RESUMO
Antiphospholipid syndrome is characterized by multiple arterial and/or venous thrombotic events, recurrent fetal losses in the presence of antiphospholipid antibodies (aPL). Catastrophic antiphospholipid syndrome is a life-threatening, rare subset of antiphospholipid syndrome when the thrombotic events affect at least three organs, and clinical manifestations develop simultaneously or within a week. Diagnostically, small vessel occlusions can be detected by histopathology in the presence of aPL. Our case report describes an 18-year-old man who has been treated for antiphospholipid syndrome associated with systemic lupus erythematosus (SLE) since 2011. The clinical findings were dominated by recurrent deep vein thrombosis, and severe proteinuria caused by lupus nephritis, accompanied by mild serological and laboratory findings. The patient was hospitalized in March 2014 because of severe thrombocytopenia and infective diarrhoea. At this time the renal functions deteriorated rapidly. Simultaneously, left upper extremity paresis was observed; computed tomography showed ischaemic lesions in the territory of the middle cerebral artery. Abdominal discomfort and pain occurred. On computed tomography scan ischaemic lesions were seen in the spleen, the right kidney and the coeliac trunk. Laboratory and serological findings verified the presence of aPL and anti-DNA antibodies, anaemia and thrombocytopenia. Based on the above-mentioned clinical and laboratory findings, the diagnosis of catastrophic antiphospholipid syndrome was established. Anticoagulation, corticosteroids and plasma exchange treatment, as well as haemodiafiltration were initiated. Although the thrombotic cascade decelerated following these interventions, we could not see an improvement in the renal function. Rituximab treatment was started, leading to a significant improvement in renal function. After 5 weeks of treatment the patient was discharged from hospital.
Assuntos
Síndrome Antifosfolipídica/complicações , Fatores Imunológicos/uso terapêutico , Nefrite Lúpica/complicações , Rituximab/uso terapêutico , Trombose/imunologia , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/patologia , Humanos , Rim/ultraestrutura , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , Masculino , Trombose/tratamento farmacológico , Trombose/patologia , Adulto JovemRESUMO
Follicular T helper (Tfh) cells have a crucial role in regulating immune responses within secondary lymphoid follicles by directing B cell differentiation towards memory B cells and plasma cells. Because abnormal humoral responses are key features in both primary Sjögren's syndrome (pSS) and systemic lupus erythematosus (SLE), the aim of this study was to profile the pathological connection between peripheral Tfh cells and B cells in the two diseases. Twenty-five pSS patients, 25 SLE patients and 21 healthy controls were enrolled into the study. We determined the ratio of circulating Tfh-like cells, their interleukin (IL)-21 production and different B cell subsets by flow cytometry. We observed higher percentages of naive B cells in both diseases, while non-switched and switched memory B cells showed decreased frequencies. The proportions of double-negative B cells and plasmablasts were elevated in SLE and decreased in pSS. The percentages of transitional B cells and mature-naive B cells were higher in SLE. Patients with more severe disease course had an elevated ratio of TFH-like cells and increased IL-21 production. Moreover, expansion of Tfh-like cells correlated positively with parameters related to antibody secretion, including serum immunoglobulin (Ig)G, immune complexes (ICs) and autoantibodies. Correlation analysis between Tfh-like cells and certain B cell subsets revealed possible defects during B cell selection. In conclusion, our observations on the profound expansion of circulating Tfh-like cells and their IL-21 production, along with the characteristic aberrant peripheral B cell distribution in both pSS and SLE, indicate the prominent role of Tfh cell in the regulation of B cell selection.
Assuntos
Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Subpopulações de Linfócitos/imunologia , Síndrome de Sjogren/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Autoanticorpos/sangue , Circulação Sanguínea/imunologia , Diferenciação Celular , Progressão da Doença , Feminino , Humanos , Switching de Imunoglobulina , Memória Imunológica , Interleucinas/sangue , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: To assess the prevalence of the main causes of morbi-mortality in the antiphospholipid syndrome (APS) during a 10-year-follow-up period and to compare the frequency of early manifestations with those that appeared later. METHODS: In 1999, we started an observational study of 1000 APS patients from 13 European countries. All had medical histories documented when entered into the study and were followed prospectively during the ensuing 10â years. RESULTS: 53.1% of the patients had primary APS, 36.2% had APS associated with systemic lupus erythematosus and 10.7% APS associated with other diseases. Thrombotic events appeared in 166 (16.6%) patients during the first 5-year period and in 115 (14.4%) during the second 5-year period. The most common events were strokes, transient ischaemic attacks, deep vein thromboses and pulmonary embolism. 127 (15.5%) women became pregnant (188 pregnancies) and 72.9% of pregnancies succeeded in having one or more live births. The most common obstetric complication was early pregnancy loss (16.5% of the pregnancies). Intrauterine growth restriction (26.3% of the total live births) and prematurity (48.2%) were the most frequent fetal morbidities. 93 (9.3%) patients died and the most frequent causes of death were severe thrombosis (36.5%) and infections (26.9%). Nine (0.9%) cases of catastrophic APS occurred and 5 (55.6%) of them died. The survival probability at 10â years was 90.7%. CONCLUSIONS: Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.
