kinase domain from the intermediate and death domains. The D325A mutation in mouse RIPK1 leads to embryonic lethality during mouse development2,3. However, the functional importance of blocking caspase-8-mediated cleavage of RIPK1 on RIPK1 activation in humans is unknown. Here we identify two families with variants in RIPK1 (D324V and D324H) that lead to distinct symptoms of recurrent fevers and lymphadenopathy in an autosomal-dominant manner. Impaired cleavage of RIPK1 D324 variants by caspase-8 sensitized patients' peripheral blood mononuclear cells to RIPK1 activation, apoptosis and necroptosis induced by TNF. The patients showed strong RIPK1-dependent activation of inflammatory signalling pathways and overproduction of inflammatory cytokines and chemokines compared with unaffected controls. Furthermore, we show that expression of the RIPK1 mutants D325V or D325H in mouse embryonic fibroblasts confers not only increased sensitivity to RIPK1 activation-mediated apoptosis and necroptosis, but also induction of pro-inflammatory cytokines such as IL-6 and TNF. By contrast, patient-derived fibroblasts showed reduced expression of RIPK1 and downregulated production of reactive oxygen species, resulting in resistance to necroptosis and ferroptosis. Together, these data suggest that human non-cleavable RIPK1 variants promote activation of RIPK1, and lead to an autoinflammatory disease characterized by hypersensitivity to apoptosis and necroptosis and increased inflammatory response in peripheral blood mononuclear cells, as well as a compensatory mechanism to protect against several pro-death stimuli in fibroblasts.

9.
J Clin Invest ; 130(4): 1669-1682, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31874111

RESUMO

BACKGROUNDUndifferentiated systemic autoinflammatory diseases (USAIDs) present diagnostic and therapeutic challenges. Chronic interferon (IFN) signaling and cytokine dysregulation may identify diseases with available targeted treatments.METHODSSixty-six consecutively referred USAID patients underwent underwent screening for the presence of an interferon signature using a standardized type-I IFN-response-gene score (IRG-S), cytokine profiling, and genetic evaluation by next-generation sequencing.RESULTSThirty-six USAID patients (55%) had elevated IRG-S. Neutrophilic panniculitis (40% vs. 0%), basal ganglia calcifications (46% vs. 0%), interstitial lung disease (47% vs. 5%), and myositis (60% vs. 10%) were more prevalent in patients with elevated IRG-S. Moderate IRG-S elevation and highly elevated serum IL-18 distinguished 8 patients with pulmonary alveolar proteinosis (PAP) and recurrent macrophage activation syndrome (MAS). Among patients with panniculitis and progressive cytopenias, 2 patients were compound heterozygous for potentially novel LRBA mutations, 4 patients harbored potentially novel splice variants in IKBKG (which encodes NF-κB essential modulator [NEMO]), and 6 patients had de novo frameshift mutations in SAMD9L. Of additional 12 patients with elevated IRG-S and CANDLE-, SAVI- or Aicardi-Goutières syndrome-like (AGS-like) phenotypes, 5 patients carried mutations in either SAMHD1, TREX1, PSMB8, or PSMG2. Two patients had anti-MDA5 autoantibody-positive juvenile dermatomyositis, and 7 could not be classified. Patients with LRBA, IKBKG, and SAMD9L mutations showed a pattern of IRG elevation that suggests prominent NF-κB activation different from the canonical interferonopathies CANDLE, SAVI, and AGS.CONCLUSIONSIn patients with elevated IRG-S, we identified characteristic clinical features and 3 additional autoinflammatory diseases: IL-18-mediated PAP and recurrent MAS (IL-18PAP-MAS), NEMO deleted exon 5-autoinflammatory syndrome (NEMO-NDAS), and SAMD9L-associated autoinflammatory disease (SAMD9L-SAAD). The IRG-S expands the diagnostic armamentarium in evaluating USAIDs and points to different pathways regulating IRG expression.TRIAL REGISTRATIONClinicalTrials.gov NCT02974595.FUNDINGThe Intramural Research Program of the NIH, NIAID, NIAMS, and the Clinical Center.

