Acometimento vascular na doença de Behçet: o processo imunopatológico / Vascular involvement in Behçet's disease: the immunopathological process

Resumo A doença de Behçet constitui uma forma rara de vasculite sistêmica, que acomete de pequenos a grandes vasos. É caracterizada por manifestações mucocutâneas, pulmonares, cardiovasculares, gastrointestinais e neurológicas. Sua apresentação clínica é bastante ampla, variando de casos mais brandos a casos graves, com acometimento multissistêmico, caracteristicamente com exacerbações e remissões. Suas causas ainda são desconhecidas; entretanto, há evidências genéticas, ambientais e imunológicas, como a associação com o alelo HLA-B51. Todas essas, em conjunto, apontam para um processo imunopatológico anormal, com ativação de células da imunidade inata e adaptativa, como as células natural killer, neutrófilos e células T, que geram padrões de respostas e citocinas específicos capazes de gerar mediadores que podem lesionar e inflamar o sistema vascular, resultando em oclusões venosas, arteriais e/ou formação de aneurismas.

Abstract Behçet's disease is a rare form of systemic vasculitis that affects small to large vessels. It is characterized by mucocutaneous, pulmonary, cardiovascular, gastrointestinal, and neurological manifestations. Its clinical presentation is quite wide, ranging from milder cases to severe cases, with multisystemic involvement, characteristically with exacerbations and remissions. Its etiopathogenesis is still unclear, although there is evidence of genetic, environmental, and immunological factors, such as the association with the HLA-B51 allele. In conjunction, all of these point to an abnormal immunopathological process, with activation of cells of innate and adaptive immunity, such as NK cells, neutrophils, and T cells, which generate specific response patterns and cytokines capable of generating mediators that can damage and inflame blood vessels, resulting in venous and arterial occlusions and/or aneurysm formation.

Behçet's disease: review with emphasis on dermatological aspects

Abstract: Behçet's disease is a systemic vasculitis characterized by attacks of acute inflammation, which can affect almost every vascularized area of the body. There is a close correlation between the geographical distribution of HLA-B51 and its prevalence. In the etiopathogenesis there are indications of genetic susceptibility associated with environmental influence. Among the involved genes are those that encompass innate and adaptive immunities. Polymorphisms and epistatic interactions in several genes are described, as well as the presence of imbalance lineage between HLA-B51 and A (MICA). Herpes simplex and Streptococcus sanguinis may be important extrinsic factors. An increase of Th1 response and of IL-21 is observed. The production of IL-21 is positively related to Th17 cells and negatively to T-regs. The mucocutaneous manifestations are Behcet´s disease markers, and their earlier onset indicates a worse prognosis. Recurrent oral ulcers have varied sizes and arrangements, genital ulcers are recurrent, leaving scars, skin lesions are multivaried, and pathergy, although not so frequent, is important for the diagnosis. There are numerous attempts to validate indexes that can evaluate the disease activity and among them the Mucocutaneous Activity Index. This is a specific score that can help with therapeutic decisions and to reduce morbidity, but still lacks validation. The clinical manifestations of other organs are described as well as treatment options.

Angio-Behçet: a propósito de un caso clínico / Angio-Behçet: a case report

Se ha denominado Angio-Behçet, al conglomerado de fenómenos tromboembólicos en contexto de una Enfermedad de Behçet, que correspondería a una presentación atípica de esta patología. A veces se presenta como accidente vascular isquémico y trombosis venosa asociada a signos clásicos de Enfermedad de Behçet: Úlceras orales y genitales y uveítis. La patogénesis de esta enfermedad ha sido ampliamente estudiada en relación a posible origen genético, autoinmune o infeccioso. El tratamiento es difícil y frecuentemente tardío debido a que el diagnóstico es muy complejo y de gran reto para el clínico.

Angio-Behçet is called to the group of thromboembolic phenomena, associated to Behçet Disease and corresponds to an atypical manifestation of this disease. Sometimes it as an ischemic stroke with venous thrombosis associated to the classical signs of Behçet Disease: oral and genital ulcers and uveitis. The pathogenesis of this disease has been widely studied, with reference to a possible genetic, autoimmune or infectious origin. The treatment is difficult and is frequently late, because the diagnosis is very complex, being a great challenge for any clinician.

