RESUMO
Multisystem inflammatory syndrome in children (MIS-C) shares several clinical and immunological features with Kawasaki Disease (KD) and pediatric hyperinflammation, but the immuno-phenotypic overlap among these clinical mimics is still incompletely understood. Here we analyzed serum samples from treatment-naïve patients with MIS-C (n = 31) and KD (n = 11), pediatric hyperinflammation (n = 13) and healthy controls (HC, n = 10) by proximity extension assay (PEA) to profile 184 blood biomarkers. Collectively, immunophenotypic overlap between MIS-C and hyperinflammation exceeds overlap with KD. Overexpression of IL-17A in MIS-C and KD could best separate these conditions from hyperinflammatory conditions, while those were hallmarked by overabundance of adenosin deaminase and IL-18. Depletion in serum TNF-related subfamily member 9 (TNFRSF9) and apoptosis inducing ligand (TRAIL) linked with cardiovascular manifestations and myocarditis in MIS-C. Altogether, our analysis highlights important differences in molecular marker signatures also across different MIS-C and KD cohorts and suggests several previously unidentified molecular associations in context of cardiovascular inflammation.
Assuntos
Biomarcadores , Síndrome de Linfonodos Mucocutâneos , Proteômica , Síndrome de Resposta Inflamatória Sistêmica , Humanos , Biomarcadores/sangue , Síndrome de Linfonodos Mucocutâneos/sangue , Síndrome de Linfonodos Mucocutâneos/imunologia , Masculino , Feminino , Proteômica/métodos , Criança , Pré-Escolar , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Inflamação/sangue , Lactente , Interleucina-17/sangue , Ligante Indutor de Apoptose Relacionado a TNF/sangue , Interleucina-18/sangue , Adenosina Desaminase/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/imunologiaRESUMO
BACKGROUND: Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1ß-driven disease of unknown etiology. OBJECTIVE: In the present study we sought to investigate a potential role of recently described autoantibodies neutralizing the interleukin-1(IL-1)-receptor antagonist (IL-1-Ra) in the pathogenesis of Still's disease. METHODS: Serum or plasma samples from Still's disease patients (AOSD, n = 23; sJIA, n = 40) and autoimmune and/or inflammatory disease controls (n = 478) were analyzed for autoantibodies against progranulin (PGRN), IL-1Ra, IL-18 binding protein (IL-18BP), and IL-36Ra, as well as circulating IL-1Ra and IL-36Ra levels by ELISA. Biochemical analyses of plasma IL-1Ra were performed by native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signaling reporter assay. RESULTS: Anti-IL-1-Ra IgG were identified in 7 (27%) out of 29 Still's disease patients, including 4/23 with AOSD and 3/6 with sJIA and coincided with a hyperphosphorylated isoform of endogenous IL-1Ra. Anti-IL-36Ra antibodies were found in 2 AOSD patients. No anti-PGRN or anti-IL-18BP antibodies were detected. Selective testing for anti-IL-1Ra antibodies in an independent cohort (sJIA, n = 34) identified 5 of 34 (14.7%) as seropositive. Collectively, 8/12 antibody-positive Still's disease patients were either new-onset active disease or unresponsive to IL-1 blocking drugs. Autoantibody-seropositivity associated with decreased IL-1Ra plasma/serum levels. Seropositive plasma impaired in vitro IL-1Ra bioactivity, which could be reversed by anakinra or canakinumab treatment. CONCLUSION: Autoantibodies neutralizing IL-1Ra may represent a novel patho-mechanism in a subgroup of Still's disease patients, which is sensitive to high-dose IL-1 blocking therapy.
