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1.
J Scleroderma Relat Disord ; 8(3): NP6-NP8, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37744046

RESUMO

Scleroderma renal crisis is a severe complication of systemic sclerosis with a poor prognosis. Therefore, identifying precipitating factors is essential. Among known risk factors, only few are reversible. On the contrary, anti-C5 therapy appears effective, at least in some cases. We describe a 59-year-old man with diffuse cutaneous systemic sclerosis who developed life-threatening scleroderma renal crisis following ibuprofen administration. Despite aggressive management, he did not improve. Renal biopsy have displayed features of thrombotic microangiopathy but no complement deposition. We then discuss the pathomechanism of scleroderma renal crisis that could drive eculizumab treatment since some renal biopsies exhibit complement deposits and others do not.

2.
Sci Transl Med ; 15(710): eadi0252, 2023 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-37611083

RESUMO

Improvements in COVID-19 treatments, especially for the critically ill, require deeper understanding of the mechanisms driving disease pathology. The complement system is not only a crucial component of innate host defense but can also contribute to tissue injury. Although all complement pathways have been implicated in COVID-19 pathogenesis, the upstream drivers and downstream effects on tissue injury remain poorly defined. We demonstrate that complement activation is primarily mediated by the alternative pathway, and we provide a comprehensive atlas of the complement alterations around the time of respiratory deterioration. Proteomic and single-cell sequencing mapping across cell types and tissues reveals a division of labor between lung epithelial, stromal, and myeloid cells in complement production, in addition to liver-derived factors. We identify IL-6 and STAT1/3 signaling as an upstream driver of complement responses, linking complement dysregulation to approved COVID-19 therapies. Furthermore, an exploratory proteomic study indicates that inhibition of complement C5 decreases epithelial damage and markers of disease severity. Collectively, these results support complement dysregulation as a key druggable feature of COVID-19.


Assuntos
COVID-19 , Interleucina-6 , Humanos , Proteômica , Proteínas do Sistema Complemento , Ativação do Complemento
4.
J Exp Med ; 219(2)2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34914824

RESUMO

In rare instances, pediatric SARS-CoV-2 infection results in a novel immunodysregulation syndrome termed multisystem inflammatory syndrome in children (MIS-C). We compared MIS-C immunopathology with severe COVID-19 in adults. MIS-C does not result in pneumocyte damage but is associated with vascular endotheliitis and gastrointestinal epithelial injury. In MIS-C, the cytokine release syndrome is characterized by IFNγ and not type I interferon. Persistence of patrolling monocytes differentiates MIS-C from severe COVID-19, which is dominated by HLA-DRlo classical monocytes. IFNγ levels correlate with granzyme B production in CD16+ NK cells and TIM3 expression on CD38+/HLA-DR+ T cells. Single-cell TCR profiling reveals a skewed TCRß repertoire enriched for TRBV11-2 and a superantigenic signature in TIM3+/CD38+/HLA-DR+ T cells. Using NicheNet, we confirm IFNγ as a central cytokine in the communication between TIM3+/CD38+/HLA-DR+ T cells, CD16+ NK cells, and patrolling monocytes. Normalization of IFNγ, loss of TIM3, quiescence of CD16+ NK cells, and contraction of patrolling monocytes upon clinical resolution highlight their potential role in MIS-C immunopathogenesis.


Assuntos
COVID-19/complicações , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Monócitos/metabolismo , Receptores de IgG/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Linfócitos T/imunologia , Adolescente , Células Epiteliais Alveolares/patologia , Linfócitos B/imunologia , Vasos Sanguíneos/patologia , COVID-19/imunologia , COVID-19/patologia , Proliferação de Células , Criança , Estudos de Coortes , Ativação do Complemento , Citocinas/metabolismo , Enterócitos/patologia , Feminino , Humanos , Imunidade Humoral , Inflamação/patologia , Interferon Tipo I/metabolismo , Interleucina-15/metabolismo , Ativação Linfocitária/imunologia , Masculino , Receptores de Antígenos de Linfócitos T/metabolismo , SARS-CoV-2/imunologia , Superantígenos/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/patologia
6.
J Hematol ; 9(3): 84-88, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32855757

