RESUMEN
Autoimmune lymphoproliferative syndrome (ALPS) is a prototypic disorder of impaired apoptosis characterized by autoimmune features and lymphoproliferation. Heterozygous germline or somatic FAS mutations associated with preserved protein expression have been described. Very rare cases of homozygous germline FAS mutations causing severe autosomal recessive form of ALPS with a complete defect of Fas expression have been reported. We report two unrelated patients from highly inbred North African population showing a severe ALPS phenotype and an undetectable Fas surface expression. Two novel homozygous mutations have been identified underlying rare splicing defects mechanisms. The first mutation breaks a branch point sequence and the second alters a regulatory exonic splicing site. These splicing defects induce the skipping of exon 6 encoding the transmembrane domain of CD95. Our findings highlight the requirement of tight regulation of FAS exon 6 splicing for balanced alternative splicing and illustrate the importance of such studies in highly consanguineous populations.
Asunto(s)
Empalme Alternativo/genética , Síndrome Linfoproliferativo Autoinmune/genética , Receptor fas/genética , Síndrome Linfoproliferativo Autoinmune/sangre , Western Blotting , Consanguinidad , Proteína Ligando Fas/sangre , Mutación de Línea Germinal , Humanos , Lactante , Interleucina-10/sangre , Libia , Masculino , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Túnez , Receptor fas/sangreRESUMEN
Multiple myeloma (MM) is a still incurable adult's severe hematologic malignancy. It is characterized by deregulation of several cytokines and their receptors. Among these cytokines, Insulin growth factor 1 (IGF1) and its receptor (IGF1-R) are well documented as major factor of malignant plasma cells growth and survival in multiple myeloma. The objective of this study was to analyze the expression of IGF1-R in multiple myeloma at diagnosis in correlation with clinical and biological data. IGF1-R gene plasma cells expression was studied in 47 patients and 17 controls by Taqman technology RT-PCR. IGF1-R gene was down expressed in the malignant plasma cells of MM patients at diagnosis compared to normal plasma cells, isolated from healthy donors (p = 0.01). Expression decrease was accentuated in the disease advanced stage IIIB. A negative correlation was found between IGF1-R malignant plasma cells expression and the percentage of bone marrow invasion (p = 0.03). Bone marrow infiltration greater than 30% was significantly associated with a low level of IGF1-R gene expression (p = 0.04). Our results suggest that the decreased expression of IGF1-R by malignant plasma cells is a prognostic factor associated with severe disease. Understanding of mechanisms involved in IGF1-R expression negative regulation may contribute to the discovery of new targets therapy in myeloma. the discovery of new targets therapy in myeloma.
Asunto(s)
Mieloma Múltiple/diagnóstico , Mieloma Múltiple/genética , Receptor IGF Tipo 1/genética , Transcriptoma , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
Auto-reactive cytotoxic T lymphocytes play a key role in the progressive loss or destruction of melanocytes in vitiligo but the mechanism underlying the loss of self-tolerance is unknown. A deregulation of regulatory T-cell biology has recently been suggested. The analysis of the suppressive effects of peripheral T regulatory cells in vitiligo patients revealed a functional defect in seven of 15 cases. This defect was strongly correlated with disease activity. The evaluation of the percentage of peripheral regulatory T lymphocytes did not reveal any intrinsic quantitative defect. Yet, a decrease in the percentage of such cells was noted in patients with progressive forms, suggesting a recruitment of regulatory T cells from the peripheral blood to the site of injury. This was further corroborated by the significant increase of Forkhead box P3 expression in the vitiliginous skin of patients. Our data support the involvement of a functional defect of peripheral regulatory T cells in the pathogenesis of vitiligo and open new possibilities to advance therapeutic approaches.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Autotolerancia/inmunología , Linfocitos T Reguladores/inmunología , Vitíligo/inmunología , Adolescente , Adulto , Anciano , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/fisiopatología , Complejo CD3/análisis , Linfocitos T CD4-Positivos/inmunología , División Celular , Progresión de la Enfermedad , Femenino , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Humanos , Subunidad alfa del Receptor de Interleucina-2/análisis , Masculino , Melanocitos/inmunología , Persona de Mediana Edad , Modelos Inmunológicos , ARN Mensajero/biosíntesis , Linfocitos T Citotóxicos/inmunología , Vitíligo/genética , Vitíligo/fisiopatología , Adulto JovenRESUMEN
We report a patient with Sjögren's syndrome who presented with urticarial hypocomplementemic vasculitis. A 46-year-old female was admitted for assessment of ascitis. Clinical examination and computed tomographic scan disclosed evidence of multiple peripheral and intra abdominal lymph nodes. During her admission, she developed several bouts of acute angioedema and urticarial skin lesions. Minor salivary gland biopsy showed focal sialadenitis, stage IV of Chisholm. Schirmer's test was positive. Laboratory examination found low levels of C1q and high levels of C1q antibodies. Therapy with prednisone and hydroxychloroquine was initiated. Six months later, the patient presented with lower limb oedema. Urinalysis showed proteinuria (1g/day) and renal biopsy revealed membranous nephropathy with favorable outcome with corticosteroids.
