RESUMO
Chromatin undergoes extensive reprogramming during immune cell differentiation. Here we report the repression of controlled histone H3 amino terminus proteolytic cleavage (H3ΔN) during monocyte-to-macrophage development. This abundant histone mark in human peripheral blood monocytes is catalyzed by neutrophil serine proteases (NSPs) cathepsin G, neutrophil elastase and proteinase 3. NSPs are repressed as monocytes mature into macrophages. Integrative epigenomic analysis reveals widespread H3ΔN distribution across the genome in a monocytic cell line and primary monocytes, which becomes largely undetectable in fully differentiated macrophages. H3ΔN is enriched at permissive chromatin and actively transcribed genes. Simultaneous NSP depletion in monocytic cells results in H3ΔN loss and further increase in chromatin accessibility, which likely primes the chromatin for gene expression reprogramming. Importantly, H3ΔN is reduced in monocytes from patients with systemic juvenile idiopathic arthritis, an autoinflammatory disease with prominent macrophage involvement. Overall, we uncover an epigenetic mechanism that primes the chromatin to facilitate macrophage development.
Assuntos
Artrite Juvenil/imunologia , Diferenciação Celular/imunologia , Epigênese Genética/imunologia , Histonas/metabolismo , Leucócitos Mononucleares/metabolismo , Macrófagos/imunologia , Adolescente , Artrite Juvenil/sangue , Artrite Juvenil/genética , Sistemas CRISPR-Cas/genética , Catepsina G/genética , Catepsina G/metabolismo , Diferenciação Celular/genética , Núcleo Celular/metabolismo , Criança , Pré-Escolar , Cromatina/metabolismo , Ensaios Enzimáticos , Epigenômica , Feminino , Técnicas de Inativação de Genes , Humanos , Células Jurkat , Elastase de Leucócito/genética , Elastase de Leucócito/metabolismo , Leucócitos Mononucleares/imunologia , Macrófagos/metabolismo , Masculino , Mieloblastina/genética , Mieloblastina/metabolismo , Cultura Primária de Células , Proteólise , RNA-Seq , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Células THP-1 , Adulto JovemRESUMO
SARS-CoV-2 can cause acute respiratory distress and death in some patients1. Although severe COVID-19 is linked to substantial inflammation, how SARS-CoV-2 triggers inflammation is not clear2. Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D, leading to inflammatory death (pyroptosis) and the release of potent inflammatory mediators3. Here we show that about 6% of blood monocytes of patients with COVID-19 are infected with SARS-CoV-2. Monocyte infection depends on the uptake of antibody-opsonized virus by Fcγ receptors. The plasma of vaccine recipients does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in the supernatants of cultures of infected monocytes. Instead, infected cells undergo pyroptosis mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and gasdermin D. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from lung autopsies from patients with COVID-19 have activated inflammasomes. Taken together, these findings suggest that antibody-mediated SARS-CoV-2 uptake by monocytes and macrophages triggers inflammatory cell death that aborts the production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.
Assuntos
COVID-19 , Inflamação , Monócitos , Receptores de IgG , SARS-CoV-2 , COVID-19/virologia , Caspase 1/metabolismo , Proteínas de Ligação a DNA , Humanos , Inflamassomos/metabolismo , Inflamação/metabolismo , Inflamação/virologia , Monócitos/metabolismo , Monócitos/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR , Proteínas de Ligação a Fosfato , Proteínas Citotóxicas Formadoras de Poros , Receptores de IgG/metabolismoRESUMO
Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by combined immunodeficiency, eczema, microthrombocytopenia, autoimmunity, and lymphoid malignancies. Gene therapy (GT) to modify autologous CD34+ cells is an emerging alternative treatment with advantages over standard allogeneic hematopoietic stem cell transplantation for patients who lack well-matched donors, avoiding graft-versus-host-disease. We report the outcomes of a phase 1/2 clinical trial in which 5 patients with severe WAS underwent GT using a self-inactivating lentiviral vector expressing the human WAS complementary DNA under the control of a 1.6-kB fragment of the autologous promoter after busulfan and fludarabine conditioning. All patients were alive and well with sustained multilineage vector gene marking (median follow-up: 7.6 years). Clinical improvement of eczema, infections, and bleeding diathesis was universal. Immune function was consistently improved despite subphysiologic levels of transgenic WAS protein expression. Improvements in platelet count and cytoskeletal function in myeloid cells were most prominent in patients with high vector copy number in the transduced product. Two patients with a history of autoimmunity had flares of autoimmunity after GT, despite similar percentages of WAS protein-expressing cells and gene marking to those without autoimmunity. Patients with flares of autoimmunity demonstrated poor numerical recovery of T cells and regulatory T cells (Tregs), interleukin-10-producing regulatory B cells (Bregs), and transitional B cells. Thus, recovery of the Breg compartment, along with Tregs appears to be protective against development of autoimmunity after GT. These results indicate that clinical and laboratory manifestations of WAS are improved with GT with an acceptable safety profile. This trial is registered at clinicaltrials.gov as #NCT01410825.
