RESUMEN
The term pulmonary arterial hypertension (PAH) identifies a heterogeneous group of diseases characterized by a progressive increase in pulmonary arterial resistance (PVR), which causes a significant burden in terms of quality of life, right heart failure and premature death. The pathogenesis of PAH is not completely clear: the remodeling of the small pulmonary vessels is crucial, causing an increase in the resistance of the pulmonary circle. Its diagnosis is based on cardiac catheterization of the right heart. According to the present hemodynamic definition of pulmonary hypertension (PH) proposed by the Guidelines of the European Society of Cardiology/European Respiratory Society (ESC-ERS), the mean pulmonary arterial pressure (mPAP) values are ≥25 mmHg. In case of PAH, apart from an mPAP value ≥25 mmHg, patients must have a >3 Wood units increase in PVR and normal pressure values of the left heart. PH is a pathophysiological condition observed in more than 40 different diseases, while PAH is a primary disease of the pulmonary bloodstream potentially treatable with specific drugs. PAH is a severe complication of systemic sclerosis (SSc) affecting about 10% of the patients. Due to the devastating nature of SSc-PAH, there is a clear need to systematically adopt appropriate screening programs. In fact, despite awareness of the negative impact of SSc-PAH on quality of life and survival, as well as on the severity of lung function, at the moment standardized and shared guidelines and/or screening programs for the diagnosis and the subsequent early treatment of PAH in SSc are not available. The aim of the present paper is to highlight the lights and shadows of SSc-PAH, unraveling the unmet clinical needs on this topic with a proposal of clinical-diagnostic and therapeutic guidelines.
Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Esclerodermia Sistémica , Hemodinámica , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/terapia , Calidad de VidaRESUMEN
OBJECTIVES: To measure the prevalence of, and factors associated with, left ventricular (LV) dysfunction in systemic sclerosis (SSc). METHODS: The EUSTAR database was first searched. A case-control study of a patient subset was then performed to further identify independent factors associated with LV dysfunction by simple and multiple regression. RESULTS: Of 7073 patients, 383 (5.4%) had an LV ejection fraction (EF) of <55%. By multiple regression analysis, age, sex, diffuse cutaneous disease, disease duration, digital ulcerations, renal and muscle involvement, disease activity score, pulmonary fibrosis and pulmonary arterial hypertension were associated with LV dysfunction. In the second phase, 129 patients with SSc with LVEF <55% were compared with 256 patients with SSc with normal LVEF. Male sex (OR 3.48; 95% CI 1.74 to 6.98), age (OR 1.03; 95% CI 1.01 to 1.06), digital ulcerations (OR 1.91; 95% CI 1.05 to 3.50), myositis (OR 2.88; 95% CI 1.15 to 7.19) and use of calcium channel blockers (OR 0.41; 95% CI 0.22 to 0.74) were independent factors associated with LV dysfunction. CONCLUSION: The prevalence of LV dysfunction in SSc is 5.4%. Age, male gender, digital ulcerations, myositis and lung involvement are independently associated with an increased prevalence of LV dysfunction. Conversely, the use of calcium channel blockers may be protective.
Asunto(s)
Esclerodermia Sistémica/complicaciones , Disfunción Ventricular Izquierda/etiología , Adulto , Factores de Edad , Anciano , Bloqueadores de los Canales de Calcio/uso terapéutico , Métodos Epidemiológicos , Europa (Continente)/epidemiología , Femenino , Dedos , Humanos , Masculino , Persona de Mediana Edad , Miositis/complicaciones , Miositis/epidemiología , Esclerodermia Sistémica/epidemiología , Factores Sexuales , Úlcera Cutánea/complicaciones , Úlcera Cutánea/epidemiología , Volumen Sistólico , Disfunción Ventricular Izquierda/epidemiología , Disfunción Ventricular Izquierda/prevención & controlRESUMEN
Systemic sclerosis (SSc) is often complicated by severe skin ulcers that are unresponsive to traditional treatments. Vascular alterations are responsible for the ischaemic features of the disease in both the skin and visceral organs. Defective neoangiogenesis correlates with an abnormally reduced quantity of circulating endothelial progenitor cells (EPCs) caused by impaired maturation potential and proliferative capacity of bonemarrow endothelial stem cells. We report a patient with nonhealing cutaneous ulcers successfully treated with recombinant human erythropoietin (rHuEPO). The possible biological effects of this drug were also investigated. Before rHuEPO treatment, the bone-marrow sample contained reduced numbers of EPCs, which were functionally impaired. After a 6-month rHuEPO cycle, a marked increase in endothelial progenitor markers was seen, along with a significant reduction in their apoptotic rates. The clinical and laboratory data variations before and after rHuEPO treatment give new insights into the pathogenetic role of impaired endothelial stem-cell maturation and defective neoangiogenesis in patients with SSc.
