RESUMEN
Tumour necrosis factor receptor-associated periodic syndrome (TRAPS) is a hereditary autoinflammatory disorder characterized by recurrent episodes of fever and inflammation. It is associated with autosomal dominant mutations in TNFRSF1A, which encodes tumour necrosis factor receptor 1 (TNF-R1). Our aim was to understand the influence of TRAPS mutations on the response to stimulation of the pattern recognition Toll-like receptor (TLR)-9. Peripheral blood mononuclear cells (PBMCs) and serum were isolated from TRAPS patients and healthy controls: serum levels of 15 proinflammatory cytokines were measured to assess the initial inflammatory status. Interleukin (IL)-1ß, IL-6, IL-8, IL-17, IL-22, tumour necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), interferon (IFN)-γ, monocyte chemoattractant protein 1 (MCP-1) and transforming growth factor (TGF)-ß were significantly elevated in TRAPS patients' sera, consistent with constitutive inflammation. Stimulation of PBMCs with TLR-9 ligand (ODN2006) triggered significantly greater up-regulation of proinflammatory signalling intermediates [TNF receptor-associated factor (TRAF 3), IL-1 receptor-associated kinase-like 2 (IRAK2), Toll interacting protein (TOLLIP), TRAF6, phosphorylated transforming growth factor-ß-activated kinase 1 (pTAK), transforming growth factor-ß-activated kinase-binding protein 2 (TAB2), phosphorylated TAK 2 (pTAB2), IFN-regulatory factor 7 (IRF7), receptor interacting protein (RIP), nuclear factor kappa B (NF-κB) p65, phosphorylated NF-κB p65 (pNF-κB p65) and mitogen-activated protein kinase kinase (MEK1/2)] in TRAPS patients' PBMCs. This up-regulation of proinflammatory signalling intermediates and raised serum cytokines occurred despite concurrent anakinra treatment and no overt clinical symptoms at time of sampling. These novel findings further demonstrate the wide-ranging nature of the dysregulation of innate immune responses underlying the pathology of TRAPS and highlights the need for novel pathway-specific therapeutic treatments for this disease.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Genes Dominantes , Enfermedades Genéticas Congénitas/inmunología , Mutación , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptor Toll-Like 9/inmunología , Adulto , Anciano , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Citocinas/genética , Citocinas/inmunología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/inmunología , Enfermedades Genéticas Congénitas/genética , Enfermedades Genéticas Congénitas/patología , Humanos , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Masculino , Persona de Mediana Edad , Oligodesoxirribonucleótidos/farmacología , Receptores Tipo I de Factores de Necrosis Tumoral/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Síndrome , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/genéticaRESUMEN
Common variable immunodeficiency disorders (CVIDs) are a heterogeneous group of diseases characterized by hypogammaglobulinaemia and consequent susceptibility to infection. CVID patients commonly develop a variety of additional manifestations for which the causative factors are not fully understood. Two such manifestations are granulomatous disease and enteropathy. Because the ability to predict complications would aid clinical management, we continue to search for possible disease modifier genes. NOD2 acts a microbial sensor and is involved in proinflammatory signalling. Particular mutations of the NOD2 gene are associated with Crohn's disease including gly908arg, leu1007finsc and arg702trp polymorphisms. We hypothesized that NOD2 polymorphisms may be a disease modifier gene towards an enteropathic or granulomatous phenotype within CVIDs. Sequence-specific primers returned genotypes for 285 CVID patients from centres across the United Kingdom and Europe. We present the frequencies of the different phenotypes of patients within our international cohort. Arg702trp polymorphisms were significantly less frequent than wild-type (WT) (P = 0·038) among international CVID patients with splenomegaly. Gly908arg polymorphisms were more prevalent than WT in UK patients with autoimmune disorders (P = 0·049) or enteropathy (P = 0·049). NOD2 polymorphisms were not more prevalent than WT in CVID patients with clinical phenotypes of granulomata. UK allele frequencies of 0·014, 0·056 and 0·026 were found for gly908arg, arg702trp and leu1007finsc NOD2 polymorphisms, respectively. These do not differ significantly from UK immunocompetent controls confirming, as expected, that in addition these NOD2 polymorphisms do not confer susceptibility to CVIDs per se.