Assuntos
Artrite Juvenil , Proteína Antagonista do Receptor de Interleucina 1 , Humanos , Autoanticorpos , Ensaio de Imunoadsorção Enzimática , Interleucina-1betaRESUMO
Hemophagocytic lymphohistiocytosis (HLH) comprises a broad spectrum of life-threatening cytokine storm syndromes, classified into primary (genetic) or secondary (acquired) HLH. The latter occurs in a variety of medical conditions, including infections, malignancies, autoimmune and autoinflammatory diseases, acquired immunodeficiency, and metabolic disorders. Despite recent advances in the field, the pathogenesis of secondary HLH remains incompletely understood. Considering the heterogeneity of triggering factors and underlying diseases in secondary HLH, a large diversity of animal models has been developed to explore pivotal disease mechanisms. To date, over 20 animal models have been described that each recapitulates certain aspects of secondary HLH. This review provides a comprehensive overview of the existing models, highlighting relevant findings, discussing the involvement of different cell types and cytokines in disease development and progression, and considering points of interest toward future therapeutic strategies.
Assuntos
Síndrome da Liberação de Citocina , Modelos Animais de Doenças , Linfo-Histiocitose Hemofagocítica , Animais , Linfo-Histiocitose Hemofagocítica/imunologia , Linfo-Histiocitose Hemofagocítica/patologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/patologia , Síndrome da Liberação de Citocina/etiologia , Camundongos , Humanos , Citocinas/metabolismoRESUMO
OBJECTIVE: To evaluate the predictive value of biomarkers of inflammation like phagocyte-related S100 proteins and a panel of inflammatory cytokines in order to differentiate the child with acute lymphoblastic leukemia (ALL) from juvenile idiopathic arthritis (JIA). STUDY DESIGN: In this cross-sectional study, we measured S100A9, S100A12, and 14 cytokines in serum from children with ALL (n = 150, including 27 with arthropathy) and JIA (n = 236). We constructed predictive models computing areas under the curve (AUC) as well as predicted probabilities in order to differentiate ALL from JIA. Logistic regression was used for predictions of ALL risk, considering the markers as the respective exposures. We performed internal validation using repeated 10-fold cross-validation and recalibration, adjusted for age. RESULTS: In ALL, the levels of S100A9, S100A12, interleukin (IL)-1 beta, IL-4, IL-13, IL-17, matrix metalloproteinase-3, and myeloperoxidase were low compared with JIA (P < .001). IL-13 had an AUC of 100% (95% CI 100%-100%) due to no overlap between the serum levels in the 2 groups. Further, IL-4 and S100A9 had high predictive performance with AUCs of 99% (95% CI 97%-100%) and 98% (95% CI 94%-99%), respectively, exceeding both hemoglobin, platelets, C-reactive protein, and erythrocyte sedimentation rate. CONCLUSIONS: The biomarkers S100A9, IL-4, and IL-13 might be valuable markers to differentiate ALL from JIA.
Assuntos
Artrite Juvenil , Leucemia-Linfoma Linfoblástico de Células Precursoras , Criança , Humanos , Artrite Juvenil/complicações , Artrite Juvenil/diagnóstico , Proteína S100A12 , Interleucina-13 , Estudos Transversais , Interleucina-4 , Biomarcadores , Citocinas , Sedimentação Sanguínea , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnósticoRESUMO
PURPOSE: A recent phase II open-label study of the interleukin 1 (IL-1) receptor antagonist (IL-1Ra) anakinra in treating IVIG-resistant Kawasaki disease (KD) patients reported promising results. Here, we aimed to characterize the immunological impact of IL-1 blockade in this unique study population. METHODS: Patients' and control sera and supernatants of cells (whole blood, neutrophils, coronary artery endothelial cells) stimulated with recombinant IL-1ß were analyzed for single or multiple marker (n = 22) expression by ELISA or multiplexed bead array assay. Data were analyzed using unsupervised hierarchical clustering, multiple correlation, and multi-comparison statistics and were compared to retrospective analyses of KD transcriptomics. RESULTS: Inflammation in IVIG-resistant KD (n = 16) is hallmarked by over-expression of innate immune mediators (particularly IL-6 > CXCL10 > S100A12 > IL-1Ra). Those as well as levels of immune or endothelial cell activation markers (sICAM-1, sVCAM-1) declined most significantly in course of anakinra treatment. Prior as well as following IL-1R blockade, over-expression of leucine-rich-α2-glycoprotein 1 (LRG1) associated best with remnant inflammatory activity and the necessity to escalate anakinra dosage and separated inflammatory KD patients from sJIA-MAS (n = 13) and MIS-C (n = 4). Protein as well as retrospective gene expression analyses indicated tight association of LRG1 with IL-1ß signaling and neutrophilia, while particularly neutrophil stimulation with recombinant IL-1ß resulted in concentration-dependent LRG1 release. CONCLUSION: Our study identifies LRG1 as known trigger of endothelial activation and cardiac re-modeling to associate with IL-1ß signaling in KD. Besides a potential patho-mechanistic implication of these findings, our data suggest blood leukocyte and neutrophil counts to best predict response to IL-1Ra treatment in IVIG-resistant KD.