Asunto(s)
Eritropoyetina/uso terapéutico , Esclerodermia Sistémica/tratamiento farmacológico , Úlcera Cutánea/tratamiento farmacológico , Cicatrización de Heridas/efectos de los fármacos , Anciano , Apoptosis/efectos de los fármacos , Médula Ósea/química , Células Endoteliales/metabolismo , Humanos , Masculino , Neovascularización Fisiológica/efectos de los fármacos , Proteínas Recombinantes , Esclerodermia Sistémica/complicaciones , Úlcera Cutánea/complicacionesRESUMEN
We retrospectively evaluated the efficacy of autologous hematopoietic stem cell transplantation (AHSCT) in 18 patients with rapidly progressive diffuse cutaneous systemic sclerosis (rp-dcSSc), and compared their disease outcomes with those of 36 demographically- and clinically-matched patients treated with conventional therapies. Cutaneous involvement, by performing modified Rodnan skin score (mRss), lung diffusion capacity, by measuring diffusing capacity of lung for carbon monoxide (DLCO), and disease activity, by applying the European Scleroderma Study Group (ESSG) scoring system, were the outcome variables measured at the baseline time and then every 12 months for the following 60 months in both the AHSCT-treated patients and the control group. In the AHSCT group, treatment-related mortality was 5.6%. In this group, both mRss and ESSG scores showed a significant reduction 1 year after AHSCT (P<0.002); and these results were maintained until the end of follow-up. Conversely, DLCO values remained stable during the whole period of follow-up. Survival rate of AHSCT group was much higher than that observed in the whole control group (P=0.0005). The probability that the ESSG score and mRss would remain at a high level, and DLCO could decrease, was significantly higher in the control group as a whole and in the subgroup of control patients treated with cyclophosphamide than in the AHSCT group. This study confirms that the AHSCT is effective in prolonging survival, as well as in inducing a rapid reduction of skin involvement and disease activity, and preserving lung function in patients with rp-dcSSc.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Esclerodermia Difusa/mortalidad , Esclerodermia Difusa/terapia , Adulto , Autoinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Systemic sclerosis (SSc) is a rare disabling autoimmune disease with a similar mortality to many cancers. Two randomized controlled trials of autologous hematopoietic stem cell transplantation (AHSCT) for SSc have shown significant improvement in organ function, quality of life and long-term survival compared to standard therapy. However, transplant-related mortality (TRM) ranged from 3-10% in patients undergoing HSCT. In SSc, the main cause of non-transplant and TRM is cardiac related. We therefore updated the previously published guidelines for cardiac evaluation, which should be performed in dedicated centers with expertize in HSCT for SSc. The current recommendations are based on pre-transplant cardiopulmonary evaluations combining pulmonary function tests, echocardiography, cardiac magnetic resonance imaging and invasive hemodynamic testing, initiated at Northwestern University (Chicago) and subsequently discussed and endorsed within the EBMT ADWP in 2016.
