RESUMO
Agranulocytosis is a rare and serious adverse effect of antithyroid drugs, with unknown etiology. The present study aimed to uncover genetic susceptibility and underlying mechanisms of antithyroid drug-induced agranulocytosis (ATDAC). We studied two independent families with familial Graves' disease, of which several members developed ATDAC. In addition, six sporadic ATDAC patients with Graves' disease were investigated. Whole exome sequencing analysis of affected and unaffected family members was performed to identify genetic susceptibility variants for ATDAC, followed by functional characterization of primary granulocytes from patients and unrelated healthy controls. Whole exome sequencing, cosegregation analysis, and stringent selection criteria of candidate gene variants identified NOX3 as a genetic factor related to ATDAC. Functional studies revealed increased apoptosis of methimazole-treated granulocytes from patients carrying NOX3 variants. In conclusion, genetic variants in NOX3 may confer susceptibility to antithyroid drug-induced apoptosis of granulocytes. These findings contribute to the understanding of the mechanisms underlying ATDAC.
Assuntos
Agranulocitose/induzido quimicamente , Antitireóideos/efeitos adversos , Exoma/genética , Doença de Graves/genética , NADPH Oxidases/genética , Apoptose/genética , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença/genética , Granulócitos/efeitos dos fármacos , Granulócitos/patologia , Humanos , Masculino , Metimazol/efeitos adversos , LinhagemRESUMO
Moraxella catarrhalis rarely causes severe infections or bacteraemia in healthy subjects. In the literature only four cases of clinical sepsis with M. catarrhalis have been described, mostly in immunocompromised patients. We describe a case of a 34-year-old patient with Kugelberg-Welander disease and low body weight (28 kg) who developed clinical sepsis due to M. catarrhalis bacteraemia. A review of the literature is given.
Assuntos
Infecção Hospitalar/complicações , Infecções por Bactérias Gram-Negativas/complicações , Moraxella catarrhalis , Pneumonia Bacteriana/complicações , Atrofias Musculares Espinais da Infância/complicações , Adulto , Peso Corporal , Infecção Hospitalar/microbiologia , Humanos , MasculinoRESUMO
Adhesion receptors and their ligands play a vital role in the immune system. We studied the expression of different adhesion receptors, using single- and double-staining immunohistochemical techniques, in both lesional and non-lesional skin specimens from seven psoriasis patients and in skin biopsy specimens from eight normal healthy controls. Our results showed an overall increased expression of several adhesion receptors in both lesional and non-lesional psoriatic skin. We consistently found an increased expression in particular of ICAM-1 and E-selectin on endothelial cells, and ICAM-1 on T cells and Langerhans cells. In contrast, a weak expression of VCAM-1 was found on endothelial cells and mononuclear cells in lesional psoriatic skin specimens alone. Interestingly, LFA-1 was also expressed on Langerhans cells, with a greater frequency in skin from lesional than from non-lesional sites, but was never expressed in skin from normal healthy individuals. Furthermore, significantly increased numbers of Langerhans cells and T cells with a positive reactivity for MAb HECA-452 were found in both lesional and non-lesional psoriatic skin. We hypothesize that the enhanced expression of adhesion receptors on migrating immunocompetent cells and endothelial cells of psoriatic skin in general facilitates the increased influx of activated T lymphocytes and other immunocomponent cells into the skin, and thus underscores the generalized character of the disease.