Assuntos
Síndrome de Linfonodos Mucocutâneos , Biomarcadores , Criança , Células Endoteliais/metabolismo , Glicoproteínas/metabolismo , Glicoproteínas/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta , Interleucina-6/metabolismo , Leucina/uso terapêutico , Síndrome de Linfonodos Mucocutâneos/complicações , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Estudos Retrospectivos , Proteína S100A12RESUMO
OBJECTIVES: To investigate the ability of high-sensitivity C-reactive protein (hsCRP) and S100A12 to serve as predictive biomarkers of successful drug withdrawal in children with clinical remission of juvenile idiopathic arthritis (JIA). METHODS: This multicentre trial (PREVENT-JIA) enrolled 119 patients with JIA in clinical remission, and 100 patients reached the intervention phase in which the decision whether to continue or stop treatment was based on S100A12 and hsCRP levels. Patients were monitored for 12 months after stopping medication for flares of disease. Results were compared with withdrawal of therapy without biomarker-based stratification in patients from the German Biologika in der Kinderrheumatologie (BiKeR) pharmacovigilance registry. RESULTS: In the PREVENT-JIA group, 49 patients had a flare, and 45% of patients stopping medication showed flares within the following 12 months. All patients (n=8) continuing therapy due to permanently elevated S100A12/hsCRP at more than one visit flared during the observation phase. In the BiKeR control group, the total flare rate was 62%, with 60% flaring after stopping medication. The primary outcome, time from therapy withdrawal to first flare (cumulative flare rate after therapy withdrawal), showed a significant difference in favour of the PREVENT-JIA group (p=0.046; HR 0.62, 95% CI 0.38 to 0.99). As additional finding, patients in the PREVENT-JIA trial stopped therapy significantly earlier. CONCLUSION: Biomarker-guided strategies of therapy withdrawal are feasible in clinical practice. This study demonstrates that using predictive markers of subclinical inflammation is a promising tool in the decision-making process of therapy withdrawal, which translates into direct benefit for patients. TRIAL REGISTRATION NUMBER: ISRCTN69963079.
Assuntos
Antirreumáticos , Artrite Juvenil , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Biomarcadores , Proteína C-Reativa , Criança , Humanos , Proteína S100A12 , Exacerbação dos Sintomas , Resultado do TratamentoRESUMO
OBJECTIVES: JIA is characterised by a chronic disease course. Once patients achieve a state of inactive disease, there are no established biomarkers to predict the further course of inflammation for these patients. Therefore, the purpose of this study was to quantify serum biomarkers during quiescent disease to evaluate their use in identifying JIA patients at risk for future disease flare. METHODS: Patients with non-systemic JIA reaching inactive disease status were divided into two groups: 92 patients with future active disease after a median period of 6 months (range 3-9) and 80 patients with persistent inactive disease for the following period (median 11 months, range 7-16) according to the juvenile arthritis DAS (JADAS). Clinical parameters and serum levels of various biomarkers were measured in the state of inactive disease using immunoassays in both groups and were analysed for their potential to predict the further course of disease. RESULTS: Soluble interleukin-2 receptor (sIL-2R) serum levels were significantly higher in patients with future active disease (P = 0.021), which especially applied to patients with RF-negative polyarticular and extended oligoarticular JIA (P < 0.001). Higher sIL-2R serum levels during inactive disease were associated with a greater number of active joints at future active disease. CONCLUSION: Patients without clinical signs of disease activity already presented with increased sIL-2R serum levels several months before disease relapses, whereas conventional inflammation parameters were not elevated. Determination of sIL-2R serum levels during inactive disease may facilitate identifying patients with subclinical disease activity at risk for future active disease.