Asunto(s)
Síndrome de Sjögren/complicaciones , Urticaria/etiología , Vasculitis/etiología , Proteínas del Sistema Complemento/análisis , Femenino , Humanos , Persona de Mediana Edad , Síndrome de Sjögren/sangre , Urticaria/sangre , Vasculitis/sangreRESUMEN
INTRODUCTION: Peripartum cardiomyopathy (PPCM) is a rare and life-threatening disease of unknown aetiology. The primary objective of this review was to analysed aetiopathogeneses, clinical presentation and diagnosis, as well as pharmacological, perioperative and intensive care management and prognosis of this pathology. METHODS: We undertook a systematic review of the literature using Medline, Google Scholar and PubMed searches. RESULTS: Unlike other parts of the world in which cardiomyopathy are rare, dilated cardiomyopathy is a major cause of heart failure throughout Africa. Its aetiopathogenesis is still poorly understood, but recent evidence supports inflammation, viral infection and autoimmunity as the leading causative hypotheses. This diagnosis should be limited to previously healthy women who present with congestive heart failure (CHF) and decreased left ventricular systolic function in the last month of pregnancy or within 5 months after delivery. Recently, introduction of echocardiography has made diagnosis of PPCM easier and more accurate. Conventional treatment consists of diuretics, vasodilators, and sometimes digoxin and anticoagulants, usually in combination. Patients who fail to recover may require inotropic therapy. In resistant cases, newer therapeutic modalities such as immunomodulation, immunoglobulin and immunosuppression may be considered. Prognosis is highly related to reversal of ventricular dysfunction. Compared to historically higher mortality rates, recent reports describe better outcome, probably because of advances in medical care. Based on current information, future pregnancy is usually not recommended in patients who fail to recover normal heart function. CONCLUSION: PPCM is a rare but serious form of cardiac failure affecting women in the last months of pregnancy or early puerperium. Its aetiopathogenesis is still poorly understood. Introduction of echocardiography has made diagnosis of PPCM easier and more accurate. Prognosis is highly related to reversal of ventricular dysfunction.
Asunto(s)
Cardiomiopatías/epidemiología , Cardiomiopatías/terapia , Parto Obstétrico , Complicaciones Cardiovasculares del Embarazo/epidemiología , Complicaciones Cardiovasculares del Embarazo/terapia , Adulto , Factores de Edad , Cardiomiopatías/tratamiento farmacológico , Cardiomiopatía Dilatada/complicaciones , Cardiomiopatía Dilatada/epidemiología , Cardiomiopatía Dilatada/terapia , Cuidados Críticos , Etnicidad , Femenino , Humanos , Recién Nacido , Embarazo , Complicaciones Cardiovasculares del Embarazo/diagnóstico , Pronóstico , Recurrencia , Resultado del Tratamiento , Túnez/epidemiología , Adulto JovenRESUMEN
OBJECTIVE: The aim of this study was to investigate mucosal expression of INF-gamma and IL-10 in patients with Crohn's disease (CD) or ulcerative colitis (UC). METHODS: Fourteen patients with CD and 11 patients with ulcerative colitis participated and 7 healthy subjects were also included. Study of the mucosal expression of INF-gamma and IL-10 was conducted using biopsies from healthy and damaged colons, using the inverse transcription and genetic amplification (RT-PCR) technique in real time (Taqman). Our results were expressed as ratio between messenger cytokine (mRNA) levels and ribosomal RNA level of a reference molecule (rRNA 18S), then multiplied by 108. RESULTS: In the cases of Crohn's disease, the mucosa expressed increased INF-gamma and IL-10 compared with controls (respective medians: 23.03 vs. 1.87 p=0.04 and 20.61 vs. 2.13 p=0.08). A strong positive correlation was found in the mucosal expression of IL-10 and INF-gamma during CD (r=0.9 p<0.0001). In contrast, in patients with UC, the expression of INF-gamma and IL-10 were comparable to those observed in the controls (7.18 vs. 2.18 p=0.36 and 3.66 vs. 1.87 p=0.44). CONCLUSION: During Crohn's disease, the expression of both IL-10 and INF-gamma was increased and strongly correlated, compared with the controls.