Asunto(s)
Inmunodeficiencia Variable Común/genética , Proteína Adaptadora de Señalización NOD2/genética , Polimorfismo de Nucleótido Simple , Estudios de Cohortes , Inmunodeficiencia Variable Común/patología , Enfermedad de Crohn/genética , Europa (Continente) , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Mutación , Fenotipo , Reino UnidoAsunto(s)
Fiebre Mediterránea Familiar/diagnóstico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Inmunoglobulina G/administración & dosificación , Receptores Tipo I de Factores de Necrosis Tumoral/efectos adversos , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Receptores del Factor de Necrosis Tumoral/administración & dosificación , Adalimumab , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales Humanizados , Compuestos Aza/administración & dosificación , Enfermedad Crónica , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Etanercept , Femenino , Fluoroquinolonas , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino , Estudios Prospectivos , Quinolinas/administración & dosificación , Medición de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVE: To investigate the levels of the pro-inflammatory cytokines IL-6, TNF-alpha, IL-1beta, IL-8, IL-10 and IL-12p70 in the plasma of patients with TNF receptor-associated periodic syndrome (TRAPS) in relation to CRP levels and treatment with etanercept. METHODS: Cytokine concentrations were measured in sequential plasma samples obtained from eight patients with a C33Y mutation in TNFRSF1A and diagnosed with TRAPS, using cytokine bead array. The TRAPS samples were compared with samples from normal controls and rheumatoid arthritis patients. RESULTS: Levels of IL-6 were significantly elevated in C33Y TRAPS patients and these correlated with CRP levels in some of the patients. IL-8 levels were also significantly elevated in the TRAPS patients. However, neither TNF-alpha nor IL-1beta demonstrated a similar increase. This differed from the patients with rheumatoid arthritis, for whom levels of IL-6, IL-8, TNF-alpha, IL-1beta and IL-10 were significantly elevated. The levels of detectable TNF-alpha in the TRAPS patients' plasma were elevated during etanercept treatment. CONCLUSIONS: The cytokine profile of C33Y TRAPS differs from that of a typical autoimmune inflammatory condition such as rheumatoid arthritis, as only IL-6 and IL-8 were elevated in C33Y TRAPS patients, as distinct from a generalized elevation of pro-inflammatory cytokines. However, only some of the C33Y patients tested showed a relationship between elevated IL-6 and CRP. This is consistent with clinical observations that there is marked heterogeneity between individuals with TRAPS, including those in the same family cohort. Although etanercept has a therapeutic effect in some TRAPS patients, it induces increased plasma concentrations of TNF-alpha, possibly by increasing TNF-alpha stability.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Citocinas/sangre , Fiebre Mediterránea Familiar/genética , Inmunoglobulina G/uso terapéutico , Mutación/genética , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Adulto , Anciano , Proteína C-Reactiva/metabolismo , Etanercept , Fiebre Mediterránea Familiar/tratamiento farmacológico , Femenino , Humanos , Masculino , Persona de Mediana Edad , SíndromeRESUMEN
OBJECTIVE: To describe the effect of Etanercept treatment in systemic AA amyloidosis in tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Etanercept therapy was given to a 27 year old woman, with systemic amyloidosis and nephrotic syndrome, and to her 51 year old father, also affected by TRAPS, who had previously undergone renal transplant for amyloidosis. Serum SAA levels, plasma cytokines, glomerular filtration rate and serum amyloid P scanning were monitored. RESULTS: Etanercept treatment resulted in initial clinical resolution of nephrotic syndrome in the 27 year old female. Both subjects demonstrated improvements in GFR and initial reduction or stabilisation of amyloid deposits on SAP scanning. CONCLUSION: Etanercept may reverse or slow the progression of systemic AA amyloidosis in subjects with C33Y TNFRSF1A mutation. Treatment may however need to be continuous and life-long to prevent progression to end stage disease.
Asunto(s)
Amiloidosis/tratamiento farmacológico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Síndrome Nefrótico/tratamiento farmacológico , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Adulto , Amiloidosis/genética , Citocinas/sangre , Etanercept , Fiebre Mediterránea Familiar/genética , Femenino , Humanos , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Mutación , Síndrome Nefrótico/genética , Proteína Amiloide A Sérica/metabolismoAsunto(s)
Enfermedades Musculares/patología , Dolor/patología , Periodicidad , Receptores del Factor de Necrosis Tumoral , Adulto , Antígenos CD/genética , Familia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedades Musculares/etiología , Enfermedades Musculares/genética , Mutación , Dolor/etiología , Dolor/genética , Receptores del Factor de Necrosis Tumoral/genética , Receptores Tipo I de Factores de Necrosis Tumoral , SíndromeRESUMEN
OBJECTIVE: To assess the effects prospectively of tumour necrosis factor (TNF) receptor superfamily (TNFRSF) fusion proteins TNFRSF1B (etanercept) and TNFRSF1A (p55TNFr-Ig) in patients with TNF receptor associated periodic syndrome (TRAPS). METHODS: Seven patients with a clinical and genetic diagnosis of TRAPS received subcutaneous etanercept for 24 weeks. One of these patients had previously received an intravenous infusion of p55TNFr-Ig. Therapeutic response was assessed by comparing corticosteroid requirement, acute-phase response and an established scoring system over 20 weeks, both on and off etanercept. RESULTS: Etanercept was well tolerated. The five corticosteroid-responsive patients required significantly less corticosteroids and demonstrated reductions in acute-phase reactants on etanercept. The two patients not requiring corticosteroids had small reductions in disease activity scores. The effect of p55TNFr-Ig in a single patient with TRAPS remains unclear. CONCLUSIONS: Etanercept does not abolish inflammatory attacks but improves disease activity allowing corticosteroid reduction. Etanercept may be clinically useful in replacing or reducing steroid requirements in the treatment of TRAPS. A formal trial of etanercept to establish its role in clinical management is indicated.