Assuntos
Artrite Juvenil , Humanos , Artrite Juvenil/diagnóstico , Receptores de Interleucina-2 , Biomarcadores , Recidiva , InflamaçãoRESUMO
OBJECTIVES: Differential diagnosis in children with prolonged fever is challenging. In particular, differentiating systemic-onset JIA (SJIA) from infectious diseases is difficult. Biomarkers are needed that support the diagnostic work-up. The aim of this study was to validate the usefulness of Myeloid-related protein 8/14 (MRP8/14) measurements in the diagnostic work-up of febrile children and to transfer it to clinical practice. METHODS: Data for 1110 paediatric patients were included and divided into two cohorts: (cohort A) for validation of MRP8/14 test performance with three different testing systems: the experimental ELISA, commercial ELISA and an innovative (point-of-care test) lateral flow immunoassay (LFIA); (cohort B) to validate the diagnostic accuracy with the two latter assays. RESULTS: In cohort A (n = 940), MRP8/14 was elevated in SJIA (12 110 ± 2650 ng/ml mean ± 95% CI) compared with other diagnoses (including infections and autoinflammatory diseases; 2980 ± 510 ng/ml) irrespective of fever and anti-inflammatory treatment (P < 0.001). In untreated patients with fever (n = 195) MRP8/14 levels in SJIA (19 740 ± 5080 ng/ml) were even higher compared with other diagnoses (4590 ± 1160 ng/ml) (P < 0.001, sensitivity 73%, specificity 90%). In group B1, the performance of the tests was confirmed in untreated patients with fever (n = 170): commercial ELISA (sensitivity 79%, specificity 89%) and LFIA (sensitivity 84%, specificity 81%). Compared with ferritin, IL-18, ESR, soluble IL-2 receptor and procalcitonin, MRP8/14 showed the best accuracy. CONCLUSION: MRP8/14 serum analyses have been validated as a helpful tool supporting the diagnosis of SJIA in febrile children. The results could be confirmed with commercial ELISA and LFIA enabling a rapid diagnostic point-of-care screening test.
Assuntos
Artrite Juvenil , Anti-Inflamatórios/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Biomarcadores , Calgranulina A/metabolismo , Criança , Estudos de Coortes , Febre/tratamento farmacológico , Febre/etiologia , HumanosRESUMO
OBJECTIVES: The monoclonal IL-1ß antibody canakinumab is approved for the treatment of systemic juvenile idiopathic arthritis (SJIA). Its efficacy has been proven in several trials, but not all patients show a complete and sustained response to therapy. We aimed to analyse the association of baseline serum biomarkers with treatment outcome in patients with SJIA treated with canakinumab. METHODS: Serum samples from 54 patients with active SJIA without recent macrophage activation syndrome (MAS) treated with canakinumab in an open-label response characterization study were subjected to a multiplexed bead array assay. Interesting targets from these analyses were validated by ELISA. Clinical treatment outcomes included modified paediatric ACR (pACR) 30 and 90 responses, clinically inactive disease (CID) within 15 days of treatment and sustained complete response, defined as pACR100 or CID within 15 days of treatment plus no future flare or MAS. RESULTS: In canakinumab-naïve patients most biomarkers were elevated when compared with healthy controls at baseline and some rapidly decreased by day 15 [IL-1 receptor antagonist (IL-1RA), IL-6, IL-18 and S100A12]. Responders had higher IL-18 and IFN-γ levels and lower chemokine (C-X-C motif) ligand 9 (CXCL9) levels at baseline, emphasized by the IL-18: CXCL9 and IFN-γ: CXCL9 ratios. These ratios had significant accuracy in predicting treatment responses. CONCLUSION: Differential regulation of the IL-18-IFN-γ-CXCL9 axis is observed in patients with SJIA. Higher IL-18: CXCL9 and IFN-γ: CXCL9 ratios at baseline are associated with a better clinical response to canakinumab treatment in SJIA. Future studies are needed to validate these findings and determine their generalizability to patients with recent MAS.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Quimiocina CXCL9/sangue , Interferon gama/sangue , Interleucina-18/sangue , Adolescente , Artrite Juvenil/sangue , Biomarcadores/sangue , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , MasculinoRESUMO