Asunto(s)
Colitis Ulcerosa/patología , Colon/química , Enfermedad de Crohn/patología , Expresión Génica/genética , Interferón gamma/genética , Interleucina-10/genética , Mucosa Intestinal/química , Adolescente , Adulto , Biopsia , Estudios de Casos y Controles , Niño , Colitis Ulcerosa/inmunología , Colon/inmunología , Colonoscopía , Enfermedad de Crohn/inmunología , Regulación hacia Abajo/genética , Regulación hacia Abajo/inmunología , Femenino , Expresión Génica/inmunología , Perfilación de la Expresión Génica , Humanos , Inmunidad Mucosa/genética , Inmunidad Mucosa/inmunología , Interferón gamma/análisis , Interferón gamma/inmunología , Interleucina-10/análisis , Interleucina-10/inmunología , Mucosa Intestinal/inmunología , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Ribosómico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Transcripción Genética/genética , Transcripción Genética/inmunologíaRESUMEN
OBJECTIVE: To investigate a possible pathogenic role of cytokines in Behçet's disease (BD) by focusing on the analysis of cytokine gene expression within mucocutaneous BD lesions. METHODS: The study group comprised 20 patients with active BD. In this group, a set of chemokines as well as Th1 and Th2 cytokines in biopsy specimens obtained from oral and genital ulcers, pseudofolliculitis lesions, and lesions at the site of pathergy testing were studied using real-time quantitative reverse transcriptase-polymerase chain reaction. RESULTS: We observed important increases in the expression of interleukin-8 (IL-8) ( approximately 700-fold), monocyte chemoattractant protein 1 ( approximately 65-fold), interferon-gamma ( approximately 71-fold), and IL-12 ( approximately 69-fold) messenger RNA in BD lesions compared with normal skin. Except for IL-10 ( approximately 75-fold increase), Th2 cytokines (i.e., IL-4 and IL-13) were absent. CONCLUSION: Our data suggest a direct role of Th1 lymphocytes in the pathogenesis of mucocutaneous BD lesions.
Asunto(s)
Síndrome de Behçet/metabolismo , Quimiocinas/metabolismo , Citocinas/metabolismo , Enfermedades de los Genitales Femeninos/etiología , Enfermedades de los Genitales Masculinos/etiología , Úlceras Bucales/etiología , Úlcera/etiología , Adulto , Síndrome de Behçet/complicaciones , Citocinas/genética , Femenino , Enfermedades de los Genitales Femeninos/metabolismo , Enfermedades de los Genitales Masculinos/metabolismo , Humanos , Masculino , Úlceras Bucales/metabolismo , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Células TH1/metabolismo , Úlcera/metabolismoAsunto(s)
Síndrome de Behçet/fisiopatología , Enfermedades del Sistema Nervioso Central/etiología , Adulto , Edad de Inicio , Enfermedades del Sistema Nervioso Central/epidemiología , Femenino , Antígenos HLA-B/sangre , Antígeno HLA-B51 , Humanos , Masculino , Selección de Paciente , Prevalencia , Factores de RiesgoAsunto(s)
Síndrome de Behçet/genética , Antígenos HLA-B/sangre , Antígenos de Histocompatibilidad Clase I/genética , Síndrome de Behçet/sangre , Síndrome de Behçet/inmunología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Antígeno HLA-B51 , Antígenos de Histocompatibilidad Clase I/química , Humanos , Masculino , Fenotipo , Valores de Referencia , TúnezAsunto(s)
Síndrome de Behçet/inmunología , Citocinas/sangre , Citocinas/genética , Inflamación/sangre , Enfermedades de la Piel/inmunología , Células TH1/inmunología , Síndrome de Behçet/genética , Regulación de la Expresión Génica/inmunología , Humanos , Inflamación/inmunología , Interleucinas/sangre , ARN Mensajero/genética , Enfermedades de la Piel/genéticaRESUMEN