Assuntos
Síndrome Antifosfolipídica/mortalidade , Lúpus Eritematoso Sistêmico/mortalidade , Trombose/mortalidade , Aborto Espontâneo/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/etiologia , Feminino , Retardo do Crescimento Fetal/epidemiologia , Humanos , Lactente , Recém-Nascido , Infecções/etiologia , Infecções/mortalidade , Ataque Isquêmico Transitório/etiologia , Livedo Reticular/etiologia , Estudos Longitudinais , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez/epidemiologia , Nascimento Prematuro/epidemiologia , Estudos Prospectivos , Embolia Pulmonar/etiologia , Embolia Pulmonar/mortalidade , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Trombocitopenia/etiologia , Trombose/etiologia , Trombose Venosa/etiologia , Trombose Venosa/mortalidade , Adulto JovemRESUMO
Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with highest prevalence among women of childbearing age. However, children younger than 16 years also can develop SLE (childhood-onset lupus/juvenile-type SLE). The aim of our study was to compare the clinical course of adult and pediatric-onset SLE. Data from 342 adult patients followed at the University of Debrecen, Hungary, and 79 children documented in the Hungarian National Pediatric SLE registry were analyzed using hospital medical records. Organ manifestations, laboratory parameters, and immunoserological characteristics were reviewed and the results were evaluated using SPSS for Windows software.Gender distribution was not significantly different between groups with disease starting in childhood vs adulthood. The prevalence of the following manifestations was significantly higher for pediatric than for adult-onset disease including: lupus nephritis (43% pediatric vs 26.4% for adult-onset), hematological disorders (57% vs 36.4%), photosensitivity (20% vs 9%), butterfly rash (61% vs 35.5%) and mucosal ulceration (11.4% vs 4%). For adult-onset SLE, neurological symptoms (30% vs 6%) and polyarthritis (86% vs 68%) occurred significantly more frequently than in children. Anti-SSA, anti-SSB and antiphospholipid antibodies were detected at significantly higher levels in adult-onset patients compared to those in pediatrics. Children were more commonly given high-dose intravenous immunoglobulin treatment (6.3% vs 0.6%) and mycophenolate mofetil (15.2% vs 5.3%) than adults.These results suggest that pediatric and adult-onset SLE differ in multiple aspects, and it is important to recognize these differences for optimal treatment and prognosis of these patients.
Assuntos
Autoanticorpos/sangue , Autoanticorpos/classificação , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/epidemiologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Feminino , Humanos , Hungria , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Fatores Sexuais , Adulto JovemRESUMO
The clearance of apoptotic cells has an important role in the maintenance of tissue homeostasis and in the protection of tissues from the inflammatory and immunogenic contents of dying cells. A defect in the recognition and phagocytosis of apoptotic cells contributes to the development of chronic inflammation and autoimmune disorders. We have observed that compared with healthy donors, differentiated macrophages from patients with untreated systemic lupus erythematosus (SLE) showed decreased phagocytosis of apoptotic neutrophils. A TaqMan Low Density Array was designed to determine the mRNA expression levels of 95 apopto-phagocytic genes in differentiated non-phagocytosing and phagocytosing macrophages. In the macrophages of clinically and immunoserologically active SLE patients, 39 genes were expressed at lower levels than in the control macrophages. When inactive patients were compared with those with minor immunoserological abnormalities or patients in an immunoserologically active state, a relationship was observed between the altered gene expression profile and the disease state. In the macrophages of patients with engulfing apoptotic cells, an upregulation of genes involved in inflammation, autophagy, and signaling was observed. These results indicate that novel immune-pathological pathways are involved in SLE and suggest targets for potential therapeutic modulation.