Rationale: IL-18 is a member of the IL-1 cytokine family, and elevated blood IL-18 concentrations associate with disease activity in macrophage activation syndrome (MAS) and poor clinical outcomes in severe inflammatory and septic conditions.Objectives: Although recent investigations provide mechanistic evidence for a contribution of IL-18 to inflammation and hyperinflammation in sepsis and MAS, we sought to study regulatory mechanisms underlying human IL-18 expression.Methods: Samples from in vivo and in vitro endotoxin rechallenge experiments, patients with inflammatory disease, and isolated human monocytes treated with various stimulants and drugs were tested for cytokine gene and protein expression. Serum IL-18 expression with or without JAK/STAT inhibition was analyzed in two MAS mouse models and in a patient with recurrent MAS.Measurements and Main Results: Peripheral blood and monocytic IL-18 expression escaped LPS-induced immunoparalysis. LPS-stimulated primary human monocytes revealed specific IL-18 expression kinetics controlled by IFNα/ß signaling. JAK/STAT inhibition or IFNß neutralization during LPS stimulation blunted cytokine expression. Similarly, microtubule-destabilizing drugs abrogated LPS-induced IL18 expression, but this effect could be fully reversed by addition of IFNα/ß. Ex vivo analysis of inflammatory disease patients' whole blood revealed strong correlation of type I IFN score and IL18 expression, whereas JAK/STAT inhibition strongly reduced IL-18 serum levels in two MAS mouse models and in a patient with recurrent MAS.Conclusions: Our data indicate that IL-18 (but not IL-1ß) production from human monocytes requires cooperative Toll-like receptor and IFNα/ß signaling. Interference with IFNα/ß expression or signaling following JAK/STAT inhibition may control catastrophic hyperinflammation in MAS.
Assuntos
Tolerância Imunológica/imunologia , Interferon-alfa/imunologia , Interferon beta/imunologia , Interleucina-18/imunologia , Síndrome de Ativação Macrofágica/imunologia , Receptores Toll-Like/imunologia , Adulto , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Modelos Animais de Doenças , Endotoxinas , Expressão Gênica , Humanos , Técnicas In Vitro , Interferon-alfa/efeitos dos fármacos , Interferon beta/efeitos dos fármacos , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-1beta/efeitos dos fármacos , Interleucina-1beta/imunologia , Inibidores de Janus Quinases/farmacologia , Lipopolissacarídeos/farmacologia , Síndrome de Ativação Macrofágica/genética , Síndrome de Ativação Macrofágica/metabolismo , Masculino , Camundongos , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Pirróis/farmacologia , Transdução de Sinais , Inibidores do Fator de Necrose Tumoral/farmacologiaAssuntos
Anticorpos , Vacinas contra COVID-19 , COVID-19 , Proteína Antagonista do Receptor de Interleucina 1 , Miocardite , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/imunologia , Miocardite/etiologia , Miocardite/imunologia , SARS-CoV-2 , VacinaçãoRESUMO
OBJECTIVE: To study two neutrophil activation markers, myeloid-related protein (MRP) 8/14 and neutrophil elastase (NE), for their ability to predict treatment response and flare in patients with JIA. METHODS: Using samples from two cohorts (I and II), we determined MRP8/14 and NE levels of 32 (I) and 81 (II) patients with new-onset, DMARD-naïve arthritis and compared patients who responded to treatment (defined as fulfilling ≥ adjusted ACRpedi50 response and/or inactive disease) with non-responders (defined as fulfilling < adjusted ACRpedi50 response and/or active disease) at 6 and 12 months. Secondly, we compared biomarker levels of 54 (I) and 34 (II) patients with clinically inactive disease who did or did not suffer from a flare of arthritis after 6 or 12 months. Receiver operating characteristic analyses were carried out to study the predictive value of MRP8/14 and NE for treatment response and flare. RESULTS: For both cohorts, baseline MRP8/14 and NE levels for patients who did or did not respond to treatment were not different. Also, MRP8/14 and NE levels were not different in patients who did or did not flare. Receiver operating characteristic analysis of MRP8/14 and NE demonstrated areas under the curve <0.7 in both cohorts. CONCLUSION: In our cohorts, MRP8/14 and NE could not predict treatment response. Also, when patients had inactive disease, neither marker could predict flares.