Asunto(s)
Cardiopatías/diagnóstico , Trasplante de Células Madre Hematopoyéticas/mortalidad , Esclerodermia Sistémica/terapia , Cardiopatías/complicaciones , Cardiopatías/diagnóstico por imagen , Humanos , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/mortalidadRESUMEN
OBJECTIVE: To assess the prevalence of anti-Ro/SSA in RA and to analyse clinical and serological features of anti-Ro/SSA positive patients with RA. METHODS: 195 consecutive patients affected by RA were studied by counterimmunoelectrophoresis and ELISA for the detection of anti-Ro/SSA antibodies. Anti-Ro were found in 12 patients, with a prevalence of 6%. These 12 patients were pooled with other 15 patients known to have anti-Ro/SSA antibodies and RA, in order to evaluate their clinical and laboratory features. RESULTS: Anti-Ro positive patients showed a common pattern of joint involvement at onset and a comparable progression of disease compared to anti-Ro negative subjects. In addition, extra-articular manifestations (such as xerophthalmia, xerostomia, scleritis, oral ulcers and amyloidosis) and peculiar autoantibody profile (hypergammaglobulinemia, anti-dsDNA and AMA) were found significantly associated to anti-Ro/SSA positivity. Even though DMARDs withdrawals were more frequently detected in anti-Ro/SSA patients, especially when using gold salts, no statistical difference between the two groups was detected. In addition, anti-TNFalpha treatment did not cause further progression of autoimmunity neither on laboratory nor on clinical ground. CONCLUSION: Anti-Ro/SSA can be detected in about 6% of patients affected by RA. These patients presented a peculiar clinical picture characterised by extra-articular manifestations some of which are known to be anti-Ro/SSA correlated, while others are more disease-specific (amyloidosis, episcleritis). Anti-Ro/SSA are significantly associated with other autoantibodies not specific for RA such as anti-dsDNA and AMA. Treatment with anti-TNF drugs did not cause further progression of autoimmunity neither on laboratory nor on clinical ground.
Asunto(s)
Amiloidosis/inmunología , Anticuerpos Antinucleares/sangre , Artritis Reumatoide/inmunología , Oftalmopatías/inmunología , Úlceras Bucales/inmunología , Amiloidosis/complicaciones , Amiloidosis/diagnóstico , Artritis Reumatoide/complicaciones , Artritis Reumatoide/diagnóstico , Autoanticuerpos/análisis , Autoanticuerpos/inmunología , Contrainmunoelectroforesis , Ensayo de Inmunoadsorción Enzimática , Oftalmopatías/complicaciones , Oftalmopatías/diagnóstico , Femenino , Humanos , Hipergammaglobulinemia/complicaciones , Hipergammaglobulinemia/diagnóstico , Hipergammaglobulinemia/inmunología , Masculino , Persona de Mediana Edad , Mitocondrias/inmunología , Úlceras Bucales/complicaciones , Úlceras Bucales/diagnóstico , Escleritis/complicaciones , Escleritis/diagnóstico , Escleritis/inmunología , Xeroftalmia/complicaciones , Xeroftalmia/diagnóstico , Xeroftalmia/inmunologíaRESUMEN
This EBMT Autoimmune Disease Working Party study aimed to evaluate the influence of CD34+ positive graft selection (CD34+) on the outcome of systemic sclerosis (SSc) patients after autologous hematopoietic stem cell transplantation (AHSCT). Clinical and laboratory data from 138 SSc patients at diagnosis, before and after AHSCT were retrospectively analyzed. CD34+ selection was performed in 47.1% (n=65) patients. By multivariate analysis adjusting for all factors differing between the two groups (without or with CD34+), there was no statistically significant difference in terms of overall survival (hazard ratio (HR): 0.98, 95% confidence interval (CI) 0.40-2.39, P=0.96), PFS (HR: 1.55, 95% CI 0.83-2.88, P=0.17) and incidence of relapse or progression (HR: 1.70, 95% CI 0.85-3.38, P=0.13). We demonstrate that CD34+ does not add benefit to the outcome of SSc patient treated with AHSCT. These findings should be further confirmed by prospective randomized trials.
Asunto(s)
Antígenos CD34 , Trasplante de Células Madre Hematopoyéticas/métodos , Esclerodermia Sistémica/mortalidad , Esclerodermia Sistémica/terapia , Adolescente , Adulto , Autoinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
OBJECTIVE: Circulating endothelial cells (CECs) have been described in different conditions with vascular injury. Vascular abnormalities play a key role in the pathogenesis of Systemic Sclerosis (SSc). The aim of our study was to look for the presence of CECs in SSc patients and to evaluate their clinical significance. METHODS: We studied 52 SSc patients and 40 healthy controls (HC). Five-parameter, 3-color flow cytometry was performed with a FACScan. CECs were defined as CD45 negative, CD31 and P1H12 positive, and activated CECs as CD45 negative and P1H12, CD62, or CD106 positive. RESULTS: Total and activated CEC counts were significantly higher in SSc patients when compared with HC and positively correlated with disease activity score. We found a significant association between CECs and disease activity; as regard with organ involvement, CEC number correlate with the severity of pulmonary hypertension. CONCLUSIONS: Raised counts of CECs may represent direct evidence of active vascular disease in SSc as regard as visceral involvement, the association between CECs and pulmonary hypertension suggest a relevant role for CECs as a marker of prominent endothelial involvement.
Asunto(s)
Células Endoteliales , Esclerodermia Sistémica/sangre , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Recently, several studies have demonstrated the presence of circulating endothelial progenitors (CEPs) responsible for angiogenesis. Notably, these cells are able to migrate to ischemic tissues and differentiate in situ in mature endothelial cells. Aim of this study was to assess the presence of CEPs in the peripheral blood of patients with Sistemic Sclerosis (SSc) and evaluate their significance as an attempt of re-vascularization MATERIAL AND METHODS: Samples of peripheral blood from 40 healthy subjects and 56 patients with SSc were studied. Five-parameter, 3-color flow cytometry was performed with a FACScan. CEPs were defined as CD45 negative, CD34 and CD133 positive. In addition, plasma levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were detected by commercial ELISA (R&D Systems). RESULTS: Levels of CEPs (CD133+/CD34+/CD45-) were significantly higher in patients with SSc in comparison to HC (P = 0.01). No correlation was found between CEPs and any clinical parameter of disease neither activity score. CEPs were significantly higher in the group of patients with early disease, while their number decreased in the late phases of disease. Plasma levels of VEGF, but not bFGF, were significantly higher in SSc in comparison to HC (P<0.001) but no correlation was found between VEGF concentrations and CEP number. CONCLUSIONS: The presence of CEPs in patients with SSc suggest that sclerodermic hypoxic tissues could induce the mobilization of bone-marrow derived cells in an attempt to provided new vessels, in the early phase of the disease, at least.
Asunto(s)
Células Endoteliales , Esclerodermia Sistémica/sangre , Células Madre , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neovascularización Patológica/etiología , Esclerodermia Sistémica/inmunologíaRESUMEN
Sera from patients affected either by the classic/Mediterranean form (5 patients) and human immune deficiency virus (HIV)-associated (12 patients) form of Kaposi's sarcoma (KS) were compared in supporting endothelial cell in-vitro proliferation. Healthy blood donors (15) and a group of 7 HIV-positive drug addicts with no dermatological involvement were used as control groups. Endothelial cell growth was assessed by means of a [3H]thymidine incorporation and by an optical density direct cell-counting assay. Our results indicate that, at the highest concentrations, sera obtained from patients affected by KS with no sign of HIV infection induced significantly higher levels of endothelial cell proliferation when compared with HIV-associated KS and with normal controls. This growth-promoting activity was apparently cell selective, being present in endothelial cell but not in fibroblast cultures.
Asunto(s)
Endotelio Vascular/citología , Infecciones por VIH/complicaciones , Sarcoma de Kaposi/sangre , Recuento de Células , División Celular , Células Cultivadas , Femenino , Fibroblastos , Humanos , Masculino , Sarcoma de Kaposi/etiologíaRESUMEN
On the basis of the role of immuno-mediated inflammation in atherosclerosis we investigated, (1) the prevalence of anti-endothelial cell antibodies (AECA) in ischaemic heart disease (IHD); (2) if beta2-glycoprotein I (beta2-GPI) was the target antigen of AECA; (3) the relationship between AECA, tissue factor (TF) and tissue factor pathway inhibitor (TFPI). In 93 consecutive IHD patients undergoing percutaneous transluminal coronary angioplasty (PTCA) and 105 controls AECA were detected by ELISA on human umbilical vein endothelial cells (HUVEC). AECA positive sera were evaluated for anti-beta2-GPI antibodies by ELISA. TF and TFPI plasma levels were assessed by ELISA. Twelve of 93 (12.9%) IHD patients and only one of 105 controls (0.95%) were AECA positive. The prevalence of AECA was higher in unstable angina (UA) than in effort angina (EA) (P=0.01). Three of 12 AECA positive sera resulted positive for anti-beta2-GPI and showed a marked decrease in EC-binding when tested on HUVEC cultured in serum-free medium. The binding was restored by the addition of beta2-GPI. TF and TFPI levels were similar in AECA positive and AECA negative patients. The rate of angiographically documented clinical recurrences was 66.7% in the AECA positive and 14.8% in the AECA negative group (P=0.0004) with a significant relationship between restenosis and AECA (P<0.0001), unchanged by the inclusion of cardiovascular risk factors in the regression model. Our results suggest a 'role' for AECA in the immune-mediated inflammation in UA beta2-GPI is not the only AECA target antigen. AECA are not responsible for high TF and TFPI levels. The high rate of clinical recurrences after PTCA, confirmed by angiography, in AECA positive patients is in line with such a role and suggests further large-scale 'ad hoc' studies.
Asunto(s)
Autoanticuerpos/inmunología , Enfermedad Coronaria/inmunología , Angioplastia Coronaria con Balón , Apolipoproteínas/inmunología , Apolipoproteínas/metabolismo , Biomarcadores , Angiografía Coronaria , Enfermedad Coronaria/diagnóstico por imagen , Enfermedad Coronaria/metabolismo , Enfermedad Coronaria/terapia , Progresión de la Enfermedad , Endotelio Vascular/inmunología , Endotelio Vascular/metabolismo , Ensayo de Inmunoadsorción Enzimática , Inhibidores del Factor Xa , Femenino , Glicoproteínas/inmunología , Glicoproteínas/metabolismo , Humanos , Lipoproteínas/inmunología , Lipoproteínas/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia , Tromboplastina/inmunología , Tromboplastina/metabolismo , Venas Umbilicales/metabolismo , beta 2 Glicoproteína IRESUMEN
BACKGROUND: Transplant-induced coronary artery disease is a leading cause of graft failure in cardiac allograft recipients after the first year of transplantation, but there presently is no test to identify patients at high risk for developing the disease. Our research is focused on development of a predictive test to identify patients at high risk of developing the disease. METHODS: Sixty-eight cardiac allograft recipients transplanted and followed at Methodist Hospital between 1982 and 1996 were studied. Serial annual angiograms were used to diagnose coronary artery disease, and serial endomyocardial biopsies were used to detect cellular infiltrates and microvascular disease. Biopsy-matched serum samples were used for cardiac troponin-T determinations as measures of myocardial damage, and serum antibodies to endothelial cells were determined by using flow cytometry, enzyme-linked immunosorbent assay and immunoblotting techniques. The endothelial antibody data were evaluated statistically for associations with angiographic changes, biopsy findings and biochemical evidence of myocardial damage. FINDINGS: Antibodies to endothelial cells were identified by all three techniques, and significant associations were found for the amount of antibody identified by Western immunoblotting with histological rejection grades in biopsies, which were confirmed immunocytochemically as macrophages (p<0.01) and T lymphocytes (P = 0.03). These antibodies also associated significantly with vascular antithrombin depletion (p = 0.02), biochemical evidence of myocardial damage (p = 0.005) and subsequent development of coronary artery disease (p = 0.03). INTERPRETATION: The significant association of anti-endothelial antibodies with cellular infiltrates, depletion of vascular antithrombin and myocardial damage suggests a role for antibody in the development of transplant-induced arteriopathy. The significant association of antiendothelial antibodies with the future development of coronary artery disease further suggests that assessment of these antibodies may provide a non-invasive test to predict the development of transplant-induced coronary artery disease.
Asunto(s)
Anticuerpos/inmunología , Enfermedad Coronaria/inmunología , Endotelio Vascular/inmunología , Trasplante de Corazón , Miocardio/inmunología , Complicaciones Posoperatorias/inmunología , Adulto , Células Cultivadas , Endotelio Vascular/citología , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Miocardio/patologíaRESUMEN
It is still uncertain which, if any, immunologic parameters may help diagnose a renal flare of lupus nephritis. Anti-C1q antibody (Ab) titers have been elevated in patients with lupus with renal involvement, but little information is available on whether the titers are different in quiescent and active phases of lupus nephritis. In this study, we compared anti-C1q Ab titers with other serological test results in 48 patients with biopsy-proven lupus nephritis to assess which parameter could offer the best reliability for differentiating between quiescent and active phases of lupus nephritis. Serum C3 and C4 levels, as well as anti-double-stranded DNA, antiendothelial cell, anti-C1q, and antiphospholipid Ab titers, were evaluated in patients with quiescent renal disease (38 samples) and those with clinical evidence of renal activity (23 samples). Only anti-C1q Ab titers correlated with active renal disease in both univariate (P < 0.0001) and multivariate analysis (P < 0.0001), with a sensitivity of 87% and a specificity of 92%. In six patients, immunologic parameters were measured serially. In all patients, the high anti-C1q Ab titers returned to normal values after treatment-induced remission. The other serological parameters did not show a significant association with renal disease activity. In patients with biopsy-proven lupus nephritis, anti-C1q Ab titers appear to be strongly related to renal disease activity. Their measurement may be useful for confirming the diagnosis of renal flares of lupus nephritis.
Asunto(s)
Complemento C1q/análisis , Nefritis Lúpica/diagnóstico , Adulto , Análisis de Varianza , Anticuerpos/inmunología , Anticuerpos Antifosfolípidos/sangre , Complemento C1q/inmunología , Complemento C3/análisis , Complemento C4/análisis , ADN/sangre , Progresión de la Enfermedad , Endotelio/citología , Endotelio/inmunología , Femenino , Humanos , Nefritis Lúpica/inmunología , Masculino , Análisis de Regresión , Sensibilidad y EspecificidadRESUMEN
Several experimental conditions were used in this study to evaluate the in vitro effects of 15-deoxyspergualin on the function of T lymphocytes, B lymphocytes and monocytes from healthy subjects and patients suffering from systemic lupus erythematosus. Whilst the secretion of polyclonal immunoglobulin (Ig) M and IgG from the B lymphocytes of the healthy subjects was diminished by 15-deoxyspergualin, neither the proliferative response of normal T and B cells to mitogenic stimulation nor the cytokine secretory capacity of these cells (e.g. interleukin-2, -4, -6 and gamma-interferon) and monocytes (e.g. interleukin-1 beta and -6) were affected by the drug. In contrast, on the mononuclear cells obtained from the lupus patients not only did 15-deoxyspergualin inhibit the spontaneous production of polyclonal and anti-DNA IgG antibodies but also suppressed interleukin-1 beta secretion from the monocytes. Other functional responses of T and B cells and monocytes from lupus patients, including mitogenic activation and cytokine secretion, were not altered by the drug. These data suggest that 15-deoxyspergualin possesses a novel mechanism of pharmacological immunosuppression apparently different from that of other immunosuppressants, such as cyclosporin A, FK506 and corticosteroids, that seems to be primarily displayed at the level of autoreactive B cells and monocytes.
Asunto(s)
Citocinas/sangre , Guanidinas/farmacología , Inmunosupresores/farmacología , Lupus Eritematoso Sistémico/inmunología , Linfocitos/efectos de los fármacos , Monocitos/efectos de los fármacos , ADN/inmunología , Relación Dosis-Respuesta a Droga , Humanos , Inmunoglobulina G/biosíntesis , Inmunoglobulina M/biosíntesis , Técnicas In Vitro , Lupus Eritematoso Sistémico/fisiopatologíaRESUMEN
OBJECTIVE: Since the early activation antigen CD69 has been implicated in the pathogenesis of some inflammatory diseases, we evaluated the expression of the molecule on peripheral blood (PB) and synovial fluid (SF) neutrophils obtained from RA patients and its possible correlation with PB and SF cytokine concentration. METHODS: CD69 membrane expression (and CD11b as control marker) was assessed by indirect immunofluorescence and flow cytometry analysis on purified PB and SF neutrophils. Cytokine levels (GM-CSF, IFN-gamma, TNF-alpha) in plasma and SF supernatants were measured by ELISA. RESULTS: CD69 was absent on control neutrophils, while it was expressed on PB neutrophils from RA patients although no detectable GM-CSF, IFN-gamma or TNF-alpha was observed in their plasma. CD69 expression was still more evident on SF neutrophils from RA patients; 59% had detectable levels of INF-gamma in their SF while GM-CSF and TNF-alpha were detectable in SF from 95% and 33% of RA patients, respectively. However, no correlation was observed between cytokine concentrations and CD69 expression on SF neutrophils. SF but not PB neutrophils from RA patients expressed increased amounts of CD11b when compared to control PB neutrophils without any correlation with CD69 membrane expression. CONCLUSION: The activation antigen CD69 is significantly expressed on PB and SF neutrophils from RA patients. However, the mechanism(s) of induction and its possible role in the pathogenesis of RA remain to be defined.
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Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Artritis Reumatoide/sangre , Neutrófilos/metabolismo , Líquido Sinovial/citología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Citocinas/sangre , Humanos , Lectinas Tipo C , Activación de Linfocitos , Persona de Mediana Edad , Líquido Sinovial/metabolismoRESUMEN
OBJECTIVE: To determine the prevalence of anti-chromatin antibodies (Abs) in juvenile rheumatoid arthritis (JRA) and to assess any association between the presence of anti-chromatin Abs and clinical subsets of the disease. METHODS: IgG anti-chromatin Abs and anti-extractable nuclear antigens (ENA) Abs were detected by an enzyme-linked immunosorbent assay (ELISA), and antinuclear Abs (ANA) by indirect immunofluorescence in sera of 89 children with JRA. Ten children with systemic, 32 with polyarticular and 47 with pauciarticular disease onset (uveitis occurred in 17/47 children) were studied. As a control group, 12 sera of patients suffering from idiopathic uveitis and 31 age- and-sex-matched healthy children (HC) were examined. RESULTS: Abs to chromatin were detected in 14/47 (29.8%) of children suffering from pauciarticular onset JRA and in this group the higher prevalence of anti-chromatin Abs has been found in children with chronic uveitis (p = 0.002). Anti-chromatin positivity was observed in 2/10 (20%) of systemic and in 3/32 (9.3%) of polyarticular onset JRA. Furthermore, none of the patients with idiopathic uveitis and HC had Abs to chromatin. anti-chromatin Abs titers remained relatively stable over a 6-month control period. CONCLUSION: Our results confirm previous data about the presence of circulating anti-chromatin Abs in juvenile arthritis. Interestingly, anti-chromatin Abs were significantly higher in the group of patients with pauciarticular onset with past or present history of uveitis, than in patients without ocular involvement. A long-term follow-up study could be useful to demonstrate the potential utility of these autoantibodies in diagnosing, classifying and treating children affected.
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Anticuerpos Antinucleares/sangre , Artritis Juvenil/sangre , Cromatina/inmunología , Artritis Juvenil/inmunología , Artritis Juvenil/fisiopatología , Ensayo de Inmunoadsorción Enzimática , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , MasculinoRESUMEN
The association between antiphospholipid antibodies (aPL) and arterial or venous thrombosis, fetal loss and thrombocytopenia defines the so-called "antiphospholipid syndrome" (APS). Despite serial studies in recent years, a clear pathogenetic mechanism(s) has not yet been demonstrated. Several authors have investigated the interaction between aPL and the membranes of blood cells (endothelial cells and platelets) involved in coagulation. aPL is also thought to affect the balance between the procoagulant and anticoagulant states by interacting with plasma or tissue cofactors. Finally, the strong association between aPL and experimental animal models of fetal loss supports a direct pathogenetic role for aPL in inducing a poor pregnancy outcome in APS women.
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Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/inmunología , Aborto Espontáneo/inmunología , Animales , Sangre/inmunología , Plaquetas/inmunología , Endotelio Vascular/citología , Endotelio Vascular/inmunología , Membrana Eritrocítica/inmunología , Femenino , Humanos , EmbarazoRESUMEN
Sera positive for autoimmune anti-phospholipid antibodies were studied by a cell surface radioimmunoassay for their cross-reactivity with resting or activated human endothelial cells. The endothelial cell activation by interleukin 1 beta, gamma-interferon, lipopolysaccharide or phorbol-12 myristate-13 acetate did not affect the cross-reactivity. Comparable findings were also found by testing anti-cardiolipin affinity purified preparations. Taken together these data indicate that endothelial cell activation is not sufficient per se to modulate the expression of antigenic determinants recognizable by the anti-phospholipid antibodies. However, anti-cardiolipin affinity purified preparations displayed enhanced cell binding after cell membrane perturbation by paraformaldehyde fixation, suggesting that an alteration in endothelial cell integrity might further trigger the reaction of circulating anti-phospholipid antibodies with vessel walls in vivo.
Asunto(s)
Anticuerpos/análisis , Citocinas/farmacología , Endotelio Vascular/citología , Endotelio Vascular/inmunología , Fosfolípidos/inmunología , Anticuerpos/inmunología , Reacciones Cruzadas/efectos de los fármacos , Reacciones Cruzadas/inmunología , Endotelio Vascular/efectos de los fármacos , Humanos , Interferón gamma/farmacología , Interleucina-1/farmacología , Lipopolisacáridos/fisiología , Radioinmunoensayo , Acetato de Tetradecanoilforbol/farmacologíaRESUMEN
We describe a patient with primary antiphospholipid syndrome (PAPS) and haemolytic anemia with cryoagglutinins, in whom antibodies eluted from red blood cells (RBC) displayed anti-cardiolipin (CL) binding activity. This activity was confined to the IgG isotype and was directed to the negatively-charged phospholipids only. In addition, the patient's IgG fraction displayed a higher binding to RBC in comparison to normal control IgG and this reactivity was inhibited after absorption of the anti-CL activity with CL-micelles. These findings further sustain the association between antiphospholipid antibodies (APA) and Coombs' positivity with or without haemolytic anemia and suggest that APA could be at least in part responsible for anti-RBC activity.
Asunto(s)
Anticuerpos Antifosfolípidos/inmunología , Membrana Eritrocítica/inmunología , Anciano , Anemia Hemolítica/complicaciones , Anemia Hemolítica/inmunología , Anticuerpos Antifosfolípidos/metabolismo , Especificidad de Anticuerpos/inmunología , Síndrome Antifosfolípido/complicaciones , Síndrome Antifosfolípido/inmunología , Reacciones Cruzadas/inmunología , Membrana Eritrocítica/metabolismo , Femenino , Humanos , Inmunoglobulina G/inmunología , Isotipos de Inmunoglobulinas/inmunologíaRESUMEN
OBJECTIVE: To investigate the role of antibodies reacting with beta 2 glycoprotein I (beta 2GPI) in the antiendothelial cell binding activity present in sera from patients with the anti-phospholipid syndrome. METHODS: Sera positive for anti-phospholipid, anti-endothelial and anti-beta 2 GPI antibodies were studied for their binding activity on endothelial monolayers cultured in the presence or absence of media containing bovine serum as a source of beta 2GPI. Anti-endothelial activity was also evaluated on endothelial cells cultured without serum and supplemented with exogenous human purified beta 2GPI. Affinity purified anti-beta 2 GPI antibodies were investigated under the same experimental conditions. Finally, the effect of the incubation of these affinity purified fractions on the expression of adhesion molecules (ELAM-1) was studied. RESULTS: The reactivity of the sera decreased on endothelial cells incubated in serum-free medium, while endothelial cell binding was restored in a dose dependent manner after the addition of exogenous purified human beta 2 GPI. Affinity purified anti-beta 2 GPI antibodies obtained from the same sera retained their endothelial cell binding and were able to activate endothelial cells by inducing the ex novo surface expression of adhesion molecules (ELAM-1). CONCLUSIONS: These findings indicate that the close association between anti-endothelial and anti-phospholipid antibodies is sustained by antibodies which recognize beta 2 GPI adhering to the endothelial cells, and can promote their activation.