Assuntos
Moléculas de Adesão Celular/análise , Molécula 1 de Adesão Intercelular/análise , Antígeno-1 Associado à Função Linfocitária/análise , Psoríase/metabolismo , Pele/química , Adulto , Selectina E , Endotélio Vascular/química , Feminino , Humanos , Queratinócitos/química , Células de Langerhans/química , Macrófagos/química , Masculino , Pessoa de Meia-Idade , Linfócitos T/química , Molécula 1 de Adesão de Célula VascularRESUMO
OBJECTIVE: Only a small percentage of Graves' ophthalmopathy (GO) patients develop optic neuropathy with impending loss of visual acuity. Therapy with methylprednisolone pulses is the treatment of first choice in severe and active GO patients. When the effect is insufficient, patients are usually treated with surgical decompression. We investigated whether surgery could become the first-line treatment, thus preventing treatment with steroids. DESIGN AND SUBJECTS: We performed a randomized trial in 15 patients with very active GO and optic neuropathy. Six patients were treated with surgical decompression, and nine with methylprednisolone i.v. pulses for 2 weeks, followed by oral prednisone for 4 months. The primary outcome was determined by changes in visual acuity. If the eye disease deteriorated despite treatment or did not improve sufficiently, patients were switched to the other treatment arm. RESULTS: The severity and activity of GO in both groups were similar at baseline. The Clinical Activity Score (CAS) was 6.3+/- 0.8 in the surgical group vs. 6.0+/- 0.5 in the steroids group and the Total Eye Score was 24+/- 6 vs. 25+/- 6. In the surgery group, 5/6 patients (82%) did not respond because of insufficient improvement in vision (n=3) or persistent chemosis (n=2), and all needed further immunosuppression. In the steroids group, 4/9 patients (45%) did not improve in visual acuity (P=0.132 vs. surgery group), and these needed decompressive surgery. All patients in whom therapy failed were switched to the other treatment arm and visual acuity improved in almost all patients. Visual acuity improved from 0.36 (0.02--0.40) to 0.90 (0.63--1.0) in the surgery group and from 0.50 (0.32--0.63) to 0.75 (0.32--1.0) in the steroids group at 52 weeks. At long-term follow-up in the surgery group 3/6 patients required squint surgery and 5/9 patients in the steroids group. Eyelid surgery was performed in 5/6 patients in the surgery group and in 4/9 patients in the steroids group. CONCLUSION: Immediate surgery does not result in a better outcome and therefore methylprednisolone pulse therapy appears to be the first-choice therapy.
Assuntos
Descompressão Cirúrgica , Doença de Graves/cirurgia , Neuropatia Óptica Isquêmica/cirurgia , Doença Aguda , Adulto , Feminino , Seguimentos , Glucocorticoides/uso terapêutico , Doença de Graves/complicações , Doença de Graves/tratamento farmacológico , Humanos , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Neuropatia Óptica Isquêmica/tratamento farmacológico , Neuropatia Óptica Isquêmica/etiologia , Prednisolona/uso terapêutico , Pulsoterapia , Resultado do Tratamento , Acuidade VisualRESUMO
OBJECTIVE: Cytokines play an important role in autoimmune thyroid diseases, and serum levels may reflect the activity of the immune process. This is particularly interesting in Graves' ophthalmopathy, where a reliable serum activity marker is warranted. Interleukin-18 (IL-18) is a potent Th1 cytokine, known to induce interferon (IFN)-gamma and the aim of this study was to evaluate serum IL-18 levels in Graves' ophthalmopathy. METHODS: Serum IL-18 was measured by ELISA in 52 patients with untreated Graves' ophthalmopathy (who all had been rendered euthyroid with antithyroid drugs), 52 healthy controls matched for sex, age, and smoking habits, and 15 euthyroid patients who had been treated for Graves' hyperthyroidism and ophthalmopathy in the past. RESULTS: Serum IL-18 (median values in pg/ml with range) levels did not differ between the untreated Graves' ophthalmopathy patients-226 (61-704) pg/ml, matched healthy controls-194 (17-802) pg/ml, and Graves' ophthalmopathy patients treated in the past-146 (0-608) pg/ml. No correlation was observed between serum IL-18 levels and thyroid function or antithyroid antibodies. There was no correlation between serum IL-18 levels and smoking habits. CONCLUSION: We conclude that Graves' ophthalmopathy does not affect serum IL-18.