RESUMO

Thrombotic thrombocytopenic purpura (TTP) is a rare and unpredictable disease with a high mortality rate (90%) if untreated. It results from systemic microvascular thrombosis and leads to profound thrombocytopenia, hemolytic anemia and organ failure of varying severity. However, macrovascular thrombosis has been described in very rare cases. Caplacizumab has emerged as a promising new drug for the management of TTP. We report the case of a patient with idiopathic refractory TTP treated with caplacizumab who developed thrombotic complications upon discontinuation of treatment.

7.
Front Pediatr ; 8: 579607, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33681093

RESUMO

Background: Hemolytic uremic syndrome (HUS) is rare in neonates. It is probably an under-recognized condition in the early postnatal period as it presents similarly to the most common perinatal asphyxia and to differentiate the two conditions is challenging. We describe the clinical presentation of a potential new subtype of neonatal HUS triggered by hypoxic-ischemic event. Our patient was successfully treated by a single dose of Eculizumab as early as at 9 days of life. Case Report: A 35-weeks infant was born with low hemoglobin and subsequently developed respiratory distress, hypotension, and acidosis. Blood transfusion was administered, acidosis corrected, neurological examination remained reassuring. Few hours later he developed renal failure, macroscopic hematuria, hemobilia, thrombocytopenia and coagulopathy refractory to platelet and fresh frozen plasma transfusions. No infection was found. Haptoglobin was non-measurable, and schistocytes present, complement factors C3, C4 and B were low, FBb increased. HUS was suspected. A single dose of Eculizumab™ was administered on day 9 of life. No genetic mutation of atypical HUS was found. He was discharged with improving renal function and developing cholestasis. Conclusion: In neonates with hemolytic anemia, thrombocytopenia, hematuria and renal failure, HUS should be suspected. In neonatal HUS Eculizumab should be considered as first-line therapy and discontinuation can be considered if no genetic mutation is found and clinical condition improves. In very young patients, cholestasis could appear as potential side effect of Eculizumab™.

8.
J Crohns Colitis ; 13(11): 1372-1379, 2019 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-30944925

RESUMO

BACKGROUND AND AIMS: Several factors have been reported to affect faecal calprotectin [FC] values, and significant variation in FC concentrations has been observed in inflammatory bowel disease [IBD] patients. We aimed to evaluate FC variability in IBD patients, and to assess the robustness of a single stool punch. METHODS: This is a single-centre observational case-control study. Disease activity was assessed using endoscopic and clinical activity scores, as well as C-reactive protein levels. Stool samples were collected twice within a 1 to 6 days interval, and FC was measured on punches and homogenates by fluorometric enzyme immunocapture assay. RESULTS: In all, 260 stool samples were collected from 120 patients. Intrastool variability was low, with an intraclass correlation coefficient for single measures between three punches from a single stool sample of 0.91, and median coefficient of variation [CV] of 17%. CV of two stool samples a few days apart [intra-individual variability] were significantly higher [p <0.01] with median CV of 36%. FC standard deviations correlated with mean FC levels either for intrastool or for intra-individual variability, with a Spearman's coefficient of rank correlation of 0.85 and 0.78, respectively [p <0.01]. Disease type, location, activity, and FC levels did not influence variability. CONCLUSIONS: A single stool punch is reliable for FC measurement, considering that intrastool variability is low. Intra-individual variability a few days apart is significantly higher. Therefore, decision-making strategies based on single measurements should consider this variability, to determine the minimum optimal variation to be achieved, rather than a cut-off, especially in high FC levels.


