RESUMO
The goal of this study was to investigate the glycosylation profile of native immunoglobulin (Ig)G present in serum immune complexes in patients with rheumatoid arthritis (RA). To accomplish this, lectin binding assays, detecting the accessibility of glycans present on IgG-containing immune complexes by biotinylated lectins, were employed. Lectins capturing fucosyl residues (AAL), fucosylated tri-mannose N-glycan core sites (LCA), terminal sialic acid residues (SNA) and O-glycosidically linked galactose/N-acetylgalactosamine (GalNac-L) were used. Patients with recent-onset RA at baseline and after 3-year follow-up were investigated. We found that native IgG was complexed significantly more often with IgM, C1q, C3c and C-reactive protein (CRP) in RA patients, suggesting alterations of the native structure of IgG. The total accessibility of fucose residues on captured immune complexes to the respective lectin was significantly higher in patients with RA. Moreover, fucose accessibility on IgG-containing immune complexes correlated positively with the levels of antibodies to cyclic citrullinated peptides (anti-CCP). We also observed a significantly higher accessibility to sialic acid residues and galactose/GalNAc glyco-epitopes in native complexed IgG of patients with RA at baseline. While sialic acid accessibility increased during treatment, the accessibility of galactose/GalNAc decreased. Hence, successful treatment of RA was associated with an increase in the SNA/GalNAc-L ratio. Interestingly, the SNA/GalNAc-L ratio in particular rises after glucocorticoid treatment. In summary, this study shows the exposure of glycans in native complexed IgG of patients with early RA, revealing particular glycosylation patterns and its changes following pharmaceutical treatment.
Assuntos
Complexo Antígeno-Anticorpo/imunologia , Artrite Reumatoide/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Polissacarídeos/química , Polissacarídeos/imunologia , Adulto , Idoso , Complexo Antígeno-Anticorpo/química , Artrite Reumatoide/terapia , Proteína C-Reativa/imunologia , Proteína C-Reativa/metabolismo , Complemento C1q/imunologia , Complemento C1q/metabolismo , Complemento C3c/imunologia , Complemento C3c/metabolismo , Feminino , Fucose/metabolismo , Galactose/metabolismo , Glicosilação , Humanos , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Imunoglobulina G/química , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Lectinas/metabolismo , Masculino , Pessoa de Meia-Idade , Polissacarídeos/metabolismo , Sambucus nigra , Ácidos Siálicos/metabolismoRESUMO
BACKGROUND: The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion. AIM: To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors. METHODS: One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded. RESULTS: Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016). CONCLUSIONS: A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.
Assuntos
Adenoma/patologia , Adenoma/prevenção & controle , Neoplasias Colorretais/patologia , Neoplasias Colorretais/prevenção & controle , Suplementos Nutricionais , Caracteres Sexuais , Vitamina D/administração & dosagem , Vitamina D/sangue , Adenoma/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Colorretais/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vitamina D/farmacologiaRESUMO
OBJECTIVES: Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly tumour necrosis factor (TNF) and interleukin-1 (IL1), are thought to play a key role in the pathogenesis of inflammation-induced bone loss, but their exact roles are yet to be determined. METHODS: To determine whether TNF directly triggers bone loss or requires IL1, human TNFalpha mice (hTNFtg) were crossed with mice lacking IL1alpha and IL1beta (IL1(-/-)hTNFtg). Systemic bone architecture was evaluated using CT scanning, static and dynamic bone histomorphometry and serum markers of bone metabolism. RESULTS: hTNFtg mice developed severe bone loss accompanied by a severe distortion of bone microarchitecture. Bone trabeculae were thinner and decreased in numbers, resulting in increased trabecular separation. Histomorphometric analyses revealed strongly increased bone resorption in hTNFtg mice compared with wild-type mice. In contrast, IL1(-/-)hTNFtg mice were fully protected from systemic bone loss despite still developing inflammation in their joints. Lack of IL1 completely reversed increased osteoclast formation and bone resorption in hTNFtg mice and the increased levels of RANKL in these mice. Structural parameters and osteoclast and osteoblast numbers were indistinguishable from wild-type mice. CONCLUSIONS: These data indicate that IL1 is essential for TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis, systemic bone is fully protected by the absence of IL1, which suggests that IL1 is an essential mediator of inflammatory osteopenia.