Assuntos
Eczema , Transplante de Células-Tronco Hematopoéticas , Síndrome de Wiskott-Aldrich , Humanos , Síndrome de Wiskott-Aldrich/genética , Síndrome de Wiskott-Aldrich/terapia , Proteína da Síndrome de Wiskott-Aldrich/genética , Células-Tronco Hematopoéticas/metabolismo , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Terapia Genética/métodos , Eczema/etiologia , Eczema/metabolismo , Eczema/terapiaRESUMO
IMPORTANCE: Human cytomegalovirus (HCMV) requires inactivation of AKT to efficiently replicate, yet how AKT is shut off during HCMV infection has remained unclear. We show that UL38, an HCMV protein that activates mTORC1, is necessary and sufficient to destabilize insulin receptor substrate 1 (IRS1), a model insulin receptor substrate (IRS) protein. Degradation of IRS proteins in settings of excessive mTORC1 activity is an important mechanism for insulin resistance. When IRS proteins are destabilized, PI3K cannot be recruited to growth factor receptor complexes, and hence, AKT membrane recruitment, a rate limiting step in its activation, fails to occur. Despite its penchant for remodeling host cell signaling pathways, our results reveal that HCMV relies upon a cell-intrinsic negative regulatory feedback loop to inactivate AKT. Given that pharmacological inhibition of PI3K/AKT potently induces HCMV reactivation from latency, our findings also imply that the expression of UL38 activity must be tightly regulated within latently infected cells to avoid spontaneous reactivation.
Assuntos
Citomegalovirus , Proteínas Substratos do Receptor de Insulina , Proteínas Proto-Oncogênicas c-akt , Humanos , Citomegalovirus/fisiologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Estabilidade Proteica , Proteólise , Resistência à Insulina , Retroalimentação Fisiológica , Ativação Viral , Latência ViralRESUMO
OBJECTIVE: To describe the clinical features of patients with congenital heart disease (CHD) who subsequently developed systemic juvenile idiopathic arthritis (sJIA). METHODS: We conducted a retrospective review of patients diagnosed with CHD and sJIA at our institution. Detailed clinical, laboratory, and radiographic data were collected from the medical record and reviewed with each patient's primary medical team. RESULTS: Five patients with sJIA and CHD were identified. Each child had a unique cardiac anatomy, but all the patients required surgical repair during the first year of life. Four children had thymectomies at the time of cardiac surgery. Classic signs of sJIA such as fever (n = 5), rash (n = 5), and arthritis (n = 4) developed after surgical intervention in all the patients. The individuals in this cohort displayed risk factors associated with severe sJIA, including disease onset before 2 years of age (n = 5), elevated interleukin 18 levels (n = 5), baseline eosinophilia prior to initiation of biologic disease-modifying antirheumatic drugs (n = 4), and positivity for HLA-DRB1*15:01 alleles (n = 4). Macrophage activation syndrome (MAS) occurred in 3 patients and sJIA-associated lung disease (sJIA-LD) was identified in 4 patients. Two children died from complications of their cardiac and/or pulmonary disease. CONCLUSION: We identified an association between CHD and severe forms of sJIA. Although these findings will need to be confirmed in larger, multicenter cohorts, the results highlight the importance of considering a diagnosis of sJIA in children with CHD and remaining vigilant for complications such as MAS and sJIA-LD.
