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- Causas biológicas de depressão em doentes com Lúpus Eritematoso Sistémico: um estudo de revisãoPublication . Braga, J.; Campar, A.A elevada prevalência de depressão em doentes com lúpus eritematoso sistémico (LES) pode resultar tanto do impacto psicossocial desta doença crónica como de lesão do sistema nervoso central (SNC). Recentemente, a base biológica de depressão no LES tem vindo a ser confirmada, sob influência de vários factores, que serão revistos neste artigo. A evidência publicada aponta para a participação de alterações bioquímicas e neurofisiológicas, induzidas por citocinas, no desenvolvimento de sintomas neuropsiquiátricos no LES. Através da activação da enzima indoleamina 2,3-dioxigenase (IDO), da alteração da biodisponibilidade de neurotransmissores, da modificação da neuroplasticidade e neurogénese e da sobrestimulação de determinados neurocircuitos, as citocinas são capazes de provocar alterações do humor e depressão. Por outro lado, associada à desregulação imune, a disfunção do eixo hipotálamo-hipófise-adrenal (HHA) correlaciona-se com alterações neurofisiológicas envolvidas na depressão. Adicionalmente, autoanticorpos cérebro-reactivos presentes no líquido cefalo-raquídeo (LCR), como os anti-(N-metil- -D-aspartato)NMDA e anti-proteína P ribossómica, podem causar lesão de neurónios em áreas cerebrais relevantes no humor e comportamento, podendo originar sintomas depressivos. Em termos neuroanatómicos, lesões cerebrais de áreas do sistema límbico em doentes com LES, embora de etiologia não esclarecida, sugerem atingimento cerebral com comprometimento de funções emocionais e comportamentais. Concluindo, inúmeras alterações biológicas podem causar depressão no LES, sendo a sua identificação fundamental na abordagem desta patologia.
- Autologous stem cell transplantation in a patient with severe systemic sclerosisPublication . Vaz, C.; Almeida, I.; Guedes, M.; Rosário, C.; Branca, R.; Campilho, F.; Roncon, S.; Vasconcelos, C.; Campos, A.Systemic Sclerosis (SSc) is a chronic disease of the connective tissue, whose pathogenesis involves abnormalities of the immunological system. It has a variable course and there is a subgroup of patients with rapidly progressive disease or unresponsive to conventional treatment. Thesepatients can benefit from intensive immunosuppression and autologous hematopoietic stem cell transplant. Clinical case: 19-year-old (y.o.) woman diagnosed with SSc at the age of 13 y.o. with cutaneous, vascular and articular involvement with initial response to me thotrexate. Three years later the disease progressed with severe digestive involvement (dysphagia, delayed gastric emptying and weight loss) needing gastrostomy for nutritional support. She was treated with cyclophosphamide without improvement. In May 2012 she had an autologous transplant with myeloablative regimen (BEAM): carmustine 300 mg/m2 x1day; etoposide 120 mg/kg x4days; cytarabine 120 mg/kg 12/12:h x4days; melphalan 140 mg/m2 x1day. A year and a half after transplantation she is asymptomatic, without any signs or symptoms of the disease, feeds by mouth and the gastric emptying study is normal. Currently she is free of medication.
- Recomendações para o Diagnóstico da Forma Tardia da Doença de PompePublication . Brito-Avô, L.; Alves, J.; Costa, J.; Valverde, A.; Santos, L.; Araújo, F.; Marinho, A.; Oliveira, A.; Gomes, D.INTRODUCTION: Pompe disease is a progressive and debilitating autossomal recessive myopathy due to mutations in lysossomal acid-α-glucosidase. Its late-onset form has a heterogeneous presentation mimicking other neuromuscular diseases, leading to diagnostic challenge. OBJECTIVE: To develop consensus based recommendations for the diagnosis of late-onset Pompe Disease. MATERIAL AND METHODS: Bibliographic review and analysis of an opinion questionnaire applied to a group of specialists with expertise in the diagnosis of several myopathies and lysossomal storage disorders. Discussed in consensus meeting. RECOMMENDATIONS: Patients with a progressive limb-girdle weakness, fatigue, cramps and muscle pain should be evaluated with CK levels, electromyography, dynamic spirometry and muscle biopsy in inconclusive cases. Suspected cases and those in which muscle biopsy could not allow other diagnosis should be screened for lysossomal acid-α-glucosidase deficiency with DBS (dried blood spot). The diagnosis should be confirmed by determination of lysossomal acid-α-glucosidase activity in a second sample and lysossomal acid-α-glucosidase gene sequencing.