Assuntos
Transportadores de Cassetes de Ligação de ATP/sangue , Artrite Juvenil/genética , Calgranulina B/sangue , Elastase de Leucócito/sangue , Ativação de Neutrófilo/genética , Adolescente , Antirreumáticos/uso terapêutico , Artrite Juvenil/sangue , Artrite Juvenil/tratamento farmacológico , Biomarcadores/sangue , Criança , Feminino , Humanos , Masculino , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Método Simples-Cego , Exacerbação dos Sintomas , Resultado do TratamentoRESUMO
OBJECTIVES: The International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a 'window of opportunity' to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases. METHODS: Children with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIA syst ) or polyarticular disease (SJIA poly ). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIA syst , n=45; SJIA poly , n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays. RESULTS: Signatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIA syst from SJIA poly well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIA syst vs SJIA poly ) and 77% (SJIA syst vs infection) of all cases. CONCLUSIONS: Molecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies.
Assuntos
Artrite Juvenil/classificação , Artrite Juvenil/patologia , Fenótipo , Proteômica , Adolescente , Análise de Variância , Área Sob a Curva , Artrite Juvenil/sangue , Biomarcadores/análise , Criança , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Curva ROC , Estudos Retrospectivos , Índice de Gravidade de Doença , Espectrometria de Massas em Tandem/métodosRESUMO
PURPOSE OF REVIEW: Current technical advances enable the assessment of the complex changes in body fluid proteomes and thus allow for the discovery of biomarker signatures rather than just following differences of a single marker. In this review, we aim to summarize current approaches to discover and evaluate multi-biomarker panels for improved monitoring of chronic arthritis disease activity. RECENT FINDINGS: Mass spectrometry and affinity proteomic methodologies have been used to identify biomarker panels in synovial fluid, serum, plasma, or urine of pediatric and adult chronic arthritis patients. Notably, despite the numerous efforts to develop new and better biomarker panels, very few have undergone extensive analytical and clinical validation and been adopted into routine use for patient benefit. There remains a significant gap between discovery of chronic arthritis biomarker signatures and their validation for clinical use.