Assuntos
Apoptose/genética , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Fagocitose/genética , Adulto , Antígenos de Superfície/genética , Estudos de Casos e Controles , Diferenciação Celular , Regulação para Baixo , Feminino , Humanos , Cadeias beta de Integrinas/genética , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Proteínas do Leite/genética , Monócitos/imunologia , Monócitos/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transcriptoma , Regulação para Cima , Adulto JovemRESUMO
OBJECTIVES: Although most reported patients with immunoglobulin G4-related disease (IgG4-RD) are from the Far East, we aimed to identify patients suffering from IgG4-RD in our University Centre in Debrecen, Hungary. METHOD: Serum IgG4 levels were measured at 51 of our 800 patients followed up because of Sjögren's syndrome (SS) if one or more clinical signs during the disease course raised the possibility of IgG4-RD (persisting salivary gland swelling, absence of anti-Ro/SSA and anti-La/SSB antibodies in the serum, and positive salivary gland biopsy, coexistence of autoimmune pancreatitis, autoimmune hepatitis, or primary sclerosing cholangitis, persisting lymphadenopathy). Where available, histological samples of small salivary gland biopsies were revised to detect the particular features of IgG4-RD. Pathologists and surgeons were informed about the disease and asked to refer suspicious cases. RESULTS: Based on our survey, eight patients were identified with IgG4-RD. Pancreatic, salivary gland, aortic, and retroperitoneal manifestations were detected. Of the 51 patients with SS, four appeared to have IgG4-RD, but eventually one was excluded. CONCLUSIONS: Although IgG4-RD is not yet well known to physicians of Western countries, it occurs in Caucasians and probably in other races as well. Moreover, our eight cases diagnosed with IgG4-RD demonstrate a relatively large European patient population collected in a single centre. European clinicians, and especially rheumatologists, should be informed and at least certain laboratories should be prepared to investigate patient samples if the suspicion of IgG4-RD is raised. The main clinical significance of an accurate diagnosis is the extreme corticosteroid sensitivity of IgG4-RD.
Assuntos
Doenças Autoimunes/diagnóstico , Doenças Biliares/diagnóstico , Imunoglobulina G/sangue , Pancreatopatias/diagnóstico , Espaço Retroperitoneal/patologia , Doenças das Glândulas Salivares/diagnóstico , Síndrome de Sjogren/diagnóstico , Adulto , Idoso , Doenças Autoimunes/imunologia , Doenças Biliares/imunologia , Feminino , Humanos , Hungria , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Pancreatopatias/imunologia , Doenças das Glândulas Salivares/imunologia , Síndrome de Sjogren/imunologiaRESUMO
UNLABELLED: Systemic lupus erythematosus (SLE) is a chronic relapsing systemic autoimmune disease; one of the most serious complications is renal involvement, which is occurring in almost 50% of all patients at the beginning of the disease. The aim of the present study was to compare renal function, proteinuria, activity markers and treatment regimen of active and inactive SLE patients with renal involvement. We analyzed the correlation of serum blood urea nitrogen, creatinine level, glomerular filtration rate, urine total protein/serum creatinine (uTP/creat), CRP to classic activity markers of SLE (serum complement 3, -4 level, anti-dsDNA antibody). Moreover we analyzed the treatment modalities of patients with lupus nephritis (LN). Data of 418 SLE patients were analyzed, out of these patients 128 had biopsy proven lupus nephritis or had more than 3 + proteinuria by urine dipstick analysis (30% of all cases). RESULTS: Data of 128 patients with lupus nephritis were analyzed (mean age 32.18 +/- 11.48 year, time between the diagnosis of SLE and LN was 2.78 +/- 4.59 year). 48% of patients had diffuse proliferative glomerulonephritis, 75% of them received cyclic cyclophosphamide treatment. UTp (total protein)/creatinine level was significantly higher in active LN group (p = 0.03), and correlated to erythrocyte sedimentation rate (p = 0.002, R = 0.52). Mean anti-dsDNA level of patients with active LN was significantly higher (p < 0.001). CONCLUSIONS: Patients with active lupus nephritis are at higher risk of developing renal failure, activity markers and urine protein are elevated in these patients as compared to inactive patients, early aggressive immunosuppressive treatment needs to be started to prevent end-stage renal failure.
Assuntos
Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Nefrite Lúpica/tratamento farmacológico , Adulto , Proteína C-Reativa/análise , Estudos de Coortes , Creatinina/urina , DNA/análise , Progressão da Doença , Feminino , Humanos , Nefrite Lúpica/complicações , Nefrite Lúpica/patologia , Masculino , Insuficiência Renal/etiologia , Insuficiência Renal/prevenção & controle , Pele/patologia , Uridina Trifosfato/urinaRESUMO
The effects of proteosome inhibitor Bortezomib (BZ) were studied in vitro for 24 h on the protein kinase C (PKC) profiles, rates of proliferation and apoptosis in Jurkat cells and lymphocytes of 10 patients with systemic lupus erythematosus (SLE) and nine healthy subjects. The expressions of PKC proteins, the rates of proliferation and apoptosis were determined. The effects of BZ were different in the Jurkat and lupus T cells. Whereas BZ elevated the expression of PKC θ, δ and ξ isoenzymes in the Jurkat cells, it was unable to do that in the lupus T cells. BZ induced a dose-dependent increase in the apoptosis of Jurkat cells, while decreased the proliferation. The same effect of BZ was observed on the apoptosis of lymphocytes both in SLE and healthy subjects at concentrations higher than the therapeutic dose. We conclude that BZ treatment in vitro was not able to restore the SLE-specific defect (decrease) in the expression of PKC isoenzymes in the T cells as it was expected. This can be a limiting factor in the positive clinical effects of BZ in lupus.