Assuntos
Doença de Graves/sangue , Interleucina-18/sangue , Adulto , Antitireóideos/uso terapêutico , Autoanticorpos/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Doença de Graves/tratamento farmacológico , Humanos , Imunoglobulinas Estimuladoras da Glândula Tireoide , Masculino , Pessoa de Meia-Idade , Receptores da Tireotropina/sangue , Fumar/sangueRESUMO
Increased serum cytokine levels have been reported in patients with autoimmune thyroid disease, but less is known about their levels in patients with Graves' ophthalmopathy (GO). It is not known whether GO is a cell-mediated or humoral autoimmune disease. We investigated whether serum cytokines are elevated in GO patients and whether the cytokines were Th1- or Th2-derived. In addition, elevated cytokines might reflect the activity of GO, and thus we investigated whether cytokine levels could predict the clinical response to orbital radiotherapy. We studied 62 consecutive patients with moderately severe untreated GO and 62 healthy controls, matched for sex, age and smoking habits. Serum concentrations of IL-1RA, sIL-2R, IL-6, sIL-6R, tumour necrosis factor-alpha (TNF-alpha) RI and II and sCD30 were measured using highly sensitive ELISAs, in the patients before and 3 and 6 months after radiotherapy. All patients were euthyroid, with anti-thyroid drugs, before and during the entire study period. All baseline cytokine and cytokine receptor levels were significantly elevated in GO patients compared with healthy controls, except for IL-1RA. The levels did not correlate with parameters of the thyroid disease, nor with the duration, activity or severity of GO. However, backward logistic regression analysis showed that IL-6, sCD30 and TNFalphaRI were able to predict a beneficial response to orbital radiotherapy. We therefore conclude that both Th1- and Th2-derived cytokines are elevated in GO patients compared with its controls. IL-6, sCD30 and TNFalphaRI had some value for predicting therapeutic outcome to orbital irradiation, and may thus reflect active eye disease.
Assuntos
Citocinas/sangue , Doença de Graves/imunologia , Células Th1/imunologia , Células Th2/imunologia , Adulto , Antígenos CD/sangue , Estudos de Casos e Controles , Feminino , Doença de Graves/radioterapia , Humanos , Proteína Antagonista do Receptor de Interleucina 1 , Interleucina-6/sangue , Antígeno Ki-1/sangue , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina-2/sangue , Receptores de Interleucina-6/sangue , Receptores do Fator de Necrose Tumoral/sangue , Receptores Tipo I de Fatores de Necrose Tumoral , Receptores Tipo II do Fator de Necrose Tumoral , Sialoglicoproteínas/sangue , Fumar/imunologiaRESUMO
OBJECTIVE: From in vitro studies using cultures of orbital fibroblasts, it has become clear that cytokines play an important role in the orbital inflammation in Graves' ophthalmopathy (GO). Orbital fibroblasts seem to be the key target cells of the autoimmune attack, and they are able to express the TSH receptor (TSH-R). In vivo data on the presence of cytokines in orbital tissues are sparse, and mostly limited to samples obtained from patients with endstage, inactive GO; the same holds true for the presence of the TSH-R. The aim of the present study was to determine whether the cytokine profile and TSH-R expression differ in the active vs. the inactive stage of GO. DESIGN AND MEASUREMENTS: Orbital fat/connective tissue was obtained from six patients with active, untreated GO undergoing emergency orbital decompression, and from 11 patients with inactive GO subjected to rehabilitative decompressive surgery. The mRNA levels of various cytokines and the TSH-R were assessed by real-time polymerase chain reaction (PCR) using the LightCycler. Data are expressed as ratios (unknown mRNA/beta-actin mRNA). RESULTS: Active GO patients had much higher TSH-R expression than inactive patients: 4/0-24 (median value/range) vs. 0/0-9, P = 0.01. TSH-R expression was related to the Clinical Activity Score (r = 0.595, P = 0.015). Patients with active GO compared to those with inactive GO had higher mRNA levels of the proinflammatory cytokines interleukin-1beta (IL-1beta) (445/153-877 vs. 0/0-455, P = 0.001), IL-6 (1583/968-18825 vs. 559/0-7181, P = 0.01), IL-8 (1422/38-7579 vs. 32/0-1081, P = 0.046) and IL-10 (145/58-318 vs. 27/0-189, P = 0.002). In active GO there also existed a trend towards a predominance of T helper 1 (Th1)-derived cytokines as evident from higher IL-2 (37/0-158 vs. 0/0-68, P = 0.043), interferon-gamma (IFN-gamma) (20/0-79 vs. 0/0-16, P = 0.12) and IL-12 (2.3/0-14.8 vs. 0/0-1.6, P = 0.10) mRNAs. IL-1 receptor agonist (IL-1RA), IL-2 receptor (IL-2R), IL-3, IL-4, IL-5, IL-13, IL-18 and tumour necrosis factor-alpha (TNF-alpha) mRNAs were similar in both groups. CONCLUSIONS: These data show that at the mRNA level, TSH-R expression is largely present only during the active stages of GO. The active phase is characterized by the presence of proinflammatory and Th1-derived cytokines, whereas other cytokines, among them Th2-derived cytokines, do not seem to be linked to a specific stage of GO.
Assuntos
Adipócitos/metabolismo , Células do Tecido Conjuntivo/metabolismo , Citocinas/metabolismo , Doença de Graves/metabolismo , Órbita , Receptores da Tireotropina/metabolismo , Doença Aguda , Adulto , Feminino , Fibroblastos/metabolismo , Doença de Graves/cirurgia , Humanos , Interferon gama/genética , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estatísticas não ParamétricasRESUMO
Adhesion molecules play a key role in autoimmune disorders, and serum concentrations of soluble adhesion molecules are increased in Graves' ophthalmopathy (GO). Whether this is due to the strong association with smoking is unknown. It is also not known if the severity or activity of GO determine the serum levels of adhesion molecules. We measured serum concentrations of sICAM-1, sVCAM-1 and sELAM-1 in 62 euthyroid Graves' patients with untreated GO, in 62 healthy controls matched for sex, age and smoking habits, and in 26 euthyroid Graves' patients without GO. GO severity was assessed by the Total Eye Score and the activity by the Clinical Activity Score. Adhesion molecules were measured by highly sensitive ELISAs. GO patients had higher levels than controls (median values in ng/ml with range): sICAM-1 300 [171--575] versus 244 [119--674], P < 0.001; sVCAM-1 457 [317--1060] versus 410 [238--562], P < 0.001; and sELAM-1 61 [19--174] versus 53 [23--118], P = 0.021. Euthyroid Graves' disease patients without GO had levels similar to controls: sICAM-1 273 138--453), sVCAM-1 386 [260--1041] and sELAM-1 46 [22--118]. Smoking had an independent effect and was associated with higher levels of sICAM-1 and lower levels of sVCAM-1 in both GO patients and controls; sELAM-1 levels were comparable. In the 62 GO patients, sICAM-1 correlated significantly with severity of eye disease (r = 0.40, P = 0.002). No correlation was found with the duration of GO, the Clinical Activity Score or TBII levels. Multivariate analysis of all 150 subjects showed that the presence of GO and smoking are independent determinants of sICAM-1 and sVCAM-1 concentrations. In GO patients, the Total Eye Score was a stronger determinant than smoking. It is concluded that (i) smoking is associated with increased sICAM-1 and decreased sVCAM-1 levels; (ii) independent from smoking, euthyroid GO patients have higher levels of sICAM-1, sVCAM-1 and sELAM-1 than patients with euthyroid Graves' disease or healthy controls; (iii) the major determinant of sICAM-1 in GO patients is the severity of their eye disease.