Assuntos
Artrite Experimental/complicações , Artrite Reumatoide/complicações , Doenças Ósseas Metabólicas/etiologia , Interleucina-1/fisiologia , Fator de Necrose Tumoral alfa/fisiologia , Animais , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Biomarcadores/sangue , Densidade Óssea/fisiologia , Doenças Ósseas Metabólicas/metabolismo , Doenças Ósseas Metabólicas/patologia , Doenças Ósseas Metabólicas/fisiopatologia , Reabsorção Óssea/fisiopatologia , Tomografia com Microscopia Eletrônica , Feminino , Interleucina-1/deficiência , Camundongos , Camundongos Transgênicos , Osteoblastos/patologia , Osteoclastos/patologia , Tíbia/ultraestruturaRESUMO
OBJECTIVES: (1) To show that a single-chain Fv antibody (scFv) against tumour necrosis factor alpha (TNFalpha) (ESBA105) has efficacy comparable to a full length anti-TNFalpha IgG (infliximab); (2) to evaluate whether ESBA105 has all the properties required for the local treatment of arthritis; and (3) to investigate its discriminative tissue penetration properties. METHODS: In vivo efficacy was measured in arthritis of the knee joint induced by the intra-articular injection of recombinant human TNFalpha (rhTNFalpha) in Lewis rats. Cartilage penetration of scFv (ESBA105) and full length IgG (infliximab) were studied in bovine cartilage specimens ex vivo. Tissue penetration, biodistribution and pharmacokinetics of ESBA105 were followed and compared after intra-articular and intravenous administration. RESULTS: In cell culture, ESBA105 showed similar TNFalpha inhibitory potency to infliximab. In vivo, ESBA105 inhibited rhTNFalpha-induced synovial inflammation in rats with efficacy again comparable to infliximab. An 11-fold molar excess of ESBA105 over rhTNFalpha resulted in 90% inhibition of knee joint swelling, inflammatory infiltrates and proteoglycan loss from cartilage. In ex vivo studies of bovine cartilage, ESBA105 penetrated well into the cartilage whereas infliximab remained on the surface. In vivo, rapid penetration into the synovial tissue, cartilage and surrounding tissues was observed following intra-articular injection of [(125)I]-ESBA105 into the knee joint of rabbits. CONCLUSIONS: ESBA105 potently inhibits inflammation and prevents cartilage damage triggered by TNFalpha. In contrast to a full length IgG, ESBA105 also penetrates into cartilage and can be expected to reverse the TNFalpha-induced catabolic state of articular cartilage in arthritides.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Artrite Experimental/prevenção & controle , Osteoartrite/prevenção & controle , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/farmacologia , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Apoptose/efeitos dos fármacos , Cartilagem Articular/metabolismo , Células Cultivadas , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Fibroblastos/efeitos dos fármacos , Infliximab , Injeções Intra-Articulares , Masculino , Coelhos , Ratos , Ratos Endogâmicos Lew , Proteínas Recombinantes/farmacologia , Sinovite/prevenção & controle , Distribuição TecidualRESUMO
The EULAR Executive Committee defined eight overall objectives for EULAR to achieve by 2012. The first of these objectives is to strengthen activities in areas that are currently less prioritized, such as non-inflammatory and orphan diseases. This study aims to increase awareness of rheumatologists towards rare hereditary musculoskeletal disorders, by describing their genetics, pathogenesis, and typical clinical and radiological features. We analyzed patient charts from the recent 5 years from the Rheumatology Outpatient Department of the University Erlangen-Nuremberg and of two rheumatologic practices, all joined in a regional network ("Rheumazentrum Erlangen") retrospectively for hereditary musculoskeletal disorders other than hemochromatosis, autoinflammatory syndromes, lysosomal storage diseases, and hypermobility syndromes. We were able to identify four patients with trichorhinophalangeal syndrome type I, multiple exostoses, Kirner's deformity, and osteopoikilosis. In addition, a PubMed and OMIM ("Online Mendelian Inheritance in Man") database search was carried out using these as key words and all relevant articles were reviewed for each of these diseases. Our findings show that rare hereditary musculoskeletal disorders occur in a routine rheumatological setting and that rheumatologists should know the clinical and radiological features of these diseases in order to adequately counsel the patient.