Assuntos
Ácidos Borônicos/farmacologia , Isoenzimas/genética , Lúpus Eritematoso Sistêmico/genética , Inibidores de Proteassoma/farmacologia , Proteína Quinase C-delta/genética , Proteína Quinase C-épsilon/genética , Proteína Quinase C/genética , Pirazinas/farmacologia , Linfócitos T/efeitos dos fármacos , Adulto , Apoptose/efeitos dos fármacos , Bortezomib , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Isoenzimas/imunologia , Células Jurkat , Lúpus Eritematoso Sistêmico/enzimologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos , Cultura Primária de Células , Proteína Quinase C/imunologia , Proteína Quinase C-delta/imunologia , Proteína Quinase C-épsilon/imunologia , Proteína Quinase C-theta , Linfócitos T/enzimologia , Linfócitos T/imunologia , Linfócitos T/patologiaRESUMO
OBJECTIVES: Disproportionate vitamin D levels may play an important role in the development of certain systemic autoimmune and rheumatic diseases. The aim of the present study was to investigate the prevalence of vitamin D insufficiency in patients with systemic lupus erythematosus (SLE) and to compare serological and clinical parameters in patients with different vitamin D levels from a single centre registry in Central-Eastern Europe. METHODS: A total of 177 patients with SLE were enrolled in the study. 25-Hydroxyvitamin D [25(OH)D] levels were measured by chemiluminescent immunoassay (CLIA). Autoantibody profiles, complement 3 (C3) and C4, clinical symptoms, and disease activity (using the SLE disease activity index, SLEDAI) of the patients were assessed. RESULTS: Vitamin D concentration in the total SLE group investigated was 26.88 ± 13.25 ng/mL. Vitamin D levels were normal (≥ 30 ng/mL) in 18.1% of patients, insufficient (15-30 ng/mL) in 44.6%, and deficient (< 15 ng/mL) in 37.3%. The vitamin levels were significantly reduced in postmenopausal compared to premenopausal patients (p = 0.02). Patients with pericarditis (p = 0.013), neuropsychiatric diseases (p = 0.01), and deep vein thrombosis (p = 0.014) had reduced vitamin D levels. SLEDAI score was significantly increased in patients with reduced vitamin D levels (p = 0.038). Anti-double-stranded (ds)DNA autoantibody concentrations increased from normal to insufficient and further increased from insufficient to deficient patient subsets (p = 0.021). Anti-Smith antigen (anti-Sm) concentrations increased (p < 0.001), C4 levels decreased (p = 0.027), and immunoglobulin (Ig)G concentration increased (p = 0.034) in patients with reduced vitamin D levels. CONCLUSIONS: Our data suggest that vitamin D deficiency in SLE may play a role in perpetuation of the disease.
Assuntos
Progressão da Doença , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/fisiopatologia , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/fisiopatologia , Vitamina D/fisiologia , Adolescente , Adulto , Idoso , Autoanticorpos/sangue , Complemento C4/metabolismo , DNA/imunologia , Suplementos Nutricionais , Feminino , Humanos , Hungria/epidemiologia , Imunoglobulina G/sangue , Lúpus Eritematoso Sistêmico/sangue , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Índice de Gravidade de Doença , Vitamina D/uso terapêutico , Deficiência de Vitamina D/prevenção & controle , Adulto JovemRESUMO
The authors discuss the case of a 76-year-old female patient who has been suffering from subacute cutaneous lupus erythematosus since 1983. In 1999 she was diagnosed with systemic lupus erythematosus (SLE) based on her symptoms of malar rash, polyarthritis, leukopenia, autoimmune hemolytic anemia and positive anti-DNA antibody test. For this she received methylprednisolone and cyclophosphamide. After 3 years of remission, symptoms of cutaneous vasculitis appeared in 2004, which transitionally responded to treatment with azathioprin and methylprednisolone. Her cutaneous symptoms, however, progressed quickly along with generalized lymphadenopathy, splenomegaly and thrombocytopenia. Immunohistological evaluation of the lymph node biopsy showed diffuse large B-cell lymphoma. She developed complete remission after treatment with six-cycle R-CHOP (rituximab, and reduced doses of cyclophosphamide, vincristin, adriablastin, methylprednisolone). SLE became inactive and her symptoms of vasculitis resolved. The authors are bringing attention to one of the possible late complications of systemic lupus, and also underscoring that treatment with rituximab (+CHOP) was beneficial not only for the lymphoma but the SLE as well.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Linfoma Difuso de Grandes Células B/complicações , Linfoma não Hodgkin/complicações , Idoso , Anticorpos Monoclonais Murinos , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Prednisona/uso terapêutico , Rituximab , Resultado do Tratamento , Vincristina/uso terapêuticoRESUMO