Assuntos
Artrite/diagnóstico , Biomarcadores/análise , Proteômica/métodos , Doença Crônica , Humanos , Espectrometria de Massas/métodos , Reprodutibilidade dos TestesRESUMO
RATIONALE: S100A12 is overexpressed during inflammation and is a marker of inflammatory disease. Furthermore, it has been ascribed to the group of damage-associated molecular pattern molecules that promote inflammation. However, the exact role of human S100A12 during early steps of immune activation and sepsis is only partially described thus far. OBJECTIVES: We analyzed the activation of human monocytes by granulocyte-derived S100A12 as a key function of early inflammatory processes and the development of sepsis. METHODS: Circulating S100A12 was determined in patients with sepsis and in healthy subjects with experimental endotoxemia. The release of human S100A12 from granulocytes as well as the promotion of inflammation by activation of human monocytes after specific receptor interaction was investigated by a series of in vitro experiments. MEASUREMENTS AND MAIN RESULTS: S100A12 rises during sepsis, and its expression and release from granulocytes is rapidly induced in vitro and in vivo by inflammatory challenge. A global gene expression analysis of S100A12-activated monocytes revealed that human S100A12 induces inflammatory gene expression. These effects are triggered by an interaction of S100A12 with Toll-like receptor 4 (TLR4). Blocking S100A12 binding to TLR4 on monocytes or TLR4 expressing cell lines (HEK-TCM) abrogates the respective inflammatory signal. On the contrary, blocking S100A12 binding to its second proposed receptor (receptor for advanced glycation end products [RAGE]) has no significant effect on inflammatory signaling in monocytes and RAGE-expressing HEK293 cells. CONCLUSIONS: Human S100A12 is an endogenous TLR4 ligand that induces monocyte activation, thereby acting as an amplifier of innate immunity during early inflammation and the development of sepsis.
Assuntos
Inflamação/etiologia , Monócitos/fisiologia , Proteínas S100/fisiologia , Sepse/imunologia , Receptor 4 Toll-Like/fisiologia , Adulto , Idoso , Células Cultivadas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas S100/sangue , Proteína S100A12 , Sepse/sangue , Receptor 4 Toll-Like/sangue , Adulto JovemAssuntos
Cálcio/metabolismo , Proteína S100A12/metabolismo , Receptor 4 Toll-Like/metabolismo , Zinco/metabolismo , Adolescente , Adulto , Criança , Feminino , Granulócitos/metabolismo , Células HEK293 , Humanos , Inflamação/metabolismo , Antígeno 96 de Linfócito/metabolismo , Masculino , Monócitos/metabolismo , Proteínas Recombinantes/metabolismo , Transdução de Sinais , Células THP-1 , Adulto JovemRESUMO
The discovery of antibodies specific for citrullinated protein epitopes [anti-citrullinated protein antibodies (ACPAs)] is a hallmark for the diagnosis and prognosis of rheumatoid arthritis (RA) and will also be a useful tool for understanding the fundamental pathologic processes. There are several essential questions pertaining to ACPA that remain to be explored, such as understanding the early specificity of the underlying T-cell recognition, whether the production of ACPA is a primary or secondary process, and in the event of such antibodies being arthritogenic, whether they could possibly regulate the disease development. To answer these questions, animal models are needed, but unfortunately ACPA is not a prominent feature of any of the classical animal models of RA. However, we showed recently that ACPA can be isolated from animals susceptible to collagen-induced arthritis that are specific for citrullinated type II collagen (CII). The citrulline specificity could be visualized, and the specificity is determined primarily by a direct interaction with citrulline. We also demonstrated that these antibodies are specific for the citrullinated epitopes and are pathogenic in vivo. A new hypothesis to explain how inflammation in RA can be directed to cartilaginous joints and be self-perpetuating is suggested, which involves recognition of post-translational modifications (glycosylation and citrullination) on CII by T and B cells that can have both arthritogenic and regulatory consequences.
Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Autoimunidade , Citrulina/imunologia , Proteínas da Matriz Extracelular/imunologia , Processamento de Proteína Pós-Traducional , Animais , Especificidade de Anticorpos , Artrite Experimental/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/terapia , Autoimunidade/genética , Colágeno Tipo II/imunologia , Progressão da Doença , Proteínas da Matriz Extracelular/química , Proteínas da Matriz Extracelular/genética , Humanos , Mediadores da Inflamação/imunologia , Conformação ProteicaRESUMO
The cytoplasmic S100 proteins derived from cells of myeloid origin are promising new markers of (auto-)inflammation. S100A8/A9 and S100A12 are released from monocytes and granulocytes during activation of the innate immune system. Tissue and serum concentrations correlate to disease activity, both during local and systemic inflammation. In autoinflammatory diseases such as Familial Mediterranean Fever (FMF) and Systemic onset Juvenile Idiopathic Arthritis (SJIA), a dysregulation of alternative secretory pathways may be involved in pathogenesis and lead to hypersecretion of S100 proteins. Since autoinflammatory diseases can be difficult to diagnose, phagocyte-derived S100 proteins are valid tools in the diagnosis of autoinflammatory diseases. In addition, they may help achieve a better understanding of the pathophysiology of autoinflammatory disorders including SJIA and FMF, and even provide novel therapeutic targets in the future.
