RESUMEN

Behçet's Disease (BD) is an intricate medical puzzle, captivating researchers with its enigmatic pathogenesis. This complex ailment, distinguished by recurrent mouth and genital lesions, eye irritation, and skin injuries, presents a substantial obstacle to therapeutic research. This review explores the complex interaction of microRNAs (miRNAs) with BD, highlighting their crucial involvement in the disease's pathophysiology. miRNAs, recognized for regulatory influence in diverse biological processes, hold a pivotal position in the molecular mechanisms of autoimmune diseases, such as BD. The exploration begins with examining miRNA biogenic pathways and functions, establishing a foundational understanding of their regulatory mechanisms. Shifting to the molecular landscape governing BD, the review highlights miRNA-mediated impacts on critical signaling pathways like Notch, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and protein kinase B (AKT)/mammalian target of rapamycin (mTOR), offering insights into intricate pathophysiological mechanisms. Dissecting the immunological landscape reveals the profound influence of miRNAs on BD, shedding light on the intricate modulation of immune responses and offering novel perspectives on disease etiology and progression. Beyond molecular intricacies, the review explores the clinical relevance of miRNAs in BD, emphasizing their potential as diagnostic and prognostic indicators. The discussion extends to the promising realm of miRNA-based therapeutic interventions, highlighting their potential in alleviating symptoms and altering disease progression. This comprehensive review, serving as a valuable resource for researchers, clinicians, and stakeholders, aims to decipher the intricate molecular tapestry of BD and explore the therapeutic potential of miRNAs.

Asunto(s)

Síndrome de Behçet , MicroARNs , Síndrome de Behçet/terapia , Síndrome de Behçet/genética , Síndrome de Behçet/diagnóstico , Humanos , MicroARNs/genética , Transducción de Señal , Animales , Biomarcadores/metabolismo

RESUMEN

OBJECTIVES: This study aimed to investigate the association between circulating interleukin-6 (IL-6) levels and Behçet's disease (BD), and associations between polymorphisms in IL-6 gene and BD susceptibility. METHOD: A search of relevant articles was conducted in the Medline, Embase, and Web of Sciences databases. Subsequently, a meta-analysis was performed to assess circulating IL-6 levels in both the BD and control groups. Additionally, we investigated the association between the functional IL-6 promoter -174 G/C polymorphism and the risk of developing BD. RESULTS: Nineteen studies involving 923 patients with BD and 910 controls were included in this meta-analysis. The results demonstrated a significant elevation in circulating IL-6 levels in the BD group than in the control group (standardized mean difference [SMD] = 1.600, 95 % confidence interval [CI] = 0.732-2.496, P<0.001). Furthermore, IL-6 levels were significantly higher in the active disease group than in the inactive disease group (SMD=1.292, 95 % CI=0.059-2.525, P<0.001). Intriguingly, the meta-analysis revealed an association between BD and the IL-6 CC+CG genotype in Arabs (odds ratio [OR] = 0.588, 95 % CI=0.393-0.881, P=0.010), whereas no such association was observed in European or Asian populations. CONCLUSIONS: Our meta-analysis revealed significantly higher circulating IL-6 levels in patients with BD and found evidence of association between IL and 6 promoter -174 G/C and BD susceptibility.

Asunto(s)

Síndrome de Behçet , Predisposición Genética a la Enfermedad , Interleucina-6 , Síndrome de Behçet/genética , Síndrome de Behçet/sangre , Humanos , Interleucina-6/sangre , Interleucina-6/genética , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas/genética , Estudios de Asociación Genética

RESUMEN

The patient 1, a 13-year-old boy, was admitted due to "recurrent oral ulcers for 3 years, abdominal pain for 8 months, and perianal ulcers for 10 days"; The patient 2, a 3-year-old boy, was admitted due to "recurrent abdominal pain, diarrhea, and fever for over 3 months". Genetic testing of both patients revealed "deficiency in ELF4, X-linked" (DEX), and the patients were diagnosed with Behcet's disease-like syndrome due to deficiency in ELF4, accordingly. The patient 1 was successively given intravenous methylprednisolone pulses and oral prednisone and mesalazine for symptomatic treatment. The patient 2 was successively treated with corticosteroids combined with enteral nutrition, as well as oral mercaptopurine. Subsequently, both patients showed improvements in symptoms and were discharged.