10.
Front Pediatr ; 7: 480, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31803699

RESUMO

Giant cell tumor of tendon sheath (GCTTS) is characterized by diffuse proliferation of synovial-like cells and multinucleated giant cells along tendon sheaths. This benign tumor typically presents in the third to fourth decade of life and is exceeding rare in children. Here we describe a case of a 10-years-old girl with a history of soft tissue swelling involving the third digit of left hand, bilateral wrists and ankles. Pathology of the finger mass revealed abundant multinucleated giant cells consistent with GCTTS. Resection of the tendinous masses from the ankles also showed multinucleated giant cells along with chronic bursitis. She began to show features of polyarticular arthritis by age 7. Due to progression of arthritis, whole exome sequencing was performed and found a de novo heterozygous mutation in NOD2 (p. R334Q). This variant is the most common mutation responsible for early onset sarcoidosis (EOS)/Blau syndrome, an autoinflammatory disease characterized by granulomatous inflammation of joints, skin and eyes. The early onset of symptoms and presence of multinucleated giant cells and granuloma in this case are in keeping with a diagnosis of EOS/Blau syndrome. The patient responded well to treatment with methotrexate and etanercept. This case extends the clinical spectrum of EOS/Blau syndrome, which should be considered for GCTTS and other unusual presentations of tendon inflammation in children, even in the absence of the characteristic triad of arthritis, dermatitis and uveitis.

11.
JCI Insight ; 4(15)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31391335

RESUMO

Diffuse alveolar hemorrhage (DAH) is a life-threatening pulmonary complication associated with systemic lupus erythematosus, vasculitis, and stem cell transplant. Little is known about the pathophysiology of DAH, and no targeted therapy is currently available. Pristane treatment in mice induces systemic autoimmunity and lung hemorrhage that recapitulates hallmark pathologic features of human DAH. Using this experimental model, we performed high-dimensional analysis of lung immune cells in DAH by mass cytometry and single-cell RNA sequencing. We found a large influx of myeloid cells to the lungs in DAH and defined the gene expression profile of infiltrating monocytes. Bone marrow-derived inflammatory monocytes actively migrated to the lungs and homed adjacent to blood vessels. Using 3 models of monocyte deficiency and complementary transfer studies, we established a central role of inflammatory monocytes in the development of DAH. We further found that the myeloid transcription factor interferon regulatory factor 8 is essential to the development of both DAH and type I interferon-dependent autoimmunity. These findings collectively reveal monocytes as a potential treatment target in DAH.

13.
Elife ; 82019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042146

RESUMO

Bone marrow megakaryocytes engulf neutrophils in a phenomenon termed emperipolesis. We show here that emperipolesis is a dynamic process mediated actively by both lineages, in part through the ß2-integrin/ICAM-1/ezrin pathway. Tethered neutrophils enter in membrane-bound vesicles before penetrating into the megakaryocyte cytoplasm. Intracytoplasmic neutrophils develop membrane contiguity with the demarcation membrane system, thereby transferring membrane to the megakaryocyte and to daughter platelets. This phenomenon occurs in otherwise unmanipulated murine marrow in vivo, resulting in circulating platelets that bear membrane from non-megakaryocytic hematopoietic donors. Transit through megakaryocytes can be completed as rapidly as minutes, after which neutrophils egress intact. Emperipolesis is amplified in models of murine inflammation associated with platelet overproduction, contributing to platelet production in vitro and in vivo. These findings identify emperipolesis as a new cell-in-cell interaction that enables neutrophils and potentially other cells passing through the megakaryocyte cytoplasm to modulate the production and membrane content of platelets.


Assuntos
Plaquetas/metabolismo , Emperipolese/genética , Inflamação/genética , Megacariócitos/metabolismo , Animais , Células da Medula Óssea/metabolismo , Antígenos CD18/genética , Comunicação Celular , Citoplasma/genética , Citoplasma/metabolismo , Proteínas do Citoesqueleto/genética , Humanos , Inflamação/sangue , Inflamação/patologia , Molécula 1 de Adesão Intercelular/genética , Proteínas de Membrana Transportadoras/genética , Camundongos , Neutrófilos/metabolismo
14.
Pediatrics ; 143(5)2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30948682

RESUMO

Systemic juvenile idiopathic arthritis (sJIA) is an aggressive form of childhood arthritis accompanied by persistent systemic inflammation. Patients with sJIA often exhibit poor response to conventional disease-modifying antirheumatic drugs, and chronic glucocorticoid use is associated with significant adverse effects. Although biologics used to target interleukin 1 and interleukin 6 are efficacious, the long-term commitment to frequent injections or infusions remains a challenge in young children. Janus-activated kinase (JAK) inhibitors block the signaling of numerous proinflammatory cytokines and are now used clinically for the treatment of rheumatoid arthritis in adults. Whether this new class of medication is effective for sJIA has not been reported. Here, we describe the case of a 13-year-old girl with recalcitrant sJIA characterized by polyarticular arthritis, fever, lymphadenopathy, and serological features of inflammation. She showed minimal response to nonsteroidal antiinflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs, and etanercept. She also developed osteoporosis and vertebral compression fracture as the result of chronic glucocorticoid therapy. Oral therapy with the JAK inhibitor tofacitinib was initiated, and the patient experienced steady improvement of both arthritis and systemic features. Complete remission was achieved after 3 months, and no evidence of disease activity or adverse effects was seen through 6 months of follow-up. Our experience reveals the effectiveness of JAK inhibition in a case of refractory sJIA. Tofacitinib is an intriguing oral alternative to the available biologics for children with sJIA, and its efficacy and safety should be further assessed by clinical trial.


Assuntos
Artrite Juvenil/diagnóstico por imagem , Artrite Juvenil/tratamento farmacológico , Piperidinas/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Adolescente , Feminino , Humanos , Resultado do Tratamento
15.
Blood Adv ; 3(3): 256-267, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30696624

RESUMO

Antibody ligation of the murine neutrophil surface protein Ly6G disrupts neutrophil migration in some contexts but not others. We tested whether this variability reflected divergent dependence of neutrophil migration on ß2 integrins, adhesion molecules that interact with Ly6G at the neutrophil surface. In integrin-dependent murine arthritis, Ly6G ligation attenuated joint inflammation, even though mice lacking Ly6G altogether developed arthritis normally. By contrast, Ly6G ligation had no impact on integrin-independent neutrophil migration into inflamed lung. In peritoneum, the role of ß2 integrins varied with stimulus, proving dispensable for neutrophil entry in Escherichia coli peritonitis but contributory in interleukin 1 (IL-1)-mediated sterile peritonitis. Correspondingly, Ly6G ligation attenuated only IL-1 peritonitis, disrupting the molecular association between integrins and Ly6G and inducing cell-intrinsic blockade restricted to integrin-dependent migration. Consistent with this observation, Ly6G ligation impaired integrin-mediated postadhesion strengthening for neutrophils arresting on activated cremaster endothelium in vivo. Together, these findings identify selective inhibition of integrin-mediated neutrophil emigration through Ly6G ligation, highlighting the marked site and stimulus specificity of ß2 integrin dependence in neutrophil migration.

16.
Front Pediatr ; 6: 282, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30406060

RESUMO

Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of systemic vasculopathy that often presents during early childhood. Linked to biallelic mutations in ADA2 (previously CECR1), DADA2 was initially described as a syndrome of recurrent fever, livedo racemosa, early-onset strokes, and peripheral vasculopathy that resembles polyarteritis nodosum. However, the wide spectrum of clinical findings and heterogeneity of disease, even among family members with identical mutations, is increasingly recognized. Evidence of systemic inflammation and vasculopathy is not uniformly present in DADA2 patients and some can remain asymptomatic through adulthood. Humoral immunodeficiency characterized by low immunoglobulin levels and increased risk of infection is another common feature of DADA2. Variable cytopenias including pure red cell aplasia that mimics Diamond-Blackfan anemia can also be primary manifestations of DADA2. How defects in a single gene translate into these heterogeneous presentations remains to be answered. In this review, we will summarize lessons learned from the pleiotropic clinical manifestations of DADA2.

18.
J Clin Invest ; 127(9): 3300-3312, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28758901

RESUMO

M2 macrophages, innate lymphoid type 2 cells (ILC2s), eosinophils, Tregs, and invariant NK T cells (iNKT cells) all help to control adipose tissue inflammation, while M1 macrophages, TNF, and other inflammatory cytokines drive inflammation and insulin resistance in obesity. Stromal cells regulate leukocyte responses in lymph nodes, but the role of stromal cells in adipose tissue inflammation is unknown. PDGFRα+ stromal cells are major producers of IL-33 in adipose tissue. Here, we show that mesenchymal cadherin-11 modulates stromal fibroblast function. Cadherin-11-deficient mice displayed increased stromal production of IL-33, with concomitant enhancements in ILC2s and M2 macrophages that helped control adipose tissue inflammation. Higher expression levels of IL-33 in cadherin-11-deficient mice mediated ILC2 activation, resulting in higher IL-13 expression levels and M2 macrophage expansion in adipose tissue. Consistent with reduced adipose tissue inflammation, cadherin-11-deficient mice were protected from obesity-induced glucose intolerance and adipose tissue fibrosis. Importantly, anti-cadherin-11 mAb blockade similarly improved inflammation and glycemic control in obese WT mice. These results suggest that stromal fibroblasts expressing cadherin-11 regulate adipose tissue inflammation and thus highlight cadherin-11 as a potential therapeutic target for the management of obesity.


Assuntos
Tecido Adiposo/fisiopatologia , Caderinas/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Inflamação/fisiopatologia , Adipócitos/citologia , Tecido Adiposo/metabolismo , Animais , Diferenciação Celular , Cruzamentos Genéticos , Diabetes Mellitus Experimental/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Intolerância à Glucose/metabolismo , Inflamação/metabolismo , Resistência à Insulina , Interleucina-13/metabolismo , Interleucina-33/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Camundongos Transgênicos , Obesidade/metabolismo , Fenótipo
19.
Sci Immunol ; 2(11)2017 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-28763796

RESUMO

Monocytes are derived from hematopoietic stem cells through a series of intermediate progenitor stages, but the factors that regulate this process are incompletely defined. Using a Ccr2/Cx3cr1 dual-reporter system to model murine monocyte ontogeny, we conducted a small-molecule screen that identified an essential role of mechanistic target of rapamycin complex 1 (mTORC1) in the development of monocytes and other myeloid cells. Confirmatory studies using mice with inducible deletion of the mTORC1 component Raptor demonstrated absence of mature circulating monocytes, as well as disruption in neutrophil and dendritic cell development, reflecting arrest of terminal differentiation at the granulocyte-monocyte progenitor stage. Conversely, excess activation of mTORC1 through deletion of the mTORC1 inhibitor tuberous sclerosis complex 2 promoted spontaneous myeloid cell development and maturation. Inhibitor studies and stage-specific expression profiling identified failure to down-regulate the transcription factor Myc by the mTORC1 target ribosomal S6 kinase 1 (S6K1) as the mechanistic basis for disrupted myelopoiesis. Together, these findings define the mTORC1-S6K1-Myc pathway as a key checkpoint in terminal myeloid development.

20.
Arthritis Rheumatol ; 69(6): 1280-1293, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28217966

RESUMO

OBJECTIVE: Diffuse alveolar hemorrhage (DAH) in lupus patients confers >50% mortality, and the cause is unknown. We undertook this study to examine the pathogenesis of DAH in C57BL/6 mice with pristane-induced lupus, a model of human lupus-associated DAH. METHODS: Clinical/pathologic and immunologic manifestations of DAH in pristane-induced lupus were compared with those of DAH in humans. Tissue distribution of pristane was examined by mass spectrometry. Cell types responsible for disease were determined by in vivo depletion using clodronate liposomes and antineutrophil monoclonal antibodies (anti-Ly-6G). The effect of complement depletion with cobra venom factor (CVF) was examined. RESULTS: After intraperitoneal injection, pristane migrated to the lung, causing cell death, small vessel vasculitis, and alveolar hemorrhage similar to that seen in DAH in humans. B cell-deficient mice were resistant to induction of DAH, but susceptibility was restored by infusing IgM. C3-/- and CD18-/- mice were also resistant, and DAH was prevented in wild-type mice by CVF. Induction of DAH was independent of Toll-like receptors, inflammasomes, and inducible nitric oxide. Mortality was increased in interleukin-10 (IL-10)-deficient mice, and pristane treatment decreased IL-10 receptor expression in monocytes and STAT-3 phosphorylation in lung macrophages. In vivo neutrophil depletion was not protective, while treatment with clodronate liposomes prevented DAH, which suggests 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.


Assuntos
Hemorragia/etiologia , Pneumopatias/etiologia , Lúpus Eritematoso Sistêmico/complicações , Animais , Modelos Animais de Doenças , Feminino , Hemorragia/patologia , Humanos , Interleucina-10/metabolismo , Pulmão/patologia , Pneumopatias/patologia , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/patologia , Ativação de Macrófagos/fisiologia , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/patologia , Terpenos
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