BACKGROUND: Rapamycin is an immunosuppressant natural product, which blocks T-cell mitogenesis and yeast proliferation. In the cytoplasm, rapamycin binds to the immunophilin FKBP12 and the complex of these two molecules binds to a recently discovered protein, FRAP. The rapamycin molecule has two functional domains, defined by their interaction with FKBP12 (binding domain) or with FRAP (effector domain). We previously showed that the allylic methoxy group at C-7 of rapamycin could be replaced by a variety of different substituents. We set out to examine the effects of such substitutions on FKBP12 binding and on biological activity. RESULTS: Rapamycin C-7-modified analogs of both R and S configurations were shown to have high affinities for FKBP12, yet these congeners displayed a wide range of potencies in splenocyte and yeast proliferation assays. The X-ray crystal structures of four rapamycin analogs in complexes with FKBP12 were determined and revealed that protein and ligand backbone conformations were essentially the same as those observed for the parent rapamycin-FKBP12 complex and that the C-7 group remained exposed to solvent. We then prepared a rapamycin analog with a photoreactive functionality as part of the C-7 substituent. This compound specifically labeled, in an FKBP12-dependent manner, a protein of approximately 250 kDa, which comigrates with recombinant FRAP. CONCLUSIONS: We conclude that the C-7 methoxy group of rapamycin is part of the effector domain. In the ternary complex, this group is situated in close proximity to FRAP, at the interface between FRAP and FKBP12.
Assuntos
Proteínas de Transporte/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Choque Térmico/metabolismo , Imunofilinas , Imunossupressores/farmacologia , Fosfotransferases (Aceptor do Grupo Álcool) , Polienos/farmacologia , Animais , Western Blotting , Proteínas de Transporte/química , Proteínas de Transporte/efeitos dos fármacos , Divisão Celular/fisiologia , Cristalografia por Raios X , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/efeitos dos fármacos , Eletroforese em Gel de Poliacrilamida , Feminino , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/efeitos dos fármacos , Imunossupressores/química , Camundongos , Modelos Moleculares , Conformação Molecular , Marcadores de Fotoafinidade , Polienos/química , Ligação Proteica , Sirolimo , Baço/citologia , Baço/efeitos dos fármacos , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR , Proteínas de Ligação a Tacrolimo , Leveduras/efeitos dos fármacosRESUMO
The objective of this study was to analyse whether primary antiphospholipid syndrome (PAPS) may precede and modify the characteristics of systemic lupus erythematosus (SLE). Out of the total 362 SLE patients in our service, 223 patients had antiphospholipid antibodies (aPL), of whom 110 met the criteria of antiphospholipid syndrome. In 26 cases (7.2%) PAPS appeared 5.5 years before the onset of lupus (PAPS+SLE Group). Their clinical findings were compared to lupus patients without (SLE only Group, n = 26) and with secondary APS (SLE+SAPS Group, n = 26). The prevalence of deep venous thrombosis, stroke/TIA, recurrent fetal loss, coronary heart disease and myocardial infarction was significantly higher in PAPS+SLE Group as compared to SLE only Group. The difference in prevalence of fetal loss (P = 0.014) between PAPS+SLE and SLE+SAPS Groups was also recorded. On comparison to PAPS+SLE Group, patients without APS (SLE only Group) were younger at onset of lupus, with more frequent flares and a higher prevalence of WHO type III/IV nephritis (P = 0.007), requiring higher doses of cyclophosphamide and corticosteroids. Lupus started in the form of PAPS in 7.2% of our SLE patients, who presented with more thrombotic and less inflammatory complications than in SLE patients without a prior or with a following secondary APS. Considering the long latency between the two diseases, PAPS may be a forerunner of lupus, but it may also coexist with SLE as an independent autoimmune disorder.