- Group B Streptococcus Hijacks the Host Plasminogen System to Promote Brain Endothelial Cell InvasionPublication . Magalhães, V.; Andrade, E.; Alves, J.; Ribeiro, A:; Kim, K.; Lima, M.; Trieu-Cuot, P.; Ferreira, P.Group B Streptococcus (GBS) is the leading cause of meningitis in neonates. We have previously shown that plasminogen, once recruited to the GBS cell surface and converted into plasmin by host-derived activators, leads to an enhancement of bacterial virulence. Here, we investigated whether plasmin(ogen) bound at the GBS surface contributes to blood-brain barrier penetration and invasion of the central nervous system. For that purpose, GBS strain NEM316 preincubated with or without plasminogen plus tissue type plasminogen activator was analyzed for the capacity to adhere to, invade and transmigrate the human brain microvascular endothelial cell (hBMEC) monolayer, and to penetrate the central nervous system using a neonatal mouse model. At earlier times of infection, plasmin(ogen)-treated GBS exhibited a significant increase in adherence to and invasion of hBMECs. Later, injury of hBMECs were observed with plasmin(ogen)-treated GBS that displayed a plasmin-like activity. The same results were obtained when hBMECs were incubated with whole human plasma and infected with untreated GBS. To confirm that the observed effects were due to the recruitment and activation of plasminogen on GBS surface, the bacteria were first incubated with epsilon-aminocaproic acid (εACA), an inhibitor of plasminogen binding, and thereafter with plasmin(ogen). A significant decrease in the hBMECs injury that was correlated with a decrease of the GBS surface proteolytic activity was observed. Furthermore, plasmin(ogen)-treated GBS infected more efficiently the brain of neonatal mice than the untreated bacteria, indicating that plasmin(ogen) bound to GBS surface may facilitate the traversal of the blood-brain barrier. A higher survival rate was observed in offspring born from εACA-treated mothers, compared to untreated mice, and no brain infection was detected in these neonates. Our findings suggest that capture of the host plasmin(ogen) by the GBS surface promotes the crossing of the blood-brain barrier and contributes to the establishment of meningitis.
- Mutations in STAT3 and IL12RB1 impair the development of human IL-17 – producing T cellsPublication . Beaucoudrey, L.; Puel, A.; Filipe-Santos, O.; Cobat, A.; Ghandil, P.; Chrabieh, M.; Feinberg, J.; Bernuth, H.; Samarina, A.; Jannière, L.; Fieschi, C.; Stéphan, J.; Boileau, C.; Lyonnet, S.; Jondeau, G.; Cormier-Daire, V.; Merrer, M.; Hoarau, C.; Lebranchu, Y.; Lortholary, O.; Chandesris, M.; Tron, F.; Gambineri, E.; Bianchi, L.; Rodriguez-Gallego, C.; Zitnik, S.; Vasconcelos, J.; Guedes, M.; Vitor, A.; Marodi, L.; Chapel, H.; Reid, B.; Roifman, C.; Nadal, D.; Reichenbach, J.; Caragol, I.; Garty, B.; Dogu, F.; Camcioglu, Y.; Gülle, S.; Sanal, O.; Fischer, A.; Abel, L.; Stockinger, B.; Picard, C.; Casanova, J.Abstract The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.
- Low frequency of CD4+CD25+ Treg in SLE patients: a heritable trait associated with CTLA4 and TGFbeta gene variants.Publication . Barreto, M.; Ferreira, R.; Lourenço, L.; Moraes-Fontes, M.; Santos, E.; Alves, M.; Carvalho, C.; Martins, B.; Andreia, R.; Viana, J.; Vasconcelos, C.; Mota-Vieira, L.; Ferreira, C.; Demengeot, J.; Vicente, A.Abstract BACKGROUND: CD4+CD25+ regulatory T cells play an essential role in maintaining immune homeostasis and preventing autoimmunity. Therefore, defects in Treg development, maintenance or function have been associated with several human autoimmune diseases including Systemic Lupus Erythematosus (SLE), a systemic autoimmune disease characterized by loss of tolerance to nuclear components and significantly more frequent in females. RESULTS: To investigate the involvement of Treg in SLE pathogenesis, we determined the frequency of CD4+CD25+CD45RO+ T cells, which encompass the majority of Treg activity, in the PBMC of 148 SLE patients (76 patients were part of 54 families), 166 relatives and 117 controls. SLE patients and their relatives were recruited in several Portuguese hospitals and through the Portuguese Lupus Association. Control individuals were blood donors recruited from several regional blood donor centers. Treg frequency was significantly lower in SLE patients than healthy controls (z = -6.161, P < 0.00001) and intermediate in the relatives' group. Remarkably, this T cell subset was also lower in females, most strikingly in the control population (z = 4.121, P < 0.001). We further ascertained that the decreased frequency of Treg in SLE patients resulted from the specific reduction of bona fide FOXP3+CD4+CD25+ Treg. Treg frequency was negatively correlated with SLE activity index (SLEDAI) and titers of serum anti-dsDNA antibodies. Both Treg frequency and disease activity were modulated by IVIg treatment in a documented SLE case. The segregation of Treg frequency within the SLE families was indicative of a genetic trait. Candidate gene analysis revealed that specific variants of CTLA4 and TGFbeta were associated with the decreased frequency of Treg in PBMC, while FOXP3 gene variants were associated with affection status, but not with Treg frequency. CONCLUSION: SLE patients have impaired Treg production or maintenance, a trait strongly associated with SLE disease activity and autoantibody titers, and possibly resulting from the inability to convert FOXP3+CD25- into FOXP3+CD25+ T cells. Treg frequency is highly heritable within SLE families, with specific variants of the CTLA4 and TGFbeta genes contributing to this trait, while FOXP3 contributes to SLE through mechanisms not involving a modulation of Treg frequency. These findings establish that the genetic components in SLE pathogenesis include genes related to Treg generation or maintenance.