Assuntos
Fezes/química , Doenças Inflamatórias Intestinais/metabolismo , Complexo Antígeno L1 Leucocitário/análise , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/análise , Proteína C-Reativa/análise , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Manejo de Espécimes , Adulto Jovem
9.
Clin Chem Lab Med ; 56(9): 1498-1506, 2018 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-29729138

RESUMO

BACKGROUND: The measurement of complement components is clinically useful where a deficiency is suspected, or where excessive activation and consumption are present in disease. C2 deficiency carries an increased risk of developing systemic lupus erythematosus, recurrent infections and atherosclerosis. In this study, we have evaluated The Binding Site's Human Complement C2 SPAPLUS® assay. METHODS: Linearity was tested using 13 sample dilutions covering the standard measuring range. Within- and between-assay variabilities were calculated using five samples with different C2 concentrations. The correlation between C2 concentrations in EDTA-plasma and serum was assessed, as was the correlation between C2 measurements by the automated assay and radial immunodiffusion. C2 concentrations were compared with CH50 activity, and quantified in individuals with homozygous or heterozygous C2 deficiency, acquired angioedema and patients with chronic inflammatory conditions. RESULTS: The assay was linear across the measuring range (3.8-42.3 mg/L). Intra- and interassay variability were 2.3%-3.8% and 0%-3.3%, respectively. Comparison between C2 measurements in EDTA-plasma and serum provided a strong correlation (p<0.0001, R2=0.82, slope 0.92), as did the correlation between the automated and radial immunodiffusion methods (p<0.0001, R2=0.89, slope 1.07). A positive correlation between C2 concentration and CH50 activity was demonstrated (p<0.0001, R2=0.48). Significant differences were observed between the median C2 concentrations obtained in healthy controls and the patient clinical samples, with homozygous C2-deficient patients giving below detectable results. CONCLUSIONS: This C2 SPAPLUS® assay allows the automated, rapid and precice quantification of complement C2 protein and could therefore be considered as a replacement for older, more time-consuming methods.


Assuntos
Complemento C2/análise , Imunoturbidimetria/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Angioedema/patologia , Angioedemas Hereditários/patologia , Automação , Complemento C2/normas , Feminino , Humanos , Imunoturbidimetria/normas , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Valores de Referência , Adulto Jovem
11.
Acta Clin Belg ; 72(5): 313-317, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28067125

RESUMO

OBJECTIVE: Determine the frequency of granulomatosis with polyangiitis (GPA) associated with non-identified ANCA (non-MPO, non-PR3 ANCA) and secondarily compare their clinic with GPA associated with MPO-positive or PR3-positive ANCA. METHODS: In a monocentric retrospective observational study, clinical data of 398 patients with non-identified ANCA (titer of ANCA at least 1/80 by immunofluorescence on ethanol fixed PMN) was gathered over a period of 6 years. GPA patients from this population were compared with GPA patients with identified ANCA on the basis of clinical, biological, immunological and histological features. RESULTS: The most common diseases associated with non-identified ANCA were inflammatory bowel diseases accounting for 17% of diseases. GPA accounted for only 1.8% of cases. There were no significant differences in terms of clinical and histological characteristics between GPA with non-identified ANCA and GPA with identified ANCA, but significantly higher CRP levels were observed in GPA patients with identified ANCA (p = 0.005). Localized disease (ear, nose and throat and/or lung involvement without any other systemic involvement) was more frequent in the group of GPA with nonidentified ANCA (p = 0.047) as compared to GPA with identified ANCA. This explains that the former group of patients was less frequently treated by cyclophosphamide than the latter (p = 0.016). CONCLUSION: GPA with non-MPO, non-PR3 ANCAs is relatively rare. Our study suggests that GPA with nonidentified ANCA differs from GPA with identified ANCA by the frequency of localized forms.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite/diagnóstico , Adulto , Diagnóstico Diferencial , Feminino , Granulomatose com Poliangiite/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
12.
Medicine (Baltimore) ; 95(30): e4459, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27472742