Doença de Behçet / Behçet's disease

A síndrome de Behçet é uma desordem multissistêmica inflamatória crônica caracterizada por uma vasculitede vasos de grande (artéria pulmonar), médio (artérias cerebrais, veias superficiais) e pequeno calibre. Possui distribuição geográfica heterogênea, não sendo rara nos países do Mediterrâneo e no Japão, contrapondo-se à ínfima prevalência no norte da Europa e nas Américas. Não tem predileção por sexo, sendo a idade médio de início em torno de 20 a 35 anos; não se conhece a taxa de incidência anual. A etiologia e a patogenia continuam obscuras. Contudo, estão envolvidos fenômenos imunológicos, demonstrados pela presença de anticorpos contra células endoteliais a e mucosa oral. Dentre os possíveis fatores etiológicos ambientais, cita-se o Streptococcus sanguis, HSV-1, proteína de choque térmico bacteriana de 65kd. Parece haver ainda um componente genético, pois em certas populações há marcante relação entre o HLA-B51 e a doença. Possui características histopatológicas de vasculite, sem especificidade, sendo diagnosticada clínicamente, de acordo com os critérios elaborados pelo Grupo Internacional de Estudos para Síndrome de Behçet. Cursa com manifestações mucocutâneas, com típicas exacerbações e recorrências, além de acometimento do SNC, TGI, musculoesquelético e, sobretudo, ocular. Sintomas inespecíficos, como cansaço, perda de peso e febre baixa, também estão presentes. Devem ser considerados no diagnóstico diferencial: doença de Crohn, Stevens-Johnson, Reiter, pênfigos, líquen plano, mielodisplasias e Aids. No que concerne ao tratamento observam-se dúvidas e desafios, seja pelo curso irregular, ora benigno, ora grave, seja pela polissintomatologia, que requer tratamentos distintos, ou pelo fato de que os muitos esquemas terapêuticos utilizados carecem de indicações precisas; pode-se lançar mão de corticoides tópicos e sistêmicos, imunossupressores, talidomida, metotrexato, colchicina, dentre outros.

Behçet’s disease is a chronic multissistemic inflammatory disorder, characterized by a vasculitides of large (pulmonary artery), medium (cerebral arteries, superficial veins) and small-calibre vases. It has a heterogeneous geographic distribution, not being occasional in Mediterranean countries and in Japan, which is the opposite of the undermost prevalence in North Europe and in the Americas. The illness doesn’t present a sex predilection, and the medium starting age is about 20 to 35 years old, the annual incidence rate is not known. The etiology and pathogeny are still obscure; however, immunologic phenomenons are involved, being demonstrated by the presence of antibodies against endothelial cells and oral mucosa; among the possible etiologic factors, can be mentioned the Streptococcus sanguis, HSV-1 and thermic shock bacterial protein of 65kd. The existence of a genetic component is probable, because there is a marking connection in some populations with HLA-B51 and the disease. Is owns histopathologic characteristics of vasculitides without specification, being clinical diagnose according to the criterions developed by International Studying Group for Behçet’s Disease. The syndrome course presents mucocutaneous manifestation, with typical exacerbations and recurrences, beyond central nervous system, gastrointestinal tract, musculoskeletal and above all, ocular compromising. Inespecific symptoms, as tiredness, weight loss and small fever are also present. Must be considered in the differential diagnose: Crohn disease, Stevens-Johnson, Reiter, pemphigus, plane lichen, mielodisplasias and Aids. Concerning the treatment, doubts and challenges are observed, considering the irregular course of the disease, sometimes benign, and sometimes grave; besides the multiple symptoms, which request distinct treatments, or for the fact that the multiple therapeutic schemes used lacks exact indications, being mostly based in personal self opinions and experiences...