Assuntos
Artrite Juvenil , Cardiopatias Congênitas , Humanos , Artrite Juvenil/complicações , Cardiopatias Congênitas/complicações , Masculino , Feminino , Estudos Retrospectivos , Pré-Escolar , Criança , Lactente , Síndrome de Ativação Macrofágica/etiologia , Síndrome de Ativação Macrofágica/complicações , Fatores de Risco , Índice de Gravidade de Doença , AdolescenteRESUMO
Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections in children. This syndrome manifests about a month after the initial viral infection and is characterized by fever, multiorgan dysfunction, and systemic inflammation. This chapter will review the emergence, epidemiology, clinical characteristics, diagnosis, pathophysiology, immunomodulatory treatment, prognosis, outcomes, and prevention of MIS-C. While the pathophysiology of MIS-C remains to be defined, it is a post-infection, hyperinflammatory syndrome of childhood with elevated inflammatory cytokines.
Assuntos
COVID-19 , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica , Humanos , COVID-19/complicações , COVID-19/imunologia , COVID-19/virologia , COVID-19/epidemiologia , Síndrome de Resposta Inflamatória Sistêmica/terapia , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Criança , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Prognóstico , Citocinas/metabolismoRESUMO
OBJECTIVE: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.
Assuntos
Linfo-Histiocitose Hemofagocítica , Síndrome de Ativação Macrofágica , Reumatologia , Criança , Adulto , Humanos , Estados Unidos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Linfo-Histiocitose Hemofagocítica/etiologia , Síndrome de Ativação Macrofágica/diagnóstico , Síndrome de Ativação Macrofágica/etiologia , Síndrome de Ativação Macrofágica/terapia , ConsensoRESUMO
CD4+ T cells are central mediators of autoimmune pathology; however, defining their key effector functions in specific autoimmune diseases remains challenging. Pathogenic CD4+ T cells within affected tissues may be identified by expression of markers of recent activation. Here we use mass cytometry to analyse activated T cells in joint tissue from patients with rheumatoid arthritis, a chronic immune-mediated arthritis that affects up to 1% of the population. This approach revealed a markedly expanded population of PD-1hiCXCR5-CD4+ T cells in synovium of patients with rheumatoid arthritis. However, these cells are not exhausted, despite high PD-1 expression. Rather, using multidimensional cytometry, transcriptomics, and functional assays, we define a population of PD-1hiCXCR5- 'peripheral helper' T (TPH) cells that express factors enabling B-cell help, including IL-21, CXCL13, ICOS, and MAF. Like PD-1hiCXCR5+ T follicular helper cells, TPH cells induce plasma cell differentiation in vitro through IL-21 secretion and SLAMF5 interaction (refs 3, 4). However, global transcriptomics highlight differences between TPH cells and T follicular helper cells, including altered expression of BCL6 and BLIMP1 and unique expression of chemokine receptors that direct migration to inflamed sites, such as CCR2, CX3CR1, and CCR5, in TPH cells. TPH cells appear to be uniquely poised to promote B-cell responses and antibody production within pathologically inflamed non-lymphoid tissues.
Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Linfócitos B/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Artrite Reumatoide/sangue , Linfócitos B/patologia , Diferenciação Celular , Movimento Celular , Quimiocina CXCL13/metabolismo , Perfilação da Expressão Gênica , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucinas/metabolismo , Fatores Ativadores de Macrófagos , Fator 1 de Ligação ao Domínio I Regulador Positivo , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CXCR5/deficiência , Receptores CXCR5/metabolismo , Receptores de Quimiocinas/metabolismo , Proteínas Repressoras/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Líquido Sinovial/imunologia , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
BACKGROUND: Deficiency of adenosine deaminase 2 (DADA2) is an autoinflammatory disease caused by deleterious ADA2 variants. The frequency of these variants in the general population, and hence the expected disease prevalence, remain unknown. OBJECTIVE: We aimed to characterize the functional impact and carrier frequency of ADA2 variants. METHODS: We performed functional studies and in silico analysis on 163 ADA2 variants, including DADA2-associated variants and population variants identified in the Genome Aggregation Database. We estimated the carrier rate using the aggregate frequency of deleterious variants. RESULTS: Functional studies of ADA2 variants revealed that 77 (91%) of 85 of DADA2-associated variants reduced ADA2 enzymatic function by >75%. Analysis of 100 ADA2 variants in the database showed a full spectrum of impact on ADA2 function, rather than a dichotomy of benign versus deleterious variants. We found several in silico algorithms that effectively predicted the impact of ADA2 variants with high sensitivity and specificity, and confirmed a correlation between the residual function of ADA2 variants in vitro and the plasma ADA2 activity of individuals carrying these variants (n = 45; r = 0.649; P < .0001). Using <25% residual enzymatic activity as the cutoff to define potential pathogenicity, integration of our results with the database population data revealed an estimated carrier frequency of at least 1 in 236 individuals, corresponding to an expected DADA2 disease prevalence of ~1 in 222,000 individuals. CONCLUSIONS: Functional annotation guides the interpretation of ADA2 variants to create a framework that enables estimation of DADA2 carrier frequency and disease prevalence.
