Decoding Behcet's Uveitis: an In-depth review of pathogenesis and therapeutic advances.

Behcet's disease (BD) is a rare but globally distributed vasculitis that primarily affects populations in the Mediterranean and Asian regions. Behcet's uveitis (BU) is a common manifestation of BD, occurring in over two-thirds of the patients. BU is characterized by bilateral, chronic, recurrent, non-granulomatous uveitis in association with complications such as retinal ischemia and atrophy, optic atrophy, macular ischemia, macular edema, and further neovascular complications (vitreous hemorrhage, neovascular glaucoma). Although the etiology and pathogenesis of BU remain unclear, numerous studies reveal that genetic factors (such as HLA-B51), dysregulated immune responses of both the innate and adaptive immune systems, infections (such as streptococcus), and environmental factors (such as GDP) are all involved in its development. Innate immunity, including hyperactivity of neutrophils and γδT cells and elevated NK1/NK2 ratios, has been shown to play an essential role in this disease. Adaptive immune system disturbance, including homeostatic perturbations, Th1, Th17 overaction, and Treg cell dysfunction, is thought to be involved in BU pathogenesis. Treatment of BU requires a tailored approach based on the location, severity of inflammation, and systemic manifestations. The therapy aims to achieve rapid inflammation suppression, preservation of vision, and prevention of recurrence. Systemic corticosteroids combined with other immunosuppressive agents have been widely used to treat BU, and beneficial effects are observed in most patients. Recently, biologics have been shown to be effective in treating refractory BU cases. Novel therapeutic targets for treating BU include the LCK gene, Th17/Treg balance, JAK pathway inhibition, and cytokines such as IL-17 and RORγt. This article summarizes the recent studies on BU, especially in terms of pathogenesis, diagnostic criteria and classification, auxiliary examination, and treatment options. A better understanding of the significance of microbiome composition, genetic basis, and persistent immune mechanisms, as well as advancements in identifying new biomarkers and implementing objective quantitative detection of BU, may greatly contribute to improving the adequate management of BU patients.

Optimizing Behçet Uveitis Management: A Review of Personalized Immunosuppressive Strategies.

Behçet uveitis poses significant management challenges, owing to its intricate pathogenesis and the severe prognosis it harbors, frequently culminating in irreversible visual impairment and an elevated risk of blindness. This review synthesizes contemporary insights into personalized immunosuppressive strategies for Behçet uveitis, emphasizing the necessity for a customized approach in recognition of the disease's heterogeneity and the variable responsiveness to treatment. This discourse elaborates on the application, efficacy, and safety profiles of traditional immunosuppressants, highlighting a paradigm shift toward integrative combination therapies aimed at diminishing reliance on glucocorticoids and mitigating their associated adverse effects. This thorough evaluation seeks to enlighten clinical practices and spearhead future investigations aimed at refining the management of Behçet uveitis, championing a personalized, multidisciplinary strategy to amplify therapeutic efficacy and enhance patient quality of life.

4-Octyl Itaconate Inhibits Proinflammatory Cytokine Production in Behcet's Uveitis and Experimental Autoimmune Uveitis.

4-octyl itaconate (4-OI) is an anti-inflammatory metabolite that activates the nuclear-factor-E2-related factor 2 (NRF2) signaling. In the current work, we investigated whether 4-OI could affect the production of proinflammatory cytokines in Behcet's uveitis (BU) and experimental autoimmune uveitis (EAU). Peripheral blood mononuclear cells (PBMCs) of active BU patients and healthy individuals with in vitro 4-OI treatment were performed to assess the influence of 4-OI on the proinflammatory cytokine production. EAU was induced and used for investigating the influence of 4-OI on the proinflammatory cytokine production in vivo. The flow cytometry, qPCR, and ELISA were performed to detect proinflammatory cytokine expression. NRF2 signaling activation was evaluated by qPCR and western blotting (WB). Splenic lymphocyte transcriptome was performed by RNA sequencing. The NRF2 expression by BU patients-derived PBMCs was lower than that by healthy individuals. After treatment with 4-OI, the proportion of Th17 cells, along with the expression of proinflammatory cytokines (IL-17, TNF-α, MCP-1, and IL-6) by PBMCs, were downregulated, and anti-inflammatory cytokine (IL-10) expression was upregulated, although IFN-γ expression was unaffected. The EAU severity was ameliorated by 4-OI in association with a lower splenic Th1/Th17 cell proportion and increased nuclear NRF2 expression. Additionally, 4-OI downregulated a set of 248 genes, which were enriched in pathways of positive regulation of immune responses. The present study shows an inhibitory effect of 4-OI on the proinflammatory cytokine production in active BU patients and EAU mice, possibly mediated through activating NRF2 signaling. These findings suggest that 4-OI could act as a potential therapeutic drug for the treatment and prevention of BU in the future study.