Assuntos
Síndrome Antifosfolipídica/complicações , Síndrome Antifosfolipídica/patologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/patologia , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Abnormalities of regulatory T cells may play an important role in the loss of self-tolerance, which is a major characteristic of lupus. The objective of this study was to determine the ratio and the number of natural CD4+CD25highFoxp3+ and inducible CD4+IL-10+ regulatory T cells in lupus patients and to search correlation with disease activity. Seventy-two Hungarian lupus patients were enrolled in the study. Fourty-one age- and sex matched healthy donors served as controls. Flow cytometry was used for the quantification of CD4+CD25high Foxp3+ (nTreg) and CD4+IL-10+ (iTreg) cells. The ratio (3.06 +/- 1.45%) and the number (0.019 +/- 0.012 x 10(9)/L) of nTreg cells decreased in lupus significantly (P < 0.001 in both) as compared to normal controls (4.26 +/- 1.01% and 0.039 +/- 0.017 x 10(9)/L). The ratio of iTreg cells were significantly higher in patients than in controls (20.92 +/- 14.02% versus 15.49 +/- 11.65%, P < 0.03), but the number of these cell type did not differ in significant manner (0.314 +/- 0.236 x 10(9)/L versus 0.259 +/- 0.183 x 10(9)/L). The 19 active patients were characterised by significantly higher disease activity index (SLEDAI 8.63 +/- 2.95 versus 1.74 +/- 1.68, P < 0.001) and anti-DNA concentration (117.85 +/- 145.89 versus 37.36 +/- 68.85 IU/mL, P = 0.001) as compered to the 52 inactive patients. Furthermore, active patients required higher dose of methylprednisolon than inactive ones (14.8 +/- 10.6 versus 4.8 +/- 3.4 mg/day, P < 0.001). However, we did not find statistical significant difference in the number and ratio of the examined cell populations regarding to disease activity. Altered ratio and number of both natural and inducible regulatory T cells may play a role in the pathogenesis of lupus. There are small but appreciable difference in the number of regulatory T cells between inactive patients and healthy controls. It suggests that immunoregulatory deficiencies are present in the inactive stage of the disease also.
Assuntos
Antígenos CD4/imunologia , Interleucina-10/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Biomarcadores/sangue , Antígenos CD4/sangue , Progressão da Doença , Feminino , Citometria de Fluxo , Seguimentos , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Interleucina-10/sangue , Subunidade alfa de Receptor de Interleucina-2/sangue , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/patologia , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Linfócitos T Reguladores/patologiaRESUMO
The objective of this study was to characterize risk factors for thrombotic events in lupus patients. A total of 272 lupus patients were followed up for five years during which the presence of aPL antibodies [anticardiolipin (aCL), anti-beta2-glycoprotein I (abeta2GPI) and lupus anticoagulant (LAC)] were determined, and all thrombotic incidents and antithrombotic therapy-related data were collected. At baseline, three groups were constituted, an aPL- group with 107 aPL negative patients, an aPL+ group with 81 aPL positive patients without clinical thrombosis and a secondary antiphospholipid syndrome (APS) group with 84 aPL+ patients who met the Sapporo criteria. LAC was more common in the APS than the aPL+ group (32.1% versus 9.9%, P < 0.001). The prevalence of clinical thrombotic events was significantly higher when all three types of aPL were present compared to only aCL positive cases. During follow up, aPL appeared in 7.5% of the aPL- group, and 2.8% of this group had thrombotic complications. In the aPL+ group, thrombotic events reoccurred in 1.9% of those receiving antithrombotic prophylaxis and 6.9% of those without primary prophylaxis. Despite anticoagulant therapy, thrombotic events reoccurred in 8.3% of the APS group. These findings indicate that LAC, constant and cumulative presence of aPL and previous thrombosis are positive predictors for the development of thrombotic complication in lupus patients.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/etiologia , Lúpus Eritematoso Sistêmico/complicações , Trombofilia/etiologia , Trombose/epidemiologia , Adulto , Anticorpos Anticardiolipina/sangue , Anticorpos Anticardiolipina/imunologia , Anticorpos Antifosfolipídeos/imunologia , Especificidade de Anticorpos , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Síndrome Antifosfolipídica/epidemiologia , Síndrome Antifosfolipídica/imunologia , Autoantígenos/imunologia , Feminino , Fibrinolíticos/efeitos adversos , Fibrinolíticos/uso terapêutico , Seguimentos , Humanos , Inibidor de Coagulação do Lúpus/sangue , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Inibidores da Agregação Plaquetária/efeitos adversos , Inibidores da Agregação Plaquetária/uso terapêutico , Fatores de Risco , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/prevenção & controle , Trombofilia/tratamento farmacológico , Trombofilia/epidemiologia , Trombofilia/imunologia , Trombose/etiologia , Trombose/prevenção & controle , beta 2-Glicoproteína I/imunologiaRESUMO
The blood/gas solubility coefficient and blood concentration of enflurane were measured at intervals in 10 patients undergoing coronary artery revascularization with cardiopulmonary bypass (CPB) and moderate hypothermia. A constant end-tidal concentration of enflurane was maintained throughout the study. Blood/gas solubility coefficient was determined at 37 degrees C, which when combined with an initial single-step equilibration of the blood sample with air, permitted the accurate measurement of blood concentration. Blood/gas solubility coefficient and blood concentration both decreased significantly with the onset of CPB. During the period of hypothermia, blood/gas solubility as measured at 37 degrees C showed little change; however, there was a progressive, marked increase in blood concentration with a mean increase of 80% prior to rewarming. Therefore, the level of anesthesia provided by enflurane may lighten with the onset of CPB, and a deeper level will accompany any decrease in blood temperature. On rewarming, blood concentration levels rapidly returned to levels similar to those measured before cooling. The increased uptake and accumulation of volatile anesthetic agent that occurred as a result of the period of hypothermic CPB was rapidly cleared. The rapidity with which blood concentration responded to the changes occurring during CPB make it unlikely that there was any significant increase in myocardial depression in response to the raised blood concentration secondary to the hypothermia.