Síndrome de Behçet: revisão da literatura / Behçet Syndrome: literature review

A síndrome de Behçet é uma desordem multissistêmica inflamatória crônica. É caracterizada por uma disfunção vascular imunológica que afeta principalmente pele, mucosas, SNC, olho e articulações. Possíveis fatores etiológicos ambientais estão envolvidos com o aumento do risco relativo de desenvolver esta doença em populações específicas, com alta freqüência de HLA-B51. A síndrome de Behçet afeta principalmente adultos jovens, e pacientes do sexo masculino têm um pior prognóstico. Possui características histopatológicas inespecíficas, sendo diagnosticada clinicamente, de acordo com os critérios elaborados pelo Grupo Internacional de Estudos para a Síndrome de Behçet. Este trabalho aborda fatores epidemiológicos, etiológicos, aspectos clínicos e tratamentos da doença.

Doença de Behçet: aspectos etiopatogênicos / Behçet's disease: etiopathogenic aspects

A doença de Behçet (DB) é uma vasculite sistêmica, recorrente e crônica com manifestações que incluem úlceras orogenitais, uveíte, sinovite, tromboflebite e sintomas envolvendo o SNC, trato gastrointestinal e pulmão. Embora a patogênese da DB não seja totalmente esclarecida, existem estudos apontando para possível participação de agentes infecciosos (virais e bacterianos), fatores genéticos e desregulação imunológica. Dentre os agentes infecciosos, alguns trabalhos sugerem o possível papel do Streptococcus sanguis (SS). Os pacientes com DB mostram aumento da frequência de ss na flora oral, comparada com controles, bem como de anticorpos séricos contra certos sorotipos de ss. No soro de alguns pacientes foi possível observar aumento de anticorpos específicos contra HSP-65 (Heat Shock Protein) de Mycobacterium tuberculosis, que são capazes de produzir reação cruzada com certos sorotipos de ss. Estudos recentes demonstraram que o HLA-B, até então estabelecido como associado à DB, poderia não ser o lócus primário responsável pela predisposição à doença, sendo sugerida a participação de outros genes localizados próximos ao lócus HLA-B, incluindo os genes MICA, PERB, e NOB. Em conclusão, uma proposta etiopatogênica é de que um antígeno particular, provavelmente de origem bacteriana, seja apresentado por macrófagos e reconhecido por células T CD4+ no contexto do MHC classe II. Linfócitos T ativados produziriam citocinas como IL-2, IFN-y, TNF-B e induziriam a proliferação e diferenciação de células B específicas. Macrófagos ativados por IFN-Y são capazes de liberar citocinas inflamatórias como TNF-alfa, IL-1, e IL-8. Fator de necrose tumoral (TNF) e IL-1 poderiam induzir a expressão de moléculas de adesão em células endoteliais, enquanto a IL-8 estaria envolvida na quimiotaxia e ativação de neutrófilos no sítio da reação inflamatória. Esses eventos seriam responsáveis pela passagem de polimorfonucleares neutrófilos e linfócitos T ativados através do endotélio na área inflamada

Doença de Behçet: relato de caso / Behçet's disease: a case report

A doença de Behçet é uma afecção multissistêmica com alterações mucocutâneas, oculares, urogenitais, vasculares, articulares e neurológicas. Os autores apresentam o caso de uma mulher de 33 anos, com história de turvação visual e úlceras orais e genitais recorrentes que requereu internação hospitalar pelo acometimento do estado geral. Após exame oftalmológico, fez-se o diagnóstico de doença de Behçet, iniciando-se tratamento com remissão completa das úlceras e melhora das alterações oculares e do estado geral. O objetivo do artigo é alertar para a importância do diagnóstico e tratamento precoces dessa doença para evitar sequelas como a cegueira.

Behcet's disease is recognized as a multisystemic disorder, featuring mucocutaneous, ocular, urogenital, vascular, articular and neurologic envolvement. The authors present the case of 33-years-old woman with visual blurring and recurrent oral and genital ulcers, requering admission due to general impairment. The diagnosis of Behçet's disease followed an ophtalmic examination, with treatment bringing about complete remission of the ulcers and improvement of both ocular involvement and general symptons. The purpose of this article is to warn for the importance of an early diagnosis and treatment to avoid sequelaes, as blindness.