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.

Meningoencefalitis de tronco como presentación de Behçet / Meningoencephalitis as a presentation form of Behçet

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Enfermedad de Behcet / Behcet's disease

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Subpopulations of Regulatory T Cells in Rheumatoid Arthritis, Systemic Lupus Erythematosus, and Behcet's Disease

Recently, subpopulations of regulatory T (Treg) cells, resting Treg (rTreg) and activated Treg (aTreg), have been discovered. The authors investigated the relationship between the change of Treg, aTreg and rTreg and autoimmune diseases. Treg cells and those subpopulations were analyzed by using the human regulatory T cell staining kit and CD45RA surface marker for 42 rheumatoid arthritis (RA), 13 systemic lupus sclerosis (SLE), 7 Behcet's disease (BD), and 22 healthy controls. The proportion of Treg cells was significantly lower in RA (3.8% +/- 1.0%) (P < 0.001) and BD (3.3% +/- 0.5%) (P < 0.01) compared to healthy controls (5.0% +/- 1.3%). The proportion of aTreg cells was also significantly lower in RA (0.4% +/- 0.2%) (P = 0.008) and BD (0.3% +/- 0.1%) (P = 0.013) compared to healthy controls (0.6% +/- 0.3%). The rTreg cells showed no significant differences. The ratio of aTreg to rTreg was lower in RA patients (0.4% +/- 0.2%) than that in healthy controls (0.7% +/- 0.4%) (P = 0.002). This study suggests that the decrement of aTreg not rTreg cells contributes the decrement of total Treg cells in peripheral blood of RA and BD autoimmune diseases. Detailed analysis of Treg subpopulations would be more informative than total Treg cells in investigating mechanism of autoimmune disease.

Serum Anti-Saccharomyces Cerevisiae Antibodies in Greek Patients with Behcet's Disease

We tested 59 Greek patients with Behcet's Disease (BD) for serum anti-Saccharomyces cerevisiae antibodies. No increase of these antibodies was detected in the cases compared to 55 healthy unrelated blood donors from the same population. This finding is in contrast with the correlation between Saccharomyces cerevisiae antibodies and BD as reported in other populations. It seems that environmental factors may contribute to disease expression in different populations, producing different effects according to the individual's genetic predisposition. Saccharomyces cerevisiae antibodies do not seem to be of any significance in the Greek population.

Anti-endothelial cell antibodies and central nervous system involvement in Behçet's disease

INTRODUCTION: Previous studies have detected the presence of anti-endothelial cell antibodies (AECA) in patients with Behçet's disease (BD). However, no real evidence exists whether these antibodies exert any influence on clinical presentation and/or activity of this disease. OBJECTIVES: To determine the frequency of AECA in patients with BD and analyze possible clinical associations. METHODS: 50 patients with BD who fulfilled diagnostic criteria were selected. Thirty-seven patients were females, and 13 were males; the mean age was 44 ± 9 years with a mean follow-up time of 10 ± 7.5 years. AECA were assayed by ELISA using ECV-304 cells as the antigenic substrate. The prevalence of AECA was determined, and their possible relationships with present and past clinical features were investigated. RESULTS: AECA were detected in the sera of 38 percent of the patients (IgG in 13, IgM in four, and IgG plus IgM in two). An association was observed between AECA and a previous history of central nervous system involvement (OR= 5.4, p= 0.03). This association was more evident for IgG-AECA (OR= 6.0, p= 0.02). A trend of an increased risk of aneurysms was also observed in patients with IgG-AECA (OR= 2.58, p= 0.77). None of the other clinical characteristics showed a relevant association with these antibodies. CONCLUSION: Our data suggest that IgG-AECA may be a marker of more severe lesions in patients with BD based on the higher frequency of previous central nervous system manifestations in patients who presently display circulating AECA.

INTRODUÇÃO: Estudos anteriores detectaram a presence de anticorpos anti-célula endotelial (AACE) em pacientes com doença de Behçet, porém não há nenhuma evidência se a presença destes anticorpos exerce alguma influência na apresentação clínica ou atividade da doença. OBJETIVOS: Determinar a freqüência de AACE em pacientes com doença de Behçet e analisar possíveis associações clínicas. MÉTODOS: Foram selecionados 50 pacientes que preencheram corretamente os critérios diagnósticos para a doença de Behçet. Trinta e sete pacientes eram do sexo feminino e 13 do sexo masculino, média de idade de 44 ± 9 anos e tempo médio de seguimento de 10 ± 7,5 anos. O AACE foram analisados por ELISA utilizando células ECV-304 como substrato antigênico. A prevalência de AACE foi determinada e foram investigadas possíveis relações com características clínicas atuais e pregressas. RESULTADOS: Os AACE foram detectados no soro de 38 por cento dos pacientes (13 na forma IgG, 4 IgM e 2 nas formas IgG e IgM). Observamos uma associação entre o AACE e história pregressa de envolvimento de sistema nervoso central (OR=5,4; p=0,03). Esta associação era mais evidente para o AACE na forma IgG (OR=6,0; p=0,02). Observamos também uma tendência de risco aumentado de aneurismas em pacientes com AACE na forma IgG (OR=2,58; p=0,77). Nenhuma outra característica clínica mostrou-se relevante com o anticorpo estudado. CONCLUSÃO: Nossos dados sugerem que o AACE na forma IgG pode ser uma marcador de lesão mais grave em pacientes com doença de Behçet baseado no fato de encontrarmos uma maior freqüência de história pregressa de manifestação de sistema nervoso central em pacientes com AACE circulante.

Enfermedad de Adamantiades-Behçet: un proceso enigmático con manifestaciones orales / Adamantiades-Behçet disease: an enigmatic process with oral manifestations

La enfermedad de Adamantiades-Behçet es una vasculitis multisistémica crónica, potencialmente capaz de afectar a cualquier órgano o sistema del cuerpo humano y en la que la aparición repetida de úlceras orales es una de sus principales expresiones clínicas. La EAB es una patología de carácter universal, con una prevalencia variable en función de la población estudiada y que muestra una curiosa distribución geográfica. A pesar de ser un proceso conocido desde la antigüedad, su etiopatogenia en la que probablemente se hayan implicados factores genéticos, microbiológicos e inmunológicos, continua siendo enigmática. Su amplio espectro de manifestaciones clínicas orales, genitales, cutáneas, oculares, neurológicas, vasculares y gastrointestinalesy su impredecible evolución con periodos de exacerbación y de remisión son dos de los aspectos más representativos de esta patología. El complejo tratamiento de la EAB requiere una estrecha cooperación multidisciplinar dado su carácter multisistémico. Gracias a ello y al desarrollo de nuevos agentes terapéuticos su pronóstico ha mejorado sensiblemente con respecto a décadas pasadas. En esta revisión analizamos los principales aspectos etiopatogénicos, clínicos y terapéuticos de esta enfermedad

Adamantiades-Behçet disease (ABD) is a chronic multisystemic vasculitis that is able to affect any human organ or system. Recurrent oral ulcers are a very important clinical sign. ABD is a worldwide pathology, which prevalence varies according to the population and geographic location. Although ABD has been known for ages, its aetiology remains an enigma. Genetic, immunological and microbiological factors have been associated. A wide spectrum of clinical manifestations (oral, genital, cutaneous, ocular, neurological, vascular and gastrointestinal) and an unpredictable evolution with repeated periods of exacerbationand remission are the most representative aspects of this pathology. The complex treatment of ABD requires a deep multidisciplinary cooperation; therefore, there is an extensive development of new therapeutic agents that have improved the prognosis of ABD. In this review were analysed the main etiological, clinical and therapeutic aspects of the disease

A Study of HLA Antigens in Behcet's Syndrome

Fifty-two Korean patients with Behcet's syndome were typed for HLA antigens. 52 apparently healthy Korean subjects were used as controls; 42 for HLA-A, B, C and all 52 for HLA-DR typing. HLA-B5 and DRw8 presented significantly high frequencies in all patiens. According to Shimizu's classification, HLA-B5 and DRw8 were significantly increased in the complete type; B5 in the incomplete type; DR3 in the suspected-possible type. According to Lehner's classification, HLA-DR3 was significantly increased in the neurological type; B5 in the ocular type; B5 in the ocular type. We confirmed the association of HLA-B5 with the severity of Beh et's syndrome. A relation might exist between DRw8, DR3 and Behcet's syndrome.