Asunto(s)

Síndrome de Behçet , Humanos , Masculino , Síndrome de Behçet/genética , Síndrome de Behçet/complicaciones , Preescolar , Adolescente

RESUMEN

Behcet's disease (BD) is a multisystem disease with altered Toll-like receptors (TLRs) on macrophages. Long noncoding RNA Maternally expressed gene 3 (lncRNA MEG3) and lncRNA Musculoaponeurotic fibrosarcoma oncogene family, protein G antisense 1 (MAFG-AS1) are regulators of microRNA (miRNA) 147-b, which is induced upon TLR stimulation. We included fifty BD patients, and fifty age and sex-matched controls. Real-time polymerase chain reaction (PCR) was used to measure the expression levels of serum lncRNA MEG3, lncRNA MAFG-AS1, and miRNA 147-b. LncRNA MEG3 and lncRNA MAFG-AS1 were significantly downregulated while miRNA 147-b was significantly upregulated in the BD patients' serum compared to the controls with p-value <0.001. Receiver operation characteristics (ROC) curve analysis revealed that the three biomarkers can discriminate between BD and control subjects with 76%, 100%, and 70% sensitivity respectively, and 100% specificity for all of them. There was a lower expression level of lnc RNA MEG3 among patients who had new eye involvement in the last month in comparison to those without new eye involvement (p-value=0.017). So, LncRNA MEG3, lncRNA MAFG-AS1, and miRNA147-b are promising diagnostic markers and therapeutic targets for BD patients. LncRNA MEG3 can be used as a predictor for new BD ocular involvement.

Asunto(s)

Síndrome de Behçet , MicroARNs , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/sangre , Síndrome de Behçet/genética , Síndrome de Behçet/sangre , MicroARNs/genética , MicroARNs/sangre , Femenino , Masculino , Adulto , Persona de Mediana Edad , Biomarcadores/sangre , Estudios de Casos y Controles , Curva ROC

RESUMEN

Behçet's disease (BD) is a multifaceted autoimmune disorder affecting multiple organ systems. Vascular complications, such as venous thromboembolism (VTE), are highly prevalent, affecting around 50% of individuals diagnosed with BD. This study aimed to identify potential biomarkers for VTE in BD patients. Three microarray datasets (GSE209567, GSE48000, GSE19151) were retrieved for analysis. Differentially expressed genes (DEGs) associated with VTE in BD were identified using the Limma package and weighted gene co-expression network analysis (WGCNA). Subsequently, potential diagnostic genes were explored through protein-protein interaction (PPI) network analysis and machine learning algorithms. A receiver operating characteristic (ROC) curve and a nomogram were constructed to evaluate the diagnostic performance for VTE in BD patients. Furthermore, immune cell infiltration analyses and single-sample gene set enrichment analysis (ssGSEA) were performed to investigate potential underlying mechanisms. Finally, the efficacy of listed drugs was assessed based on the identified signature genes. The limma package and WGCNA identified 117 DEGs related to VTE in BD. A PPI network analysis then selected 23 candidate hub genes. Four DEGs (E2F1, GATA3, HDAC5, and MSH2) were identified by intersecting gene sets from three machine learning algorithms. ROC analysis and nomogram construction demonstrated high diagnostic accuracy for these four genes (AUC: 0.816, 95% CI: 0.723-0.909). Immune cell infiltration analysis revealed a positive correlation between dysregulated immune cells and the four hub genes. ssGSEA provided insights into potential mechanisms underlying VTE development and progression in BