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1.
Clin Exp Rheumatol ; 27(3): 491-4, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19604443

RESUMO

BACKGROUND: Imbalance of haemostasis in patients with rheumatoid arthritis (RA) contributes to future risk of cardiovascular diseases (CVD). Prothrombotic molecules, e.g. fibrinogen, D-dimer, and tPA are elevated in plasma of RA patients, being associated to CVD. There is no imformation about the influence of biological drugs, e.g. anti-CD20 and tumor necrosis factor (TNF) antibodies on these prothrombotic molecules. OBJECTIVE: To assess whether anti-TNF and anti-CD20 therapies modify the profiles of cardiovascular risk factors in patients with RA. METHODS: The expression of prothrombotic molecules in plasma was investigated in 10 RA patients before and after treatment with TNF-alpha antibodies and in another 12 RA patients before and after anti-CD20 treatment. RESULTS: Both anti-TNF and anti-CD20 infusions gave rise to clear clinical improvement. However, only anti-CD20 infusion significantly (p=0.05) reduced concentration of fibrinogen (p=0.05), D-dimer (p<0.001), as well as tPA levels (p<0.01). In contrast, in TNF antibody treated patients only tPA levels were significantly decreased following the treatment (p<0.05). CONCLUSIONS: Infusion of CD20 antibodies to the patients with active RA led to a clearly reduced plasma levels of predictors of CVD indicating that this treatment, apart from its anti-inflammatory properties, may reduce the risk for future CVD in RA.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinogênio/metabolismo , Inibidor 1 de Ativador de Plasminogênio/sangue , Ativador de Plasminogênio Tecidual/sangue , Adulto , Idoso , Anticorpos/uso terapêutico , Anticorpos Monoclonais Murinos , Antígenos CD20/imunologia , Antirreumáticos/uso terapêutico , Proteína C-Reativa/metabolismo , Doenças Cardiovasculares , Relação Dose-Resposta a Droga , Feminino , Humanos , Infliximab , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Rituximab , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
2.
Genes Immun ; 10(3): 227-36, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19279651

RESUMO

Genetic variation in the antigen-presenting lectin-like receptor gene complex (APLEC) associates with autoimmunity and arthritis in rats and humans. We hypothesized that the encoded C-type lectin-like receptors might influence innate immunity and responses to infectious agents. To test this hypothesis, we compared in vivo and in vitro phenotypes in DA rats and APLEC-congenic rats. Survival rates following infection with Staphylococcus aureus and Herpes simplex virus differed significantly between the two strains. Likewise, differential delayed type hypersensitivity (DTH), an immunological reaction involving T lymphocytes and macrophages, was observed in response to provocation with the chemical oxazolone. Unstimulated bone marrow-derived macrophages from the two strains appeared to already have polarized activation states with different mRNA levels of CD163 and Dectin-1 receptors. Following stimulation with a panel of microbial agents, differences in induced mRNA and protein levels were shown for interleukin (IL)-6 and IL-10 following stimulation with lipopolysaccharide, mannan and beta-glucan. Expression levels of APLEC gene mRNAs also differed, and both strains had a notably dichotomous expression of the genes, with general downregulation of all four Dcir genes and upregulation of Mincle and Mcl. We suggest that human APLEC genes may similarly regulate infectious diseases, DTH and general macrophage activation status.


Assuntos
Doenças Transmissíveis/imunologia , Imunidade Inata , Lectinas Tipo C/imunologia , Macrófagos/imunologia , Adjuvantes Imunológicos/farmacologia , Animais , Artrite Infecciosa/genética , Artrite Infecciosa/imunologia , Artrite Infecciosa/microbiologia , Artrite Infecciosa/mortalidade , Células Cultivadas , Doenças Transmissíveis/genética , Citocinas/biossíntese , Citocinas/genética , Citocinas/imunologia , Encefalite/genética , Encefalite/imunologia , Encefalite/virologia , Herpesvirus Humano 1/imunologia , Hipersensibilidade Tardia/genética , Hipersensibilidade Tardia/imunologia , Lectinas Tipo C/genética , Lipopolissacarídeos/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Ativação de Macrófagos/genética , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/microbiologia , Macrófagos/virologia , Mananas/farmacologia , Oxazolona/farmacologia , Ratos , Infecções Estafilocócicas/genética , Infecções Estafilocócicas/imunologia , Staphylococcus aureus/imunologia , Zimosan/farmacologia , beta-Glucanas/farmacologia
3.
Mult Scler ; 15(4): 448-54, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19153172

RESUMO

BACKGROUND: Cell and animal experiments have shown that beta-site APP-cleaving enzyme 1 (BACE1) may be involved in myelination. OBJECTIVE: Here, we assess the association of cerebrospinal fluid (CSF) BACE1 activity with multiple sclerosis (MS). METHODS: BACE1 activity and levels of secreted amyloid precursor protein (APP) and amyloid-beta (Abeta) isoforms were analyzed in CSF from 100 patients with MS and 114 neurologically healthy controls. Patients with systemic lupus erythematosus (SLE), 26 with and 41 without cerebral engagement, were also included to enable comparisons with regards to another autoimmune disease. A subset of patients with MS and controls underwent a second lumbar puncture after 10 years. RESULTS: MS patients had lower CSF BACE1 activity than controls (P = 0.03) and patients with cerebral SLE (P < 0.001). Patients with cerebral SLE had higher BACE1 activity than any other group (P < 0.05 for all comparisons). BACE1 activity correlated with the different amyloid markers in all study groups. BACE1 activity decreased over 10 years in the MS group (P = 0.039) and correlated weakly with clinical disease severity scores in an inverse manner. CONCLUSIONS: These results suggest an involvement of BACE1 in the MS disease process.


Assuntos
Secretases da Proteína Precursora do Amiloide/líquido cefalorraquidiano , Ácido Aspártico Endopeptidases/líquido cefalorraquidiano , Esclerose Múltipla/metabolismo , Bainha de Mielina/metabolismo , Adulto , Idoso , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Feminino , Humanos , Lúpus Eritematoso Sistêmico/metabolismo , Masculino , Pessoa de Meia-Idade , Regeneração Nervosa/fisiologia , Fragmentos de Peptídeos/líquido cefalorraquidiano , Adulto Jovem
4.
Clin Exp Rheumatol ; 26(2): 373-8, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18565266

RESUMO

BACKGROUND: Survivin is an anti-apoptotic protein that has been recently suggested as a predictive marker of joint destruction in adult rheumatoid arthritis. We assessed the presence of extracellular survivin in patients with juvenile idiopathic arthritis (JIA). METHODS: Survivin levels were assessed in the circulation of 46 patients with JIA and in the age- and gender-matched controls (n=46) having no inflammatory disease, by ELISA. Survivin levels were analyzed with respect to the onset type and the activity of the joint disease. The intensity of inflammation and cartilage turnover was measured as levels of IL-6, serum amyloid A protein (SAA), and cartilage oligomeric matrix protein (COMP), respectively. RESULTS: The levels of extracellular survivin were significantly higher in JIA compared to the controls (p=0.0002). High levels of survivin (above mean + 2SD of the controls) were detected in 8/46 (17% JIA patients. High survivin expression was associated with polyarticular onset, active phase of arthritis. In contrast, survivin was neither related to the levels of IL-6, SAA, nor to COMP. CONCLUSION: Circulating survivin is expressed in a significant group of patients with JIA being associated to a severe course of the disease. It may be potentially used to select children with unfavorable prognosis of JIA who are in need of active pharmacologic treatment.


Assuntos
Artrite Juvenil/diagnóstico , Artrite Juvenil/metabolismo , Biomarcadores/sangue , Proteínas Associadas aos Microtúbulos/sangue , Proteínas de Neoplasias/sangue , Adolescente , Proteína de Matriz Oligomérica de Cartilagem , Criança , Proteínas da Matriz Extracelular/sangue , Espaço Extracelular/metabolismo , Feminino , Glicoproteínas/sangue , Humanos , Proteínas Inibidoras de Apoptose , Interleucina-6/sangue , Masculino , Proteínas Matrilinas , Valor Preditivo dos Testes , Prognóstico , Proteína Amiloide A Sérica/metabolismo , Índice de Gravidade de Doença , Survivina
5.
Scand J Immunol ; 67(3): 253-9, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18226012

RESUMO

Substance P (SP), acting on the neurokinin-1 receptor (NK-1R), is a neuropeptide, involved in the inflammatory processes. It promotes vasodilatation and increases vasopermeability, thus ensuing extravasation and accumulation of leucocytes at sites of injury. The aim of this study was to assess the impact of SP signalling on the responses during staphylococcal infection and the accompanying arthritis. Three experiments were performed where NK-1R-/- mice and controls were intravenously infected with different doses of Staphylococcus aureus. Clinical assessment of arthritis was performed as well as histological analysis of bone and cartilage destruction in the joints. In addition, the impact of NK-1R mutation on bacterial load in the kidneys as well as the phagocytic capacity of blood leucocytes were studied. Mice lacking the NK-1R displayed significantly higher bacterial load in the kidneys and significantly more severe synovitis and cartilage/bone destruction than the controls when inoculated with 1.4 x 10(7) staphylococci. Infection with 3.5 x 10(8) CFU/mouse induced sepsis. Thus, 11 days after bacterial inoculation 15 of 19 mice in the NK-1R-/- group had died versus 8 of 15 in the control group. Phagocytosis test revealed that significantly fewer macrophages from NK-1R-/- mice were able to phagocytose S. aureus when compared with macrophages from congenic control mice. Blocking the biological responses to substance P via its receptor NK-1R results in a less efficient clearance of bacteria leading to more severe arthritic lesions in mice.


Assuntos
Artrite Infecciosa/imunologia , Transdução de Sinais/fisiologia , Infecções Estafilocócicas/imunologia , Substância P/imunologia , Animais , Artrite Infecciosa/metabolismo , Artrite Infecciosa/patologia , Bacteriemia/imunologia , Bacteriemia/metabolismo , Bacteriemia/patologia , Feminino , Interleucina-6/sangue , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Fagocitose/fisiologia , Receptores da Neurocinina-1/genética , Receptores da Neurocinina-1/imunologia , Receptores da Neurocinina-1/metabolismo , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/patologia , Substância P/metabolismo
6.
Scand J Immunol ; 66(4): 476-83, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17850593

RESUMO

Rheumatoid arthritis (RA) is characterized by chronic joint inflammation and destruction. B cells play important role in modulating immune responses in RA. In the present study we assessed the impact of the B cell targeting as a third line treatment option. Forty-six patients with established erosive RA non-responding to combination treatment with DMARDs and TNF-alpha inhibitors were treated with anti-CD20 antibodies (rituximab). Rituximab was given intravenously once weekly on four occasions. All patients continued with the previous DMARD. Patients were followed by DAS28, levels of circulating B cells, frequency of immunoglobulin-producing cells, immunoglobulins, and rheumatoid factor levels during the period of 12-58 months. Clinical improvement was achieved in 34 of 46 patients (73%) supported by a significant reduction in DAS28 (from 6.04 to 4.64, P < 0.001). Infusion of rituximab resulted in the elimination of circulating B cells in all but one patient. Within 12 months follow-up, B cells returned to circulation in 86% of patients. Fifty-three percent of the patients were successfully retreated with rituximab or re-started with anti-TNF-alpha treatment. Of the 11 non-responders, five were retreated with anti-CD20 within 2 months, four of them with success, four patients received TNF-alpha inhibitors, the remaining two patients received an additional DMARD. Most of the RA patients resistant to TNF-alpha inhibitors may be effectively treated with anti-CD20 antibodies. The treatment is well tolerated and may be used repeatedly in the same patient and potentially increase sensitivity to previously inefficient treatment modalities.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antígenos CD20/imunologia , Antirreumáticos/uso terapêutico , Linfócitos B/imunologia , Imunoterapia/métodos , Febre Reumática/imunologia , Adulto , Idoso , Anticorpos Monoclonais Murinos , Artralgia/tratamento farmacológico , Artralgia/imunologia , Sedimentação Sanguínea/efeitos dos fármacos , Proteína C-Reativa/análise , Resistência a Medicamentos , Feminino , Hemoglobinas/análise , Humanos , Imunoglobulinas/sangue , Contagem de Leucócitos , Estudos Longitudinais , Masculino , Metotrexato/farmacologia , Pessoa de Meia-Idade , Contagem de Plaquetas , Febre Reumática/sangue , Febre Reumática/terapia , Fator Reumatoide/sangue , Rituximab , Fator de Necrose Tumoral alfa/antagonistas & inibidores
7.
Scand J Immunol ; 66(2-3): 192-8, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17635796

RESUMO

Rheumatoid arthritis (RA) is an inflammatory joint disease leading to cartilage and bone destruction. Insufficient apoptosis in the inflamed RA synovium along with accumulation of highly differentiated B- and T-lymphocytes as well as invasive growth of macrophages and fibroblasts is among the major mechanisms supporting joint destruction. We have recently shown that circulating survivin, an apoptosis inhibitor tightly bound to tumorigenesis, is an independent predictor of development and progression of joint destruction in RA. In this review we discuss the possible connectivity between viral infection, leading to interferon (IFN)-alpha production, survivin expression, and subsequent joint inflammation. The role of IFN-alpha and the involvement of IFN transcription factors and phosphoinositide-3-kinase signalling as essential modulators of arthritogenic process are discussed in the context of survivin.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/virologia , Proteínas Associadas aos Microtúbulos/biossíntese , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Infecções por Retroviridae/imunologia , Infecções Tumorais por Vírus/imunologia , Animais , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Humanos , Proteínas Inibidoras de Apoptose , Proteínas Associadas aos Microtúbulos/sangue , Proteínas de Neoplasias/sangue , Retroviridae/patogenicidade , Infecções por Retroviridae/metabolismo , Infecções por Retroviridae/patologia , Survivina , Infecções Tumorais por Vírus/metabolismo , Infecções Tumorais por Vírus/patologia
8.
Scand J Immunol ; 66(1): 77-86, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17587349

RESUMO

We have shown that human CD20(+)25(+) B cells display immunomodulatory properties. The aim of this study was to investigate if CD25(+) B cells are found within the CD27 memory B cell population, and to analyse pattern of their cytokine production. B cells isolated from healthy subjects, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients were analysed regarding the frequency of CD25(+) B cells within certain B cell subsets. Purified CD25(+) B cells from healthy subject were used in vitro to evaluate their production of immunomodulatory cytokines. In healthy subjects the majority (60%) of memory B cells (CD20(+)27(+)) also co-expressed CD25 while only 10-20% of the naïve B cells (CD20(+)27(-)) and plasmablasts (CD20-27(+)) expressed CD25. In RA and SLE patients, we found that 51% and 48%, respectively, co-expressed CD25 in the memory population, whereas only 11% and 9% co-expressed CD25 in the naïve B cell population. Phenotypic analysis of the CD20(+)25(+)27(+) and CD20(+)25(+)27(-) cells using CD10, CD24, CD38, CD45, CD71, CD80, CD86, CD95, CD138, BAFF-R, TACI, IgA, IgD, IgG and IgM showed that CD20(+)25(+)27(+) B cells preferentially represent highly activated, Ig class switched memory B cells. Cytokine profile analysis showed that CD25(+) B cells secreted significantly higher levels of IL-10 versus CD25(-) B cells. In contrast, TGF-beta1 secretion was similar between the CD25(+) and CD25(-) sub-populations. In conclusion, CD20(+)25(+) B cells constitute a unique subpopulation preferentially occurring among CD20(+)27(+) memory B cells. We suggest that CD25 can be used as a marker for a memory B cell subset.


Assuntos
Doenças Autoimunes/imunologia , Subpopulações de Linfócitos B/metabolismo , Linfócitos B/imunologia , Memória Imunológica , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/metabolismo , Citocinas/biossíntese , Feminino , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismo
9.
Rheumatology (Oxford) ; 46(8): 1367-71, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17569744

RESUMO

OBJECTIVES: The receptor for advanced glycation end products (RAGE) is expressed by many cells in joints of rheumatoid arthritis (RA) patients and interacts with a variety of pro-inflammatory ligands that are enriched in inflamed joint. The RAGE-ligand interaction leads to a sustained inflammatory response. Also, secreted form of the receptor, called soluble RAGE (sRAGE), the levels of which are decreased in RA patients, modulates inflammatory responses. We sought to determine whether RA patients display increased occurrence of autoantibodies against RAGE and whether such an autoantibody production is related to disease characteristics. METHODS: Matching samples of blood and synovial fluid were collected from 50 patients with RA with acute joint effusion. Blood from 43 healthy individuals and synovial fluid samples from 32 patients with non-inflammatory joint diseases were used for comparison. Anti-RAGE antibody levels were analysed using an ELISA. RESULTS: RA patients displayed significantly higher blood and synovial fluid levels of anti-RAGE antibodies, both of IgG as well as of IgM class as compared with healthy controls and with patients with non-inflammatory joint diseases. Patients with seropositive RA had significantly less IgG antibodies in their synovial fluid as compared to seronegative patients. Furthermore, the presence of IgG class of anti-RAGE antibodies locally in the joint was found to be related to less aggressive, i.e. non-erosive disease. CONCLUSION: These results suggest that RAGE-specific B cell response protect patients with RA from destructive course of the disease.


Assuntos
Artrite Reumatoide/imunologia , Autoanticorpos/análise , Receptores Imunológicos/imunologia , Líquido Sinovial/imunologia , Adulto , Idoso , Especificidade de Anticorpos , Complexo Antígeno-Anticorpo/análise , Artrite Reumatoide/tratamento farmacológico , Autoanticorpos/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Imunoglobulina G/análise , Imunoglobulina G/sangue , Imunoglobulina M/análise , Imunoglobulina M/sangue , Imunossupressores/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Receptor para Produtos Finais de Glicação Avançada , Receptores Imunológicos/análise , Fator Reumatoide/análise , Solubilidade
10.
Scand J Immunol ; 65(6): 530-7, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17523945

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by a persistent inflammation of the synovium, leading to the erosion of articular cartilage and bone. Synovial mast cells and their effector molecule, histamine, receive increased attention as mediators of joint inflammation. The aim of our study was to analyse levels of free histamine in serum and joint fluid of RA patients and to evaluate the potential inflammatogenic properties of histamine in vivo and in vitro. Histamine levels were measured by an ELISA in synovial fluid and sera of RA patients and of healthy controls. Histamine levels were also assessed in plasma of RA patients undergoing anti-TNF-alpha treatment. In the murine part of the study, histamine was injected intra-articularly in the knee joint of mice and the joints were subsequently analysed with respect to induction of inflammation. RA patients displayed significantly lower levels of histamine in circulation (0.93 +/- 0.16 ng/ml) compared with the healthy controls (1.89 +/- 0.45 ng/ml, P < 0.001). Locally, in synovial fluid the levels of histamine were even lower (0.37 +/- 0.16 ng/ml, P < 0.0006). Long-term anti-TNF-alpha treatment significantly increased circulating levels of histamine in RA patients. Our experiments on animals show that histamine on its own neither induces inflammation in the joint cavity nor influences the course of HMGB1 and peptidoglycan-induced joint inflammation. Based on our experimental and clinical studies we suggest that histamine lacks harmful properties in RA.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/tratamento farmacológico , Agonistas dos Receptores Histamínicos/uso terapêutico , Liberação de Histamina/efeitos dos fármacos , Histamina/sangue , Articulação do Joelho/efeitos dos fármacos , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Artrite Reumatoide/induzido quimicamente , Artrografia , Células Cultivadas , Feminino , Proteína HMGB1/administração & dosagem , Proteína HMGB1/efeitos adversos , Liberação de Histamina/imunologia , Humanos , Injeções Intra-Articulares , Articulações , Articulação do Joelho/ultraestrutura , Masculino , Camundongos , Camundongos Endogâmicos , Pessoa de Meia-Idade , Valores de Referência , Líquido Sinovial/química , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/sangue
11.
Scand J Immunol ; 65(2): 182-91, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17257224

RESUMO

B cells play an important role in the development of autoimmune diseases due to their production of autoantibodies, antigen-presenting capacity and production of pro-inflammatory cytokines. The purpose of the present study was to analyse B cells from rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients, with respect to their expression of the IL-2 receptor (IL-2R) subunit CD25. Using flow cytometry, we found that CD25(+) B cells from RA patients expressed significantly higher frequencies of CD122 and CD132 than CD25(+) B cells from control subjects, indicating a fully functional IL-2R. These CD25(+) B cells also expressed higher frequencies of the co-stimulatory molecule CD80, whereas IgM and IgA expression was decreased compared with CD25(+) B cells from healthy controls. In addition B cells from SLE patients co-expressed CD25 together with CD80, CD122, and CD132, but to a lower degree IgD and IgM, when compared with healthy controls. Taken together, our results indicate that CD25(+) B cells from RA and SLE patients are in a highly activated state, display a more mature phenotype and suggest that this B cell subset may be involved in the pathogenesis of RA and SLE.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Subunidade alfa de Receptor de Interleucina-2/análise , Lúpus Eritematoso Sistêmico/imunologia , Adulto , Idoso , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina M/imunologia , Subunidade gama Comum de Receptores de Interleucina/análise , Subunidade beta de Receptor de Interleucina-2/análise , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Fenótipo
12.
Ann Rheum Dis ; 66(1): 121-3, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16740681

RESUMO

OBJECTIVE: To analyse the inflammatory mediators, including monocyte chemoattractant protein-1 (MCP-1), in blood samples donated years before onset of rheumatoid arthritis. Previously, it has been shown in these individuals that antibodies against cyclic citrullinated peptide (anti-CCP) detectable years before the onset of symptoms have a high predictive value for development of rheumatoid arthritis. METHODS: A nested case-control study was performed: patients with rheumatoid arthritis were identified from among blood donors antedating onset by a median of three years (pre-patients, n = 92); four matched controls were selected randomly for each pre-patient. Plasma were analysed for secretory phospholipase A2 (sPLA2) and MCP-1 using ELISA, for high-sensitivity C reactive protein (hsCRP) using the chemiluminescence method and for interleukin-6 using a sensitive bioassay. RESULTS: When the results were stratified for the presence of anti-CCP antibodies and immunoglobulin M-rheumatoid factor (IgM-RF), only MCP-1 levels were found to be significantly raised in patients with anti-CCP and IgM-RF compared with controls. CONCLUSION: Levels of MCP-1 were significantly increased in the plasma of patients having anti-CCP antibodies or IgM-RF and who later developed rheumatoid arthritis. These findings indicate up regulation of chemotactic activity for leucocytes before the development of rheumatoid arthritis.


Assuntos
Artrite Reumatoide/sangue , Autoanticorpos/sangue , Quimiocina CCL2/sangue , Citrulina/imunologia , Regulação para Cima , Adulto , Idoso , Biomarcadores/sangue , Doadores de Sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Progressão da Doença , Feminino , Humanos , Imunoglobulina M/sangue , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/sangue , Índice de Gravidade de Doença , Fatores de Tempo
14.
Scand J Immunol ; 64(5): 482-92, 2006 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17032240

RESUMO

B cells are in analogy with T cells capable of expressing functional IL-2 receptors. IL-2R alpha-chain (CD25) positive T cells have been studied in detail but not much is known about CD25 positive B cells. The aim of this study was to examine the phenotypic properties of the CD25 expressing B cells collected from different lymphoid organs in mice. Samples were stained for various cell surface markers and analysed using flow cytometry. We found that approximately 49% of B cells in bone marrow, 16% in peritoneal cavity, 2% in spleen and 1% in lymph nodes express CD25. In contrast, CD25 expressing B cells were not found in the blood or in Peyer's patches. Phenotypic characterization showed that CD25+ B cells in spleen, lymph nodes and peritoneal cavity have higher expression of AA4.1, CD5, CD69, CD80, CD86, CD122, CD132, IgA, IgG and IgM on their surface in comparison with CD25- B cells. In contrast, expression of IgD and IA-IE was lower on CD25+ B cells in spleen and lymph nodes. In bone marrow, the expression of CD5, CD80, CD86, CD122, CD132, IgA, IgD and IgM was lower, while the expression of AA4.1, IgG and IA-IE was increased on CD25+ B cells compared with CD25- B cells. In conclusion, our results indicate that B cells expressing CD25 are phenotypically distinctly different from those that are CD25 negative. Our findings suggest that CD25+ B cells are more prone to efficient antigen presentation and display a more mature phenotype.


Assuntos
Antígenos CD/metabolismo , Linfócitos B/metabolismo , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Tecido Linfoide/metabolismo , Animais , Apresentação de Antígeno/imunologia , Feminino , Genes MHC da Classe II , Imunoglobulina D/metabolismo , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Tecido Linfoide/citologia , Camundongos
15.
J Thromb Haemost ; 4(8): 1781-9, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16879221

RESUMO

BACKGROUND: Several proatherothrombotic conditions are associated with enhanced levels of circulating proinflammatory cytokines, which are believed to impair endothelial fibrinolytic capacity. OBJECTIVE: This study aims at investigating how tumor necrosis factor (TNF)-alpha regulates endothelial gene expression of the key fibrinolytic enzyme tissue-type plasminogen activator (t-PA). METHODS: Cultured human umbilical vein endothelial cells were pretreated with selective inhibitors of the three major inflammatory signaling pathways activated by TNF-alpha; the nuclear factor kappa-B (NF-kappaB), the p38 mitogen-activated protein kinase (p38 MAPK), and the c-jun N-terminal kinase (JNK) pathways. Following TNF-alpha stimulation, effects on t-PA gene expression were evaluated with real-time reverse transcriptase polymerase chain reaction and interactions of nuclear proteins with potential gene regulatory elements were studied with electrophoretic mobility shift assays. RESULTS: Approximately 50% suppression of t-PA gene expression was observed after prolonged stimulation with TNF-alpha (> or =24 h). The repression was shown to be preferentially dependent on NF-kappaB activation, but also on p38 MAPK signaling. Further, we provide evidence for a TNF-alpha induced binding of NF-kappaB to the recently described kappaB site in the t-PA gene and of cyclic adenosine monophosphate response element binding protein (CREB) to the t-PA CRE-like site. CONCLUSIONS: We conclude that TNF-alpha impairs fibrinolytic capacity in vascular endothelial cells by a NF-kappaB and p38 MAPK-dependent suppression of t-PA. This mechanism sheds a light on how inflammation contributes to the pathogenesis of cardiovascular diseases.


Assuntos
Endotélio Vascular/metabolismo , Regulação da Expressão Gênica , NF-kappa B/metabolismo , Ativador de Plasminogênio Tecidual/biossíntese , Fator de Necrose Tumoral alfa/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Sítios de Ligação , Doenças Cardiovasculares/metabolismo , Células Cultivadas , Endotélio Vascular/citologia , Fibrinólise , Humanos , Inflamação , Estrutura Terciária de Proteína , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo , Veias Umbilicais/citologia
16.
Inflamm Res ; 54(9): 390-3, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16273338

RESUMO

OBJECTIVE AND DESIGN: Riboflavin, also known as vitamin B2, is a micronutrient with a key role in maintaining human health. It has also been shown to enhance host resistance to bacterial infections in mice. The aim of this study was to assess the role of vitamin B2 treatment in inflammatory conditions. SUBJECTS AND METHODS: Three models of inflammatory states were assessed. One of them encompasses neutrophil mediated but T cell/macrophage independent cutaneous inflammation. Another one is delayed type hypersensitivity reaction (DTH), a T cell/macrophage dependent but neutrophil independent inflammatory response. The third one is collagen- induced arthritis, having components from both of the above described reactions. Mice were treated with vitamin B2, administered by peritoneal injections, throughout the course of the experiments. RESULTS: The granulocyte dependent reaction to olive oil was significantly reduced in vitamin B2 treated mice. In contrast, DTH reactivity and collagen II arthritis were not affected by the treatment. CONCLUSION: Riboflavin administration affects neutrophil migration but does not alter acquired immune responsiveness.


Assuntos
Formação de Anticorpos/efeitos dos fármacos , Edema/induzido quimicamente , Edema/patologia , Neutrófilos , Riboflavina/farmacologia , Complexo Vitamínico B/farmacologia , Animais , Artrite Experimental/patologia , Dermatite/patologia , , Hipersensibilidade Tardia/patologia , Injeções Intradérmicas , Injeções Intraperitoneais , Macrófagos , Camundongos , Camundongos Endogâmicos , Neutrófilos/efeitos dos fármacos , Azeite de Oliva , Óleos de Plantas/administração & dosagem , Riboflavina/administração & dosagem , Linfócitos T , Complexo Vitamínico B/administração & dosagem
17.
Microb Pathog ; 38(2-3): 97-105, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15748811

RESUMO

Septic arthritis induced by Staphylococcus aureus causes a rapid destruction of joint cartilage and periarticular bone. The mechanisms behind this phenomenon are not fully understood. Earlier studies have shown that cytokines and metalloproteinases are of importance in bone metabolism. Matrix metalloproteinase-7 (MMP-7) has pleiotropic function including facilitating migration of both macrophages and neutrophils. The aim of this study has been to investigate the significance of MMP-7 expression in septic arthritis. MMP-7 deficient mice and congeneic controls were intravenously inoculated with an arthritogenic dose of S. aureus LS-1. This study shows that MMP-7 deficient mice exposed to S. aureus developed significantly less severe arthritis both clinically and histologically. Despite this finding, bacterial growth in the deficient animals was significantly increased. In vitro responses to staphylococcal antigens and superantigens did not differ between MMP-7(+/+) and MMP-7(-/-) mice with respect to cytokine production and if anything increased the production of certain chemokines. In addition MMP-7(-/-) mice exhibited decreased numbers of peripheral blood mononuclear cells before and one day after bacterial inoculation, but increased numbers of peripheral granulocytes on day 1. In conclusion, MMP-7 contributes to the development of a destructive course of septic arthritis despite decreased bacterial load. In addition, expression of MMP-7 is of importance for the distribution of peripheral leukocytes.


Assuntos
Artrite Infecciosa/enzimologia , Artrite Infecciosa/patologia , Articulações/patologia , Metaloproteinase 7 da Matriz/metabolismo , Infecções Estafilocócicas/enzimologia , Infecções Estafilocócicas/patologia , Staphylococcus aureus , Animais , Antígenos de Bactérias/imunologia , Artrite Infecciosa/imunologia , Artrite Infecciosa/microbiologia , Osso e Ossos/microbiologia , Osso e Ossos/patologia , Cartilagem/microbiologia , Cartilagem/patologia , Quimiocinas/análise , Quimiotaxia de Leucócito , Citocinas/análise , Modelos Animais de Doenças , Granulócitos/imunologia , Articulações/microbiologia , Contagem de Leucócitos , Leucócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infecções Estafilocócicas/imunologia , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/crescimento & desenvolvimento , Staphylococcus aureus/imunologia , Superantígenos/imunologia
18.
Osteoarthritis Cartilage ; 13(2): 146-53, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15694576

RESUMO

OBJECTIVE: Clinical cartilage repair with transplantation of cultured chondrocytes, the first described technique introduced in 1994, includes a periosteal membrane but today cells are also implanted without the periosteal combination. The aim of this study was to see if the periosteum had more than a biomechanical function and if the periosteum had a biological effect on the seeded cells tested in an agarose system in which the clonal growth in agarose and the external growth stimulation could be analysed. METHODS: Four different experiments were used to study the growth of human chondrocytes in agarose and the periosteal influence. Human chondrocytes were isolated and transferred to either primary or secondary agarose culture. After 4 weeks, the total number of clones >50 microm was counted. Cocultures of chondrocytes and periosteal tissue, cultures of chondrocytes with conditioned medium from chondrocytes, periosteal cells and fibroblast were used to study a potential stimulatory effect on growth and different cytokines and growth factors were analysed. RESULTS: It was found that the human chondrocytes had different growth properties in agarose with the formation of four different types of clones: a homogenous clone without matrix production, a homogenous clone with matrix production, a differentiated clone with matrix production and finally a differentiated clone without matrix production. The periosteum exerted a paracrine effect on cultured chondrocytes in agarose resulting in a higher degree of cloning. The chondrocytes produced significant amounts of interleukin (IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor (TGF)-beta. The periosteum produced significant amounts of IL-6, IL-8 and TGF-beta. Cocultures of chondrocytes and periosteum demonstrated a potentiation of IL-6 and IL-8 release but not of TGF-beta and GM-CSF. CONCLUSION: Articular chondrocytes are able to form clones of different properties in agarose and the periosteum has a capacity of stimulating chondrocyte clonal growth and differentiation and secretes significant amounts of IL-6, IL-8, GM-CSF and TGF-beta. It may be that the repair of cartilage defects with seeded chondrocytes could benefit from the combination with a periosteal graft. The production of TGF-beta by implanted chondrocytes could influence the chondrogenic cells in the periosteum to start a periosteal chondrogenesis and together with the matrix from implanted chondrocyte production, a repair of cartilaginous appearance may develop; a dual chondrogenic response is possible.


Assuntos
Cartilagem Articular/crescimento & desenvolvimento , Condrogênese/fisiologia , Periósteo/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Cartilagem Articular/metabolismo , Divisão Celular/fisiologia , Células Cultivadas , Condrócitos/metabolismo , Condrócitos/fisiologia , Células Clonais/fisiologia , Citocinas/biossíntese , Feminino , Humanos , Articulação do Joelho/fisiologia , Masculino , Pessoa de Meia-Idade , Sefarose
19.
Rheumatology (Oxford) ; 44(1): 32-9, 2005 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15367748

RESUMO

OBJECTIVES: The aim of the study was to assess the role of extracellular cytochrome c as an inducer of joint inflammation and to examine its levels in sera and synovial fluids of rheumatoid arthritis (RA) patients. METHODS: Mice were injected intra-articularly with different doses of cytochrome c and joints were evaluated histopathologically and immunohistochemically 3 and 10 days later. In addition, mouse spleen cells were stimulated with different concentrations of cytochrome c, followed by assessment of NF-kappaB activation and cytokine production. Sera and synovial fluid from RA patients and sera from healthy individuals were assessed with respect to cytochrome c levels by an enzyme-linked immunoassay technique. RESULTS: Histopathological signs of arthritis were evident in 75% of animals following intra-articular injection of cytochrome c. Synovitis was characterized by influx of Mac-1+ cells. In vivo depletion of neutrophils and monocytes led to abrogation of arthritis. Stimulation of mouse spleen cells in vitro with cytochrome c resulted in activation of NF-kappaB and release of proinflammatory cytokines and chemokines. Cytochrome c levels in RA patients' sera were significantly lower than in healthy controls. Further, cytochrome c levels in synovial fluid were significantly lower than in corresponding blood samples. CONCLUSIONS: Our findings demonstrate that extracellular cytochrome c displays direct proinflammatory properties mediated by activation of NF-kappaB and causing neutrophil and monocyte triggered inflammation. We hypothesize that decreased levels of cytochrome c in RA patients reflect consumption of this molecule in the synovial tissue, decreasing apoptosis and shifting the balance towards inflammation.


Assuntos
Apoptose , Artrite Experimental/induzido quimicamente , Artrite Reumatoide/metabolismo , Citocromos c/toxicidade , Adulto , Idoso , Animais , Artrite Experimental/patologia , Células Cultivadas , Quimiocinas/biossíntese , Citocromos c/análise , Citocromos c/farmacologia , Ensaio de Desvio de Mobilidade Eletroforética , Líquido Extracelular/metabolismo , Feminino , Humanos , Injeções Intra-Articulares , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Neutrófilos/fisiologia , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologia , Líquido Sinovial/química
20.
Rheumatology (Oxford) ; 44(2): 183-6, 2005 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-15494349

RESUMO

OBJECTIVE: Rheumatoid arthritis (RA) is an autoimmune disease, characterized by a chronic inflammation in the joints. The model of collagen-induced arthritis (CIA) has been extensively used to elucidate the pathogenic mechanisms relevant to human RA and is widely employed for the evaluation of potential anti-rheumatic agents. Etoposide and mitoxantrone are immunosuppressive drugs, both acting by inhibiting the topoisomerase II function. We have previously demonstrated an ameliorating effect of etoposide in CIA. The aims of this study were (1) to assess the optimal ameliorating dose of etoposide and (2) to ascertain that topoisomerase II inhibition, irrespective of the chemical composition of the drug, affects the course of autoimmunity. METHODS: Male DBA/1 mice were treated with 12.5 mg/kg body weight of etoposide five times, twice, once per week or once every second week. Mitoxantrone was administered as high dose (1 mg/kg body weight five times after immunization or after booster with collagen II) or low dose (3 microg/mouse, 5 days/week starting after collagen II immunization or after booster). RESULTS: Treatment with 12.5 mg/kg body weight five times or twice weekly with etoposide completely inhibited development of arthritis. Low-dose treatment with mitoxantrone after collagen II immunization or high-dose treatment after collagen II booster delayed the onset of arthritis. These results were observed clinically as well as histologically. In addition, serum levels of anti-collagen II antibodies were significantly lower in mice displaying less severe arthritis. CONCLUSION: Treatment of collagen-induced arthritis with topoisomerase II inhibitors ameliorates the development of disease.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Etoposídeo/uso terapêutico , Mitoxantrona/uso terapêutico , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Inibidores da Topoisomerase II , Animais , Formação de Anticorpos/efeitos dos fármacos , Colágeno Tipo II/imunologia , Relação Dose-Resposta a Droga , Regulação para Baixo , Imunização/métodos , Imunossupressores/uso terapêutico , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos DBA
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