Assuntos
Anestesia por Inalação , Ponte Cardiopulmonar , Ponte de Artéria Coronária , Enflurano/sangue , Hipotermia Induzida , Temperatura Corporal , Ponte Cardiopulmonar/métodos , Ponte de Artéria Coronária/métodos , Enflurano/administração & dosagem , Enflurano/metabolismo , Oxigenação por Membrana Extracorpórea , Humanos , Hipotermia Induzida/métodos , Masculino , Pessoa de Meia-Idade , Respiração , Solubilidade , Fatores de TempoRESUMO
Mitral valve surgery is often complicated by a postoperative low cardiac output state. In addition, some patients may have pre-existing pulmonary hypertension. Conventional inotropes, such as dopamine and dobutamine, tend to increase pulmonary vascular resistance. However, enoximone has both inotropic and vasodilatory properties. Ten patients, who had undergone mitral valve surgery and in whom weaning from cardiopulmonary bypass was unsuccessful without inotropic support, were treated with enoximone, 1 mg/kg loading dose plus 10 micrograms/kg/min continuous infusion, to assist in weaning from bypass. A significant and sustained increase in cardiac index was achieved without an increase in heart rate. At the same time, mean arterial pressure, systemic vascular and pulmonary vascular resistances were significantly decreased.
Assuntos
Ponte Cardiopulmonar , Próteses Valvulares Cardíacas , Imidazóis/uso terapêutico , Inibidores de Fosfodiesterase/uso terapêutico , Idoso , Valva Aórtica , Baixo Débito Cardíaco/tratamento farmacológico , Ponte de Artéria Coronária , Enoximona , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valva Mitral , Resistência Vascular/efeitos dos fármacosRESUMO
Mitral valve surgery may be complicated by a post-operative low output state requiring inotropic support, and a wide variety of factors may influence the choice of agents used to treat this condition. The authors have examined and compared the haemodynamic effects of the highly specific phosphodiesterase inhibitor enoximone, and the adrenergic agents dobutamine and dopamine in patients undergoing mitral valve surgery. Enoximone, 0.5 mg kg-1 bolus, followed by a continuous infusion of 5 micrograms kg-1 min-1, was compared against dobutamine, 7 micrograms kg-1 min-1, and dopamine, 5 micrograms kg-1 min-1, with the protocol allowing for an increase in the infusion rate by a factor of two if clinical and haemodynamic measurements indicated. All 25 patients receiving enoximone were successfully weaned from cardiopulmonary bypass at the first attempt, with significant increases in cardiac index and stroke index, combined with little or no change in heart rate or pulmonary artery pressures and a highly significant reduction in systemic vascular resistance, and a reduction in mean arterial pressure. Three of the 25 patients receiving dobutamine were withdrawn from the study because of inadequate haemodynamic response, while the remaining 22 patients demonstrated significant increases in heart rate, cardiac index and stroke index, with a reduction in systemic vascular resistance. Nine of the 25 patients receiving dopamine failed to respond adequately, while the remaining 16 demonstrated an increase in heart rate and cardiac index but with little change in stroke index and a modest reduction in systemic vascular resistance. Enoximone has been shown to be a highly effective first-line inotrope in patients following mitral valve surgery with significant advantages over dobutamine and dopamine.