Assuntos
Adenosina Desaminase/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adenosina Desaminase/sangue , Adenosina Desaminase/deficiência , Algoritmos , Predisposição Genética para Doença , Variação Genética , Células HEK293 , Humanos , Doenças do Sistema Imunitário/genética , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Peptídeos e Proteínas de Sinalização Intercelular/deficiênciaRESUMO
Multisystem inflammatory syndrome in children (MIS-C) is a severe complication of SARS-CoV-2 infections that occurs in the pediatric population. We sought to characterize T cell responses in MIS-C compared to COVID-19 and pediatric hyperinflammatory syndromes. MIS-C was distinct from COVID-19 and hyperinflammatory syndromes due to an expansion of T cells expressing TRBV11-2 that was not associated with HLA genotype. Children diagnosed with MIS-C, but who were negative for SARS-CoV-2 by PCR and serology, did not display Vß skewing. There was no difference in the proportion of T cells that became activated after stimulation with SARS-CoV-2 peptides in children with MIS-C compared to convalescent COVID-19. The frequency of SARS-CoV-2-specific TCRs and the antigens recognized by these TCRs were comparable in MIS-C and COVID-19. Expansion of Vß11-2+ T cells was a specific biomarker of MIS-C patients with laboratory confirmed SARS-CoV-2 infections. Children with MIS-C had robust antigen-specific T cell responses to SARS-CoV-2.
Assuntos
COVID-19 , Doenças do Tecido Conjuntivo , COVID-19/complicações , Criança , Humanos , SARS-CoV-2 , Síndrome de Resposta Inflamatória Sistêmica , Linfócitos TRESUMO
OBJECTIVE: Neutrophils are typically the most abundant leucocyte in arthritic synovial fluid. We sought to understand changes that occur in neutrophils as they migrate from blood to joint. METHODS: We performed RNA sequencing of neutrophils from healthy human blood, arthritic blood and arthritic synovial fluid, comparing transcriptional signatures with those from murine K/BxN serum transfer arthritis. We employed mass cytometry to quantify protein expression and sought to reproduce the synovial fluid phenotype ex vivo in cultured healthy blood neutrophils. RESULTS: Blood neutrophils from healthy donors and patients with active arthritis showed largely similar transcriptional signatures. By contrast, synovial fluid neutrophils exhibited more than 1600 differentially expressed genes. Gene signatures identified a prominent response to interferon gamma (IFN-γ), as well as to tumour necrosis factor, interleukin-6 and hypoxia, in both humans and mice. Mass cytometry confirmed that healthy and arthritic donor blood neutrophils are largely indistinguishable but revealed a range of neutrophil phenotypes in synovial fluid defined by downregulation of CXCR1 and upregulation of FcγRI, HLA-DR, PD-L1, ICAM-1 and CXCR4. Reproduction of key elements of this signature in cultured blood neutrophils required both IFN-γ and prolonged culture. CONCLUSIONS: Circulating neutrophils from patients with arthritis resemble those from healthy controls, but joint fluid cells exhibit a network of changes, conserved across species, that implicate IFN-γ response and ageing as complementary drivers of the synovial fluid neutrophil phenotype.