RESUMO

BACKGROUND: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis characterized by abrupt onset of hypertension, thrombotic microangiopathy, and kidney injury. The mechanisms of the disease remain ill-defined, but a growing body of evidence suggests that activation of the complement system may be involved. METHODS: Here, we report the case of a patient presenting with severe SRC and strong evidence of complement activation, both in serum and in the kidney, in the absence of genetic defect of the complement system. RESULTS: Immunofluorescence studies on kidney biopsy showed significant deposits of C1q and C4d in the endothelium of renal arterioles, pointing toward activation of the classical pathway. Because of the dramatic clinical and histological severity, and the lack of response to early treatment with angiotensin-converting enzyme inhibitors, calcium channel blockers and plasma exchange, the patient was treated with the specific C5 blocker eculizumab.Contrarily to conventional treatment, eculizumab efficiently blocked C5b-9 deposition ex vivo and maintained hematological remission. Unfortunately, the patient died from heart failure a few weeks later. Postmortem examination of the heart showed diffuse patchy interstitial fibrosis, the typical lesion of systemic sclerosis-related cardiomyopathy, but normal coronary arteries and myocardial microvasculature. CONCLUSION: SRC may lead to complement system activation through the classical pathway. Early administration of C5 inhibitor eculizumab may have therapeutic potential in patients with life-threatening SRC refractory to conventional treatment using angiotensin-converting enzyme inhibitors.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Ativação do Complemento/efeitos dos fármacos , Ativação do Complemento/imunologia , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/imunologia , Complicações na Gravidez/patologia , Gravidez Múltipla , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/imunologia , Injúria Renal Aguda/patologia , Adulto , Biópsia , Complemento C1q/análise , Complemento C4b/análise , Complemento C5/antagonistas & inibidores , Via Clássica do Complemento/efeitos dos fármacos , Via Clássica do Complemento/imunologia , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Evolução Fatal , Feminino , Humanos , Recém-Nascido , Rim/irrigação sanguínea , Rim/imunologia , Rim/patologia , Microscopia de Fluorescência , Fragmentos de Peptídeos/análise , Gravidez , Escleroderma Sistêmico/patologia
13.
Mol Immunol ; 75: 133-43, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27280846

RESUMO

A serine protease activity was detected in aqueous peanuts seeds extracts, partially purified and characterized as a thiol-dependent serine protease. The potential role of this proteolytic activity on allergic reaction to peanuts was prospected through complement activation studies in human plasma and serum, and MDCK cells to investigate a possible occludin degradation in tight junctions. The peanut protease activity induced the production of anaphylatoxins C3a and C5a, and of the terminal membrane attack complex SC5b-9 whatever the complement activation pathway. The protease activity was also involved in the partial digestion of occludin within tight junctions, with for result, an increase of the epithelial permeability to antigen absorption.


Assuntos
Anafilatoxinas/imunologia , Arachis/enzimologia , Hipersensibilidade a Amendoim/enzimologia , Serina Proteases/imunologia , Anafilatoxinas/química , Animais , Arachis/química , Cromatografia de Afinidade , Cães , Humanos , Células Madin Darby de Rim Canino , Serina Proteases/química , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Compostos de Sulfidrila
14.
BMJ Case Rep ; 20142014 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-25538218

RESUMO

The pathophysiology of atypical haemolytic-uraemic syndrome (aHUS) occurring de novo after renal transplantation may include genetic mutations of regulators of complement activation, but they are still rarely determined. A 41-year-old female renal transplant recipient presented two very different episodes of thrombotic microangiopathy. The first episode was associated with antibody-mediated rejection and the second was an isolated, acute aHUS, successfully treated with eculizumab. The diagnosis included a genetic analysis and we found a synonymous variant in the Complement Factor H (CFH) gene, c2634C>T (p.His878=) and low factor H (FH) activity during both events. In conclusion, the diagnosis of aHUS should be considered when TMA is associated with an AMR episode. In this setting, a silent polymorphism of factor H may be responsible for these rare cases of "de novo" aHUS after transplantation.


Assuntos
Síndrome Hemolítico-Urêmica Atípica/genética , Fator H do Complemento/genética , Rejeição de Enxerto/etiologia , Transplante de Rim/efeitos adversos , Rim/patologia , Mutação , Polimorfismo de Nucleotídeo Único , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Síndrome Hemolítico-Urêmica Atípica/diagnóstico , Síndrome Hemolítico-Urêmica Atípica/tratamento farmacológico , Síndrome Hemolítico-Urêmica Atípica/etiologia , Fator H do Complemento/metabolismo , Feminino , Humanos , Rim/cirurgia , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/tratamento farmacológico , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/genética , Microangiopatias Trombóticas/diagnóstico , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/genética
15.
J Clin Immunol ; 33(8): 1293-301, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24142231

RESUMO

PURPOSE: Complement regulators control the activated complement system. Defects in this homeostasis can result in tissue damage and autoimmune diseases with a heterogeneity in clinical presentation. Complement factor I (FI), a serine protease, is an important regulator of alternative pathway activation. We report a diagnostic work-up of a patient with relapsing inflammatory mediated meningo-encephalitis. Our work-up revealed a rare genetic factor I (FI) deficiency. So far, all cases of reported complete factor I deficiency have absent serum levels of FI. We present here a unique case of a complete factor I deficiency based on a functional FI defect. METHODS: Complement assays and measurement of FI activity were performed in the patient, her family, factor H-deficient patients, a patient with C3-nephritic factor and 11 healthy controls. Genetic sequencing of the FI coding regions in the patient and her parents was performed. RESULTS: The patient had absent alternative pathway activity with low levels of C3 and normal serum level of FI. The patient's plasma FI did not degrade C3b, with normalisation of C3b degradation after adding purified FI. Mutation analysis of the complement factor I gene revealed two heterozygous mutations (I322T and D506V). CONCLUSION: To our knowledge, this paper describes a complete FI deficiency caused by a defect of FI activity for the first time. Normal FI concentration does not exclude a complete FI defect, additional functional analysis of FI is required in any patient with a defect of complement activation. Recurrent aseptic meningo-encephalitis is a rare clinical presentation of complete FI deficiency.


Assuntos
Fator I do Complemento/deficiência , Fator I do Complemento/genética , Meningite Asséptica/genética , Meningite Asséptica/imunologia , Meningoencefalite/genética , Meningoencefalite/imunologia , Ativação do Complemento/genética , Ativação do Complemento/imunologia , Fator I do Complemento/fisiologia , Hemólise/genética , Hemólise/imunologia , Humanos , Meningite Asséptica/metabolismo , Meningoencefalite/metabolismo , Recidiva , Análise de Sequência de DNA
16.
Mediators Inflamm ; 2013: 164246, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23935244

RESUMO

INTRODUCTION: Severe sepsis in humans may be related to an underlying profound immune suppressive state. We investigated the link between gene expression of immune regulatory cytokines and the range of illness severity in patients with infection and severe sepsis. METHODS: A prospective observational study included 54 ICU patients with severe sepsis, 53 patients with infection without organ failure, and 20 healthy controls. Gene expression in peripheral blood mononuclear cells (PBMC) was measured using real-time polymerase chain reaction. RESULTS: Infection differed from health by decreased expression of the IL2, and IL23 and greater expression of IL10 and IL27. Severe sepsis differed from infection by having decreased IL7, IL23, IFN γ , and TNF α gene expression. An algorithm utilising mRNA copy number for TNF α , IFN γ , IL7, IL10, and IL23 accurately distinguished sepsis from severe sepsis with a receiver operator characteristic value of 0.88. Gene expression was similar with gram-positive and gram-negative infection and was similar following medical and surgical severe sepsis. Severity of organ failure was associated with serum IL6 protein levels but not with any index of cytokine gene expression in PBMCs. CONCLUSIONS: Immune regulatory cytokine gene expression in PBMC provides a robust method of modelling patients' response to infection.


Assuntos
Citocinas/metabolismo , Perfilação da Expressão Gênica , Sepse/metabolismo , Sepse/microbiologia , Adulto , Idoso , Algoritmos , Cuidados Críticos , Feminino , Expressão Gênica , Humanos , Unidades de Terapia Intensiva , Interleucinas/metabolismo , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Estudos Prospectivos , RNA Mensageiro/metabolismo , Curva ROC , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco
17.
Rheumatology (Oxford) ; 52(9): 1694-700, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23776287

RESUMO

OBJECTIVE: To determine whether levels of cryofibrinogen are increased in non-traumatic osteonecrosis (ON) and could correlate with disease staging. METHODS: We prospectively analysed cryofibrinogen levels by immunofixation electrophoresis in 50 patients with non-traumatic ON, 50 healthy volunteers and 8 patients with traumatic ON. Staging of disease involving the femoral heads and the size of necrotic lesions were assessed by the Association Research Circulation Osseous (ARCO) classification system. RESULTS: Mean cryofibrinogen levels in patients with non-traumatic ON were significantly increased relative to healthy controls and to patients with traumatic ON (222.1 ± 20.6, 59.9 ± 5.6 and 52.3 ± 14.9 mg/dl, respectively, P < 0.001). In the non-traumatic ON group, mean cryofibrinogen levels were significantly increased in patients with multifocal ON compared with patients with mono/bifocal ON (276.5 ± 56.5 and 149.3 ± 15.4 mg/dl, respectively, P = 0.03). There were no significant differences in cryofibrinogen levels observed with respect to the size of the necrotic lesions involving the femoral heads. Moreover, cryofibrinogen levels in patients with ON of the femoral heads classified according to the stage of disease were not significantly different between patients with stage 1/2 and patients with stage 3 ON (179.2 ± 31.3 vs 204.1 ± 29.0 mg/dl, respectively; P = 0.813). CONCLUSION: Cryofibrinogen levels are increased in non-traumatic ON and, more importantly, in multifocal ON. The fact that cryofibrinogen levels are not correlated with the size of lesions and the stage of disease could imply systemic rather than local involvement characterizing the pathogenesis of ON.


Assuntos
Crioglobulinas/análise , Fibrinogênios Anormais/análise , Osteonecrose/sangue , Adulto , Feminino , Cabeça do Fêmur/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Osteonecrose/patologia , Índice de Gravidade de Doença
18.
AIDS ; 27(11): 1725-34, 2013 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-23807270

RESUMO

OBJECTIVE: Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is a common complication in HIV-TB co-infected patients receiving combined antiretroviral therapy (cART). This study investigated a putative contribution of monocytes to the development of TB-IRIS. DESIGN: A prospective study was designed to compare gene expression between patients who developed TB-IRIS with matched non-TB-IRIS controls. METHODS: We performed a hypothesis-generating transcriptome analysis on monocytes of HIV-TB co-infected patients. Identified pathways were subsequently analysed in patients' monocytes before and shortly after cART initiation, in a technically independent set-up (nCounter). Additionally, protein expression and enzymatic activities of specific factors were assessed at the systemic level. RESULTS: Pathway analysis of microarray datasets and focused gene expression study revealed that, even before initiation of cART, the complement system is dysregulated in HIV-TB co-infected patients who are predisposed to developing TB-IRIS. Detailed analysis revealed differences between TB-IRIS patients and matched non-TB-IRIS cases, at the level of the balance between the effector C1Q and the inhibitor C1-INH, both before and 2 weeks after cART initiation. These differences were mirrored by increases in the downstream pro-inflammatory complement factor C5 over the course of 2 weeks of cART. Our results suggest that inappropriate control of complement activation could be associated with the 'flaring up' of inflammation observed during TB-IRIS. CONCLUSION: The current study reveals a contribution of monocytes and the complement system to TB-IRIS development. An intriguing possibility is that the development of TB-IRIS may depend partially on the relative balance between C1Q and C1-INH.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Coinfecção/complicações , Proteínas do Sistema Complemento/imunologia , Infecções por HIV/complicações , Síndrome Inflamatória da Reconstituição Imune , Monócitos/imunologia , Tuberculose/complicações , Adulto , Coinfecção/tratamento farmacológico , Coinfecção/imunologia , Feminino , Perfilação da Expressão Gênica , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Estudos Prospectivos , Tuberculose/tratamento farmacológico , Tuberculose/imunologia
19.
Clin Biochem ; 46(1-2): 79-84, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23041246

RESUMO

OBJECTIVES: Preliminary results of the IgA Hevylite™ assay including the establishment of the 95% reference interval and assessment of the specificity and sensitivity in different populations are reported. DESIGN AND METHODS: The concentrations of IgA heavy and light chains (HLC) enabling to determine an IgAκ/IgAλ ratio were quantified in 119 apparently healthy individuals to generate 95% reference intervals. The specificity of this assay was assessed in 48 patients with an isolated polyclonal IgA increase. In a retrospective analysis of 68 patients with a monoclonal component type IgA (MC-IgA) identified by serum immunofixation (IFE), IgA HLC ratio values were compared with known results for serum protein electrophoresis (SPE) and free light chain (FLC) ratios. RESULTS: The 95% reference range obtained in 119 controls (0.91-2.04) was close to that quoted by the manufacturer (0.80-2.04). Eight of the 48 patients (16.7%) with a polyclonal IgA increase had an IgA HLC ratio above the upper limit of the 95% reference interval. The IgA HLC ratio identified 65 (95.6%) among 68 patients with MC-IgA identified on the basis of IFE. For 34 of these patients (50%), MC-IgA was not detected by SPE due to its co-migration with alpha-2 or beta-globulins. CONCLUSIONS: Compared with serum IFE, the IgA HLC ratio has a sensitivity of 95.6%. Further studies are needed to assess the specificity of the IgA HLC ratio in patients with an isolated polyclonal increase of serum IgA.


Assuntos
Imunoglobulina A/sangue , Cadeias Pesadas de Imunoglobulinas/sangue , Cadeias Leves de Imunoglobulina/sangue , Paraproteinemias/sangue , Paraproteinemias/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Eletroforese das Proteínas Sanguíneas/métodos , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Controle de Qualidade , Valores de Referência , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
20.
J Rheumatol ; 39(1): 119-24, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-22089468

RESUMO

OBJECTIVE: To describe the clinical findings and prevalence of patients with cryofibrinogenemia (CF) and to determine whether CF is associated with primary Raynaud's phenomenon. METHODS: Between June 2006 and December 2009, 227 patients were tested for CF in a single university hospital. Forty-five patients with primary Raynaud's phenomenon were tested for CF. RESULTS: A total of 117 patients with CF without cryoglobulinemia were included. The main clinical manifestations included skin manifestations (50%) and arthralgia (35%). There were 67 patients with primary CF and 50 patients with secondary CF. There was no significant difference in the mean concentration of the cryoprecipitate in primary CF as compared to the secondary form (172 ± 18.6 vs 192 ± 20.9 mg/dl, respectively; p = 0.41). Highest concentrations of cryoprecipitate were observed in those containing fibrinogen only as compared to cryoprecipitates containing fibrinogen and fibronectin (301 ± 43.5 vs 125 ± 10.6 mg/dl; p < 0.001). Patients having skin necrosis (n = 3) had significantly higher values of cryofibrinogen compared to those without necrosis (638 ± 105 vs 160 ± 10.2 mg/dl; p = 0.0046). Among the 45 patients with primary Raynaud's phenomenon, 36 had associated CF. There was no significant difference in the mean concentration of the cryoprecipitate in these patients compared to those with primary CF. CONCLUSION: There seems to be a significant correlation between cryofibrinogen concentration and the severity of the clinical signs, particularly when cryoprecipitate is composed of fibrinogen alone. CF might have a possible pathophysiological role in primary Raynaud's phenomenon.


Assuntos
Crioglobulinemia/fisiopatologia , Doença de Raynaud/sangue , Doença de Raynaud/fisiopatologia , Crioglobulinemia/patologia , Feminino , Fibrinogênio/metabolismo , Fibronectinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Raynaud/patologia , Estudos Retrospectivos
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