- The family physician and the human immunodeficiency virus seropositive patientPublication . MARCOS, T.; BARBOSA, A.; ALMEIDA, I.; BARBOSA, P.; VASCONCELOS, C.Acta Med Port. 2000 Jul-Aug;13(4):173-9. [The family physician and the human immunodeficiency virus seropositive patient]. [Article in Portuguese] Marcos T, Barbosa A, Almeida I, Barbosa P, Vasconcelos C. SourceCentro de Saúde da Batalha, Porto. Abstract OBJECTIVES: To characterize a subject who is HIV positive and closely observed in the consultation of clinical immunology (Santo António General Hospital), from a demographic and socio-economic point of view; to determine the percentage of these subjects who have a family doctor; how often they go to a family doctor; the reasons for a more frequent visit to the doctor; if there has been any alteration in the reasons for consulting the family doctor after establishing the diagnosis of HIV infection; who made the diagnosis of HIV infection; to evaluate, from these patient's point of view, if there has been any alteration in the family doctor's attitude or vice versa after the diagnosis. CHARACTERISATION OF THE STUDY: A descriptive, transversal study was carried out from 30/01/97 to 13/03/1997. METHOD: A questionnaire with twenty-two questions was used in a personal interview of a random sample of 100 patients observed in the Consultation of Clinical Immunology at Santo António General Hospital and represented 40% of the population studied. RESULTS: One hundred patients answered the questionnaire, 73 were male and 27 female, with an mean age of 34.73 years. The majority were single, representing 44% of the random sample, 33% had completed primary education (or equivalent), and 28% had attended secondary school (complete or incomplete), 35% of the subjects were employed and 34% unemployed. In what concerns area of residence, the majority live in the metropolitan area of Oporto. The majority of the patients (85%) had a family doctor. Nevertheless, 1/3 had never paid a visit to their doctor and, as for the others, the majority rarely did. After the diagnosis of HIV infection, the reasons that led patients to see their doctors were merely administrative (prescriptions--24.56%, sick leave--21.05%). On the other hand, before the diagnosis, health problems were their major concern and priority (27.54%). The diagnosis was made in equal proportion (28%) by the hospital services and by institutions providing health care for drug addicts. In most cases, from the patient's point of view, there had not been any change in the family doctor's attitude after the diagnosis of HIV infection and vice versa. COMMENTS: Although the majority of the subjects have a family doctor, their demand is very low, therefore, there is a waste of opportunities in terms of primary, secondary and tertiary medical care.
- Prolidase deficiency with hyperimmunoglobulin E: a case reportPublication . LOPES, I.; MARQUES, L.; NEVES, E.; SILVA, A.; TAVEIRA, M.; PENA, R.; VILARINHO, L.; MARTINS, E.
- Immunosuppressive therapy in lupus nephritis: the Euro‐Lupus Nephritis Trial, a randomized trial of low‐dose versus high‐dose intravenous cyclophosphamide.Publication . Houssiau, F.A.; Vasconcelos, C.; D'Cruz, D.; Sebastiani, G.D.; Garrido Ed Ede, R.; Danieli, M.G.; Abramovicz, D.; Blockmans, D.; Mathieu, A.; Direskeneli, H.; Galeazzi, M.; Gül, A.; Levy, Y.; Petera, P.; Popovic, R.; Petrovic, R; Sinico, R.A.; Cattaneo, R.; Font, J.; Depresseux, G.; Cosyns, J.P.; Cervera, R.Arthritis Rheum. 2002 Aug;46(8):2121-31. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, Garrido Ed Ede R, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gül A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R. Cliniques Universitaires St. Luc, Université Catholique de Louvain, Brussels, Belgium. houssiau@ruma.ucl.ac.be Comment in: Arthritis Rheum. 2003 May;48(5):1466; author reply 1466-7. Abstract OBJECTIVE: Glomerulonephritis is a severe manifestation of systemic lupus erythematosus (SLE) that is usually treated with an extended course of intravenous (IV) cyclophosphamide (CYC). Given the side effects of this regimen, we evaluated the efficacy and the toxicity of a course of low-dose IV CYC prescribed as a remission-inducing treatment, followed by azathioprine (AZA) as a remission-maintaining treatment. METHODS: In this multicenter, prospective clinical trial (the Euro-Lupus Nephritis Trial [ELNT]), we randomly assigned 90 SLE patients with proliferative glomerulonephritis to a high-dose IV CYC regimen (6 monthly pulses and 2 quarterly pulses; doses increased according to the white blood cell count nadir) or a low-dose IV CYC regimen (6 fortnightly pulses at a fixed dose of 500 mg), each of which was followed by AZA. Intent-to-treat analyses were performed. RESULTS: Followup continued for a median of 41.3 months in the low-dose group and 41 months in the high-dose group. Sixteen percent of those in the low-dose group and 20% of those in the high-dose group experienced treatment failure (not statistically significant by Kaplan-Meier analysis). Levels of serum creatinine, albumin, C3, 24-hour urinary protein, and the disease activity scores significantly improved in both groups during the first year of followup. Renal remission was achieved in 71% of the low-dose group and 54% of the high-dose group (not statistically significant). Renal flares were noted in 27% of the low-dose group and 29% of the high-dose group. Although episodes of severe infection were more than twice as frequent in the high-dose group, the difference was not statistically significant. CONCLUSION: The data from the ELNT indicate that in European SLE patients with proliferative lupus nephritis, a remission-inducing regimen of low-dose IV CYC (cumulative dose 3 gm) followed by AZA achieves clinical results comparable to those obtained with a high-dose regimen. PMID: 12209517 [PubMed - indexed for MEDLINE]
- Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial.Publication . Houssiau, F.A.; Vasconcelos, C.; D'Cruz, D.; Sebastiani, G.D.; de Ramon Garrido, E.; Danieli, M.G.; Abramovicz, D.; Blockmans, D.; Mathieu, A.; Direskeneli, H.; Galeazzi, M.; Gül, A.; Levy, Y.; Petera, P.; Popovic, R.; Petrovic, R.; Sinico, R.A.; Cattaneo, R.; Font, J.; Depresseux, G.; Cosyns, J.P.; Cervera, R.Arthritis Rheum. 2004 Dec;50(12):3934-40. Early response to immunosuppressive therapy predicts good renal outcome in lupus nephritis: lessons from long-term followup of patients in the Euro-Lupus Nephritis Trial. Houssiau FA, Vasconcelos C, D'Cruz D, Sebastiani GD, de Ramon Garrido E, Danieli MG, Abramovicz D, Blockmans D, Mathieu A, Direskeneli H, Galeazzi M, Gül A, Levy Y, Petera P, Popovic R, Petrovic R, Sinico RA, Cattaneo R, Font J, Depresseux G, Cosyns JP, Cervera R. Université Catholique de Louvain, Brussels, Belgium. houssiau@ruma.ucl.ac.be Abstract OBJECTIVE: In the Euro-Lupus Nephritis Trial (ELNT), 90 patients with lupus nephritis were randomly assigned to a high-dose intravenous cyclophosphamide (IV CYC) regimen (6 monthly pulses and 2 quarterly pulses with escalating doses) or a low-dose IV CYC regimen (6 pulses of 500 mg given at intervals of 2 weeks), each of which was followed by azathioprine (AZA). After a median followup of 41 months, a difference in efficacy between the 2 regimens was not observed. The present analysis was undertaken to extend the followup and to identify prognostic factors. METHODS: Renal function was prospectively assessed quarterly in all 90 patients except 5 who were lost to followup. Survival curves were derived using the Kaplan-Meier method. RESULTS: After a median followup of 73 months, there was no significant difference in the cumulative probability of end-stage renal disease or doubling of the serum creatinine level in patients who received the low-dose IV CYC regimen versus those who received the high-dose regimen. At long-term followup, 18 patients (8 receiving low-dose and 10 receiving high-dose treatment) had developed permanent renal impairment and were classified as having poor long-term renal outcome. We demonstrated by multivariate analysis that early response to therapy at 6 months (defined as a decrease in serum creatinine level and proteinuria <1 g/24 hours) was the best predictor of good long-term renal outcome. CONCLUSION: Long-term followup of patients from the ELNT confirms that, in lupus nephritis, a remission-inducing regimen of low-dose IV CYC followed by AZA achieves clinical results comparable with those obtained with a high-dose regimen. Early response to therapy is predictive of good long-term renal outcome. PMID: 15593207 [PubMed - indexed for MEDLINE]