PURPOSE: To describe epidemiological and clinical characteristics of neurological involvement in Behçet's disease (BD) and to determine a subgroup of patients at high risk for this complication. PATIENTS AND METHODS: The medical notes of 105 patients with BD fulfilling the criteria of the international Study Group for Behçet's disease were retrospectively reviewed. Patients were divided into two groups according to the presence (group 1) or not (group 2) of neurological and/or psychiatric involvement attributable to BD. The epidemiological, clinical and genetic (HLA B51 and MICA 6 frequency) features in the two groups were analysed and compared using the Kruskall-Wallis and the chi-square tests. RESULTS: Twenty-seven patients (25.7%) had clinical evidence of neurological involvement. They were 20 men and 7 women. The mean age at neurological onset was 34.26 +/- 8.79 years. Nineteen patients (70.3%) had meningoparenchymal "MP" central nervous system involvement (brainstem: 9, hemispheric involvement: 6, spinal cord: 4, psychiatric involvement: 2, isolated pyramidal signs: 1, aseptic meningitis: 1). Seven patients (25.9%) had cerebral large vessels involvement that is cerebral angio-Behçet "CAB" (intracranial hypertension: 5 cases due to cerebral venous thrombosis: 3 and pseudotumor cerebri: 2, cerebral haemorrhage: 1, cerebral arterial thrombosis: 1). One patient (3.7%) had both "MP" and "CAB" involvement. Headache was significantly more frequent in non-parenchymal patients. In group 1, complete recovery or improvement with mild neurological impairment was seen in 13 cases, improvement with severe disability in 3 cases, worsening in 1 case, the course was stationary in 1 case and 3 patients died (11.2%). Arterial aneurysms were significantly more frequent in "CAB" subgroups than in subgroup 2. CONCLUSION: Frequency of neurological involvements in BD was high in our study. Arterial aneurysms seem to be a risk factor to these complications. Cerebral angio-Behçet appears to be a protector factor against uveitis.
Asunto(s)
Síndrome de Behçet/complicaciones , Enfermedades del Sistema Nervioso Central/etiología , Adulto , Edad de Inicio , Aneurisma/etiología , Síndrome de Behçet/epidemiología , Enfermedades del Sistema Nervioso Central/patología , Femenino , Cefalea/etiología , Humanos , Incidencia , Masculino , Meningoencefalitis/etiología , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: We aimed to describe the epidemiological and clinical aspects of deep vein thrombosis (DVT) in Behçet's disease (BD) and to determine the patients at high risk for this complication. METHODS: Among 113 patients with BD according to the international criteria for classification of BD, those with DVT were retrospectively studied. The diagnosis of DVT was made in all cases using conventional venous angiography, venous ultrasonography and/or thoracic or abdominal computed tomography. Patients were divided in two subgroups according to the occurrence of DVT other than cerebral thromboses. The medical records of these patients were reviewed in order to investigate their past medical history and evaluate their response to the treatment prescribed. Clinical and genetic factors (HLA B51 and MICA 6) that might contribute to DVT were analysed by comparing patients with and without DVT. Results of our series were compared to those of other series in the literature. Statistical analysis was by Chi square with necessary correction and Fischer tests. RESULTS: Forty-four patients (38.9%) had deep vein thrombosis of various systems with 81 localisations. There were 40 men and four women (mean age 28.1 years; range 17-60). DVT appeared after the onset of disease with a mean delay of 3.8 years. In 6 cases, DVT revealed BD. When we evaluated the risk of DVT coexistence with other clinical findings and genetic factors (HLA B51 and MICA 6), we found a significant positive correlation with sex, and positive pathergy test. CONCLUSION: In our series, occurrence of DVT was significantly associated with male gender and positive pathergy test.