Assuntos
Baixo Débito Cardíaco/prevenção & controle , Dobutamina/administração & dosagem , Dopamina/administração & dosagem , Enoximona/administração & dosagem , Hemodinâmica/efeitos dos fármacos , Valva Mitral/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Adulto , Idoso , Baixo Débito Cardíaco/tratamento farmacológico , Hemodinâmica/fisiologia , Humanos , Infusões Intravenosas , Injeções Intravenosas , Pessoa de Meia-Idade , Complicações Pós-Operatórias/tratamento farmacológicoRESUMO
The beta-adrenergic receptor, its occupancy and subsequent modulation of intracellular cAMP, and mRNA expression were characterized for the promonocytic leukemia cell line THP-1. We report that THP-1 cells appear to express a beta-1 receptor with a Kd of 1.8 +/- 0.3 x 10(-11) microM and a B max of 108 +/- 0.07 fmole/mg protein using 125I-iodocyanopindolol (125I-ICYP). The potency of various beta-adrenergic agonists to compete for the 125I-ICYP binding site followed the order: isoproterenol (0.8 microM) > dobutamine (2.1 microM) > salbutamol (3 microM) > epinephrine (3.8 microM) > soterenol (4.6 microM) > terbutaline (11.1 microM) > norepinephrine (13.8 microM). Occupancy of the beta receptor on THP-1 cells results in activation of adenyl cyclase suggesting that these cells have a functional beta-adrenergic receptor. This receptor also has specific immunoregulatory properties, reducing message levels for tumor necrosis factor--but not interleukin 1, following treatment with isoproterenol (approximate EC-50 of 0.01 microM). We conclude, based on the above criteria, that THP-1 cells express a beta-1 receptor which, following ligand binding, results in increased cAMP leading to downregulation of TNF expression.
Assuntos
Receptores Adrenérgicos beta/metabolismo , Células Tumorais Cultivadas/metabolismo , Adenilil Ciclases/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Ventrículos do Coração/metabolismo , Humanos , Iodocianopindolol , Cinética , Camundongos , Pindolol/análogos & derivados , Pindolol/metabolismo , RNA Mensageiro/genética , Ratos , Receptores Adrenérgicos beta/efeitos dos fármacos , Células Tumorais Cultivadas/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genéticaRESUMO
The azaspiranes are novel immunomodulators which are effective in a variety of animal models of autoimmune disease and transplantation. The compounds appear to target macrophages and alter their functional activity. One of these compounds, SK&F 106615 (N,N-diethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine++ + dihydrochloride), is now in phase II clinical trials for rheumatoid arthritis. As many drugs/compounds effective in autoimmune disease and transplantation are overtly immunosuppressive, we designed studies to show that SK&F 106615 has selective immunomodulatory effects and that it does not perform in a manner characteristic of classical immunosuppressive agents on immune function. SK&F 106615 inhibited mouse and rat spleen cell and rat peripheral blood mononuclear cell proliferation in vitro with an IC50 of 500 nM. In vivo, treatment of C57BL/6 mice (15 mg/kg/day, i.p.) or rats (20 mg/kg/day, p.o.) for 2 weeks had no effects on specific antibody synthesis to ovalbumin (OVA) compared to rapamycin (RAP) which completely suppressed the antibody response. Compared to cyclosporin A (CsA), FK 506 and RAP which suppressed the antibody (plaque forming) response to particulate (sheep red blood cells) antigen in a dose responsive manner, SK&F 106615 administered at a dose of 50 mg/kg was inactive. There was an inhibition of the proliferative response of lymph node cells from treated mice and rats to mitogen and antigen in ex vivo assays. SK&F 106615, but not RAP, induced cells in the spleens of mice that could inhibit normal spleen cell proliferation in a co-culture assay. Thus, a selective immunomodulatory effect can be shown for SK&F 106615 in the absence of generalized immunosuppression.
Assuntos
Adjuvantes Imunológicos/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Antirreumáticos/farmacologia , Compostos de Espiro/farmacologia , Animais , Formação de Anticorpos/efeitos dos fármacos , Células Cultivadas , Feminino , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Ativação Linfocitária/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ovalbumina/farmacologia , Ratos , Ratos Endogâmicos Lew , Baço/citologia , Baço/efeitos dos fármacos , Baço/imunologiaRESUMO
The immunosuppressive effects of cyclosporin A, FK506, and rapamycin were compared in mouse and rat systems of in vitro cellular stimulation. The inhibitory profile of rapamycin was distinctly different in the two species. In mouse systems, rapamycin caused a dose-dependent inhibition of both Ca(2+)-dependent (concanavalin A (Con A), phytohemagglutinin (PHA), and phorbol 12-myristate 13-acetate + ionomycin) and Ca(2+)-independent (lipopolysaccharide and PMA + interleukin-2) activation, whereas in the rat only Ca(2+)-independent responses were inhibited. Rapamycin's lack of activity in Ca(2+)-dependent responses in the rat does not appear to reside in a general insensitivity of this pathway to inhibition as cyclosporin A and FK506 demonstrated potent inhibitory activity. Additionally, rapamycin was able to block the inhibitory effect of FK506 on rat cells stimulated with the Ca(2+)-dependent stimulus, Con A. These results indicate a further dissociation in the biological activity of rapamycin compared to cyclosporin A and FK506 and may point to intriguing species differences in the immunosuppressive effects of these compounds in vitro.