Asunto(s)
Antirreumáticos/uso terapéutico , Fiebre Mediterránea Familiar/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Adulto , Antígenos CD/uso terapéutico , Proteína C-Reactiva/metabolismo , Preescolar , Esquema de Medicación , Quimioterapia Combinada , Etanercept , Femenino , Glucocorticoides/uso terapéutico , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Receptores Tipo I de Factores de Necrosis Tumoral , Resultado del TratamientoAsunto(s)
Enfermedades Autoinmunes/complicaciones , Fiebre/etiología , Poliarteritis Nudosa/diagnóstico , Adulto , Colecistectomía/métodos , Colecistitis/tratamiento farmacológico , Colecistitis/etiología , Ciclofosfamida/uso terapéutico , Diarrea/etiología , Femenino , Humanos , Deficiencia de IgG/complicaciones , Poliarteritis Nudosa/tratamiento farmacológico , Púrpura Trombocitopénica Idiopática/complicaciones , RecurrenciaRESUMEN
Monoclonal antibodies have been used in clinical diagnosis for many years but it is only now that these agents are being licensed for clinical treatments. This review will focus on UK licensed monoclonal antibodies highlighting their clinical benefits, limitations, and side effects.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales/efectos adversos , Artritis Reumatoide/terapia , Enfermedad Coronaria/terapia , Enfermedad de Crohn/terapia , Rechazo de Injerto/prevención & control , Humanos , Neoplasias/terapia , Virosis/terapiaAsunto(s)
Amiloidosis/tratamiento farmacológico , Inmunoglobulina G/uso terapéutico , Inmunosupresores/uso terapéutico , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Adulto , Esquema de Medicación , Etanercept , Femenino , Humanos , Inmunoglobulina G/administración & dosificación , Inmunosupresores/administración & dosificación , Receptores del Factor de Necrosis Tumoral/administración & dosificaciónAsunto(s)
Fiebre Mediterránea Familiar/complicaciones , Inmunoglobulina G/uso terapéutico , Síndrome Nefrótico/tratamiento farmacológico , Receptores del Factor de Necrosis Tumoral/genética , Receptores del Factor de Necrosis Tumoral/uso terapéutico , Adulto , Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Etanercept , Femenino , Humanos , Inyecciones Subcutáneas , Enfermedades Renales/complicaciones , Enfermedades Renales/diagnóstico , Síndrome Nefrótico/etiología , Componente Amiloide P Sérico , Factor de Necrosis Tumoral alfaRESUMEN
Anti-idiotypic antibodies have been developed in rabbits against three high affinity IgG class monoclonal human autoantibodies to thyroglobulin (Tg), which resemble polyclonal Tg antibodies in patients with autoimmune thyroid disease. Antibodies to 1E10 monoclonal anti-Tg (IgG2 kappa) recognised a cross-reactive idiotype (CRI) also present on 1D3 monoclonal anti-Tg (IG1 lambda) and on VB5 monoclonal anti-Tg (IgG2 lambda). The determinant to which anti-1E10 binds appears to involve, at least in part, the binding site for Tg. In contrast, anti-idiotypic antibodies raised against VB5 failed to bind to either 1E10 or 1D3, a finding consistent with previous studies on serum polyclonal Tg antibodies, which suggested that such antibodies exhibit a mixture of private and cross-reactive idiotypes. The observed sharing of idiotypic determinants was not related to subclass, light chain type or expression of a particular VH gene family in the heavy chain. Although binding of the anti-idiotypic antibodies to Tg antibodies in a panel of patients (including the donors of the lymphocytes used to produce the monoclonal antibodies) could not be detected, the monoclonal antibodies are representative of the donor patients' serum Tg antibodies, both in terms of IgG subclass and functional affinity. Thus these idiotypes may be present in patients' sera at levels below the detection limits of the assays employed. Cross-reactive regulatory idiotypes in mice often constitute a minor component of the anti-Tg repertoire. Consequently, it is possible that low levels of a CRI, such as the 1E10 CRI, may be involved in the regulation of the autoimmune response to Tg in man.
Asunto(s)
Anticuerpos Antiidiotipos/inmunología , Anticuerpos Monoclonales/inmunología , Autoanticuerpos/inmunología , Inmunoglobulina G/inmunología , Idiotipos de Inmunoglobulinas/inmunología , Tiroglobulina/inmunología , Animales , Reacciones Cruzadas , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunoglobulina M/inmunología , Conejos , Tiroiditis Autoinmune/inmunologíaRESUMEN
48 patients with unilateral frontal or non-frontal cortical lesions were given a go - no go learning task. Patients with frontal lesions in either hemisphere took longer to learn the task and made more false "go" responses than control patients. They also, unlike controls, took longer to make in correct positive responses than correct positive ones. Medial frontal lesions were found to be particularly important in giving rise to poor performance on this task. It is suggested that this task is non-unitary in nature and that the medial area may be important for more than one ability.