Assuntos
Artrite , Neutrófilos , Envelhecimento , Animais , Artrite/metabolismo , Humanos , Interferon gama/metabolismo , Camundongos , Neutrófilos/metabolismo , Fenótipo , Líquido Sinovial/metabolismoRESUMO
SerpinB1, a protease inhibitor and neutrophil survival factor, was recently linked with IL-17-expressing T cells. Here, we show that serpinB1 (Sb1) is dramatically induced in a subset of effector CD4 cells in experimental autoimmune encephalomyelitis (EAE). Despite normal T cell priming, Sb1-/- mice are resistant to EAE with a paucity of T helper (TH) cells that produce two or more of the cytokines, IFNγ, GM-CSF, and IL-17. These multiple cytokine-producing CD4 cells proliferate extremely rapidly; highly express the cytolytic granule proteins perforin-A, granzyme C (GzmC), and GzmA and surface receptors IL-23R, IL-7Rα, and IL-1R1; and can be identified by the surface marker CXCR6. In Sb1-/- mice, CXCR6+ TH cells are generated but fail to expand due to enhanced granule protease-mediated mitochondrial damage leading to suicidal cell death. Finally, anti-CXCR6 antibody treatment, like Sb1 deletion, dramatically reverts EAE, strongly indicating that the CXCR6+ T cells are the drivers of encephalitis.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/patologia , Receptores CXCR6/metabolismo , Serpinas/fisiologia , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Interferon gama/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CXCR6/genéticaRESUMO
PURPOSE OF REVIEW: To review diagnosis, clinical characteristics and treatment of multisystem inflammatory syndrome in children (MIS-C) associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). RECENT FINDINGS: MIS-C emerged in spring 2020 as a hyperinflammatory syndrome following SARS-CoV-2 exposure in children. Despite growing awareness of MIS-C, diagnosis remains challenging due to the range of phenotypes and severity. Fever accompanied by shock, cardiac dysfunction, gastrointestinal symptoms, or mucocutaneous signs suggestive of Kawasaki disease, especially in the presence of known or suspected coronavirus disease 2019 exposure, should trigger consideration of MIS-C. However, clinical presentations are highly varied and may overlap with other infectious diseases. Clinicians must maintain a high index of suspicion for MIS-C and be aware that patients may develop coronary artery aneurysms and myocarditis even with few or no Kawasaki disease symptoms. More precise diagnostic criteria and specific biomarkers are needed to aid diagnosis. Intravenous immunoglobulin (IVIG) is first-line therapy, and steroids should be considered as initial adjunctive treatment for patients with severe manifestations or other risk factors. Prompt treatment is essential, as patients may worsen acutely, though overall prognosis is reassuring. SUMMARY: MIS-C associated with SARS-CoV-2 has varied clinical manifestations. Clinicians must be aware of the common presentation and potential for decompensation and cardiac sequalae to guide appropriate evaluation and treatment.
Assuntos
COVID-19 , Síndrome de Linfonodos Mucocutâneos , Humanos , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/epidemiologia , Síndrome de Linfonodos Mucocutâneos/terapia , SARS-CoV-2 , Síndrome de Resposta Inflamatória SistêmicaRESUMO
OBJECTIVE: To characterize viscoelastic testing profiles of children with multisystem inflammatory syndrome in children (MIS-C). METHODS: This single-center retrospective review included 30 patients diagnosed with MIS-C from March 1 to September 1, 2020. Thromboelastography (TEG) with platelet mapping was performed in 19 (63%) patients and compared to age- and sex-matched controls prior to cardiac surgery. Relationships between TEG parameters and inflammatory markers were assessed using correlation. RESULTS: Patients with MIS-C had abnormal TEG results compared to controls, including decreased kinetic (K) time (1.1 vs. 1.7 minutes, p < .01), increased alpha angle (75.0° vs. 65.7°, p < .01), increased maximum amplitude (70.8 vs. 58.3 mm, p < .01), and decreased lysis in 30 minutes (Ly30) (1.1% vs. 3.7%, p = .03); consistent with increased clot formation rate and strength, and reduced fibrinolysis. TEG maximum amplitude was moderately correlated with erythrocyte sedimentation rate (ESR) (r = 0.60, p = .02), initial platelet count (r = 0.67, p < .01), and peak platelet count (r = 0.51, p = .03). TEG alpha angle was moderately correlated with peak platelet count (r = 0.54, p = .02). Seventeen (57%) patients received aspirin (ASA) and anticoagulation, five (17%) received only ASA, and three (10%) received only anticoagulation. No patients had a symptomatic thrombotic event. Six (20%) patients had a bleeding event, none of which was major. CONCLUSIONS: Patients with MIS-C had evidence of hypercoagulability on TEG. Increased ESR and platelets were associated with higher clot strength. Patients were prophylactically treated with ASA or anticoagulation with no symptomatic thrombosis or major bleeding. Further multicenter study is required to characterize the rate of thrombosis and optimal thromboprophylaxis algorithm in this patient population.