Etiopathology of Behcet's disease: immunological aspects

Behcet's disease is recognized as a systemic inflammatory disease of unknown etiology. The disease has a chronic course with periodic exacerbations and progressive deterioration. Previous reports have shown at least three major pathophysiologic changes in Behcet's disease; excessive functions of neutrophils, vasculitis with endothelial injuries, and autoimmune responses. Many reports suggested that immunological abnormalities and neutrophil hyperfunction may be involved in the etiology and the pathophysiology of this disease. HLA-B51 molecules by themselves may be responsible, in part, for neutrophil hyperfunction in Behcet's disease. T cells in this disease proliferated vigorously in response to a specific peptide of human heat shock protein (hsp) 60 in an antigen-specific fashion. T cells reactive with self-peptides produced Th1-like proinflammatory and/or inflammatory cytokines. This leads to tissue injury, possibly via delayed-type hypersensitivity reaction, macrophage activation, and activation and/or recruitment of neutrophils. These data shed new light on the autoimmune nature of Behcet's disease; molecular mimicry mechanisms may induce and/or exacerbate Behcet's disease by bacterial antigens that have activated T cells which are reactive with self-peptide(s) of hsp. This would lead to positive selection of autoreactive T cells in this disease.

Etiopathology of Behcet's disease: herpes simplex virus infection and animal model

The etiology of Behcet's disease has been proposed as being a viral, bacterial, genetic and immunological disorder. After Hulusi Behcet's viral etiological hypothesis, many investigators have tried to confirm this. Scrapings and fluids from patients were applied to subculture in chorioallantoic membranes of fertilized eggs as well as in mice and rabbits by direct intracerebral injection. Since the 1980s, in situ hybridization, blotting, and polymerase chain reaction has also been applied to identify the herpes simplex virus DNA and RNA in patients. Animal models were developed based on environmental pollutants, bacterial and human heat shock protein derived peptides and virus injection. Using these animal models separately and/or concurrently, allows for a more effective investigation into Behcet's disease.

Streptococcal infection in the pathogenesis of Behcet's disease and clinical effects of minocycline on the disease symptoms

Although the precise pathoetiology of Behcet's disease (BD) remains obscure, patients with BD have a high incidence of chronic infectious foci, indicating an enhanced susceptibility to chronic tonsillitis, and dental caries. Sometimes, clinical symptoms appear after treatment of these foci in BD patients. It is believed that BD might be related to an allergic reaction to a bacterial infection in view of the many clinical symptoms, especially the presence of aphthous and genital ulcerations. An attempt to obtain cutaneous responses to bacterial antigens has been carried out using various vaccines developed from bacteria isolated from the ulcerative lesions and oral cavities of BD patients. BD patients often show intense hypersensitivity to various strains of streptococci, not only by their cutaneous reactions but also by in vitro testing. In this report, we describe our previous studies on the correlation between streptococcal antigens and the pathogenesis of BD and also discuss the recent reports of other authors. The intense hypersensitivity to streptococcal antigens acquired after streptococcal infection is thought to play an important role in the appearance of symptoms in BD patients since the production of pro-inflammatory cytokines by peripheral blood mononuclear cells (PBMC) was enhanced when stimulated with streptococcal antigen in a culture system. Minocycline, an antibiotic to which certain strains of streptococci are sensitive, reduced the frequency of clinical symptoms in BD patients as well as the production of pro-inflammatory cytokines by BD-PBMC stimulated with streptococcal antigen.

Doença de Behçet: revisäo baseada na 6a. Conferência Internacional - Paris, 1993 / Behçet's disease: review established on 6th International Conference - Pris, 1993

Breve revisäo sobre aspectos etiopatogênicos, epidemiológicos, dermatológicos, critérios de classificaçäo e terapêutica da doença de Behçet, abordados na 6a. Conferência Internacional da Doença de Behçet, em Paris, França, em 30 de junho e 01 de julho de 1993

Doença de Behçet: análise de seis casos / Behçet's disease: analysis of six cases

A doença de Behçet é uma afecçäo multissistêmica com alteraçöes mucocutâneas, oculares, intestinais, articulares, vasculares, urogenitais e neurológicas. Embora de evoluçäo clínica intermitente, a moléstia pode se estabilizar e cronificar. Os autores relatam seis casos, dando enfoque aos achados clínicos