Assuntos
Doenças Hereditárias Autoinflamatórias/imunologia , Fagócitos/metabolismo , Proteínas S100/sangue , Proteínas S100/metabolismo , Animais , Autoimunidade/genética , Biomarcadores/sangue , Doenças Hereditárias Autoinflamatórias/sangue , Doenças Hereditárias Autoinflamatórias/genética , Humanos , Inflamação/imunologia , Fagócitos/imunologiaRESUMO
OBJECTIVES: To increase understanding of the aetiology and pathogenesis of rheumatoid arthritis (RA), genetic and environmental risk factors for RA subsets, defined by the presence or absence of different anticitrullinated protein/peptide antibodies (ACPAs) targeting citrullinated peptides from α-enolase, vimentin, fibrinogen and collagen type II, were investigated. METHODS: 1985 patients with RA and 2252 matched controls from the EIRA case-control cohort were used in the study. Serum samples were assayed by ELISA for the presence of anticyclic citrullinated peptides (anti-CCP) antibodies and four different ACPA fine specificities. Cross-reactivity between ACPAs was examined by peptide absorption experiments. Genotyping was performed for HLA-DRB1 shared epitope (SE) alleles and the PTPN22 gene, while information regarding smoking was obtained by questionnaire. The association of genetic and environmental risk factors with different subsets of RA was calculated by logistic regression analysis. RESULTS: Limited cross-reactivity was observed between different ACPA fine specificities. In total, 17 RA subsets could be identified based on their different ACPA fine specificity profiles. Large differences in association with genetic and environmental determinants were observed between subsets. The strongest association of HLA-DRB1 SE, PTPN22 and smoking was identified for the RA subset which was defined by the presence of antibodies to citrullinated α-enolase and vimentin. CONCLUSION: This study provides the most comprehensive picture to date of how HLA-DRB1 SE, PTPN22 and smoking are associated with the presence of specific ACPA reactivities rather than anti-CCP levels. The new data will form a basis for molecular studies aimed at understanding disease development in serologically distinct subsets of RA.
Assuntos
Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genética , Autoanticorpos/sangue , Citrulina/imunologia , Cadeias HLA-DRB1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Citrulina/metabolismo , Colágeno Tipo II/imunologia , Colágeno Tipo II/metabolismo , Reações Cruzadas/imunologia , Epitopos/genética , Fibrinogênio/imunologia , Fibrinogênio/metabolismo , Predisposição Genética para Doença/epidemiologia , Predisposição Genética para Doença/genética , Genótipo , Humanos , Modelos Logísticos , Peptídeos/imunologia , Peptídeos/metabolismo , Fosfopiruvato Hidratase/imunologia , Fosfopiruvato Hidratase/metabolismo , Fatores de Risco , Estudos Soroepidemiológicos , Fumar/epidemiologia , Suécia/epidemiologia , Vimentina/imunologia , Vimentina/metabolismoRESUMO
Systemic juvenile idiopathic arthritis (sJIA) is a rare childhood chronic inflammatory disorder with risk for life-threatening complications including macrophage activation syndrome and lung disease. At onset, sJIA pathogenesis resembles that of the autoinflammatory periodic fever syndromes with marked innate immune activation, expansion of neutrophils and monocytes, and high levels of interleukin-18. Here, we review the current conceptual understanding of sJIA pathogenesis with a focus on both innate and adaptive immune pathways. Finally, we consider how recent progress toward understanding the immunologic basis of sJIA may support new therapies for refractory disease courses.