Absence of lupus anticoagulants in Behcet's disease

The presence of a lupus anticoagulant was evaluated in patients with Bechet's disease by the kaolin clotting time method. Four percents (three patients) of 69 patients analyzed were found positive for the lupus anticoagulant. However, no statistically significant association existed between the presence of this antibody and the presence of thrombosis, clinical activity, clinical type, antinuclear antibodies and the positive VDRL test.

Behcet's disease sera containing antiendothelial cell antibodies promote adhesion of T lymphocytes to cultured human dermal microvascular endothelial cells

Antiendothelial cell antibodies (AECA) have been detected in the sera of patients of autoimmune diseases showing vasculitis. Using IgM-ELISA, we found AECA in 42 (56%) of 75 sera samples from patients with Behcet's disease in a previous study. All of the 15 AECA-positive sera of Behcet's disease patients had an increased expression of the intercellular cell adhesion molecule-1 (ICAM-1), 93.3% of the sera induced the vascular cell adhesion molecule-1 (VCAM-1), and 100% of the serum induced the E-selectin molecule on human dermal microvascular endothelial cells (HDMEC). After stimulation of HDMEC with AECA-positive sera of Behcet's disease patients, the expression of ICAM-1 and VCAM-1 on HDMEC increased significantly at 4 hours, reaching a peak at 16 hours. Expression of E-selectin was induced at 1 hour after stimulation with a peak at 4 hours and it decreased thereafter. Adherence of T lymphocytes to HDMEC increased significantly after stimulation with AECA-positive sera from Behcet's disease patients. Also, the adherence of T lymphocytes to HDMEC increased at 4 hours and returned to its normal level at 48 hours. These results show that AECA-positive sera of Behcet's disease patients are capable of activating HDMEC to promote the adherence of T lymphocytes to increase the expression of ICAM-1, VCAM-1, and E-selectin on the cell surfaces. The whole process may play an important role in the pathogenesis of vasculitis in Behcet's disease.

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.

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.

Detecçäo de anticorpos e anticomponentes lipídicos (cardiolipina, gangliosídios e galactocerebrosídios) em pacientes com doença de Behçet / Detection of antibodies and lipid anticomponents (cardiolipin, gangliosides and galactosilceramidas) in patients with Behçet's disease

Os autores avaliam a presença de anticorpos antifraçöes lipídicas (cardiolipina, gangliosídios e galactocerebrosídios) em 13 pacientes com doença de Behcet. Anticorpos séricos anticardiolipina do isotipo IgG foram detectados em 30// dos casos, 50// do isotipo IgM. Em nenhum dos pacientes foi observada presença de isotipo IgA. Antigalactocerebrosídio foram detectados em apenas dois (15//) dos pacientes. Com relaçäo às manifestaçöes clínicas, observou-se que a presença de anticorpos anticardiolipina configura fator de risco para o desenvolvimento do acometimento neurológico

Sindrome de Bechet: a poposito de un nuevo caso

Se estudia un nuevo caso de Enfermedad de Behcet observado en Panamá. El paciente acudió por primera vez a la consulta externa el año de 1971 por úlcera aftosa, en mucosa bucal del labio inferior, que curó con esteroides local y sistémico en pequeñas dosis. Dos anos después presentó, por primera ocasión, conjuntivitis bilateral, que tambien mejoró con el mismo tratamiento. Quince años después presentó una úlcera genital urente, que producía mal olor. El cultivo de la secreción de la úlcera bucal reveló el crecimiento de Estreptococo alfa hemolítico; y la biopsia del labio demostró que tenía inflamación crónica y erosión inespecífica. Los exámenes de laboratório revelaron aumento de las inmunoglobulinas G y A, una relación OKT4/OKT8 invertida y ausencia del antígeno HLA-B5