Assuntos
Coagulação Sanguínea , COVID-19/complicações , Síndrome de Resposta Inflamatória Sistêmica/sangue , Trombofilia/sangue , Adolescente , Anticoagulantes/uso terapêutico , Aspirina/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Plaquetas/efeitos dos fármacos , COVID-19/sangue , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Estudos Retrospectivos , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Tromboelastografia , Trombofilia/tratamento farmacológico , Tratamento Farmacológico da COVID-19RESUMO
Inflammatory conditions are increasingly described in patients with primary immunodeficiencies; however, little is known about the prevalence of immune defects in patients who present first with autoimmunity. We describe the immunologic features of children with early-onset/polyautoimmunity followed in the Multiple Autoimmunity and Immunodeficiency (MAID) Clinic, where patients are co-managed by rheumatologists and immunologists. The most common autoimmune manifestations were cytopenias, lymphoproliferation, and colitis. Recurrent infections were noted in 65% of patients. Abnormalities in lymphocyte subsets and immunoglobulins were common. A pathogenic variant was identified in 19% of patients, and 2 novel inherited disorders were discovered. Additionally, 42% of patients had treatment changes implemented in the MAID clinic. By evaluating this unique cohort of patients, we report on the immunologic underpinning of early-onset/polyautoimmunity. The high rate of genetic diagnoses and treatment interventions in this population highlights the value of collaboration between rheumatologists and immunologists in the care of these complex patients.
Assuntos
Autoimunidade/imunologia , Síndromes de Imunodeficiência/imunologia , Adolescente , Autoimunidade/genética , Criança , Pré-Escolar , Feminino , Humanos , Hipersensibilidade/genética , Hipersensibilidade/imunologia , Síndromes de Imunodeficiência/genética , Infecções/genética , Infecções/imunologia , MasculinoRESUMO
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.
Assuntos
Adenosina Desaminase/sangue , Artrite Juvenil/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Síndrome de Ativação Macrofágica/diagnóstico , Adolescente , Adulto , Artrite Juvenil/complicações , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/análise , Quimiocina CXCL9/sangue , Criança , Dermatomiosite/sangue , Dermatomiosite/imunologia , Feminino , Ferritinas/sangue , Humanos , Interleucina-18/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/imunologia , Síndrome de Ativação Macrofágica/imunologia , Masculino , Síndrome de Linfonodos Mucocutâneos/sangue , Síndrome de Linfonodos Mucocutâneos/imunologia , Valores de Referência , Sensibilidade e EspecificidadeRESUMO
Integrity of the T-cell receptor/CD3 complex is crucial for positive and negative selection of T cells in the thymus and for effector and regulatory functions of peripheral T lymphocytes. In humans, CD3D, CD3E, and CD3Z gene defects are a cause of severe immune deficiency and present early in life with increased susceptibility to infections. By contrast, CD3G mutations lead to milder phenotypes, mainly characterized by autoimmunity. However, the role of CD3γ in establishing and maintaining immune tolerance has not been elucidated. In this manuscript, we aimed to investigate abnormalities of T-cell repertoire and function in patients with genetic defects in CD3G associated with autoimmunity. High throughput sequencing was used to study composition and diversity of the T-cell receptor ß (TRB) repertoire in regulatory T cells (Tregs), conventional CD4+ (Tconv), and CD8+ T cells from 6 patients with CD3G mutations and healthy controls. Treg function was assessed by studying its ability to suppress proliferation of Tconv cells. Treg cells of patients with CD3G defects had reduced diversity, increased clonality, and reduced suppressive function. The TRB repertoire of Tconv cells from patients with CD3G deficiency was enriched for hydrophobic amino acids at positions 6 and 7 of the CDR3, a biomarker of self-reactivity. These data demonstrate that the T-cell repertoire of patients with CD3G mutations is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition.
Assuntos
Complexo CD3/genética , Imunomodulação , Mutação , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Biomarcadores , Complexo CD3/metabolismo , Expressão Gênica , Humanos , Imunofenotipagem , Ativação Linfocitária/imunologia , Complexos Multiproteicos/metabolismo , Ligação Proteica , Receptores de Antígenos de Linfócitos T/metabolismoRESUMO
OBJECTIVE: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA). METHODS: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data. RESULTS: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features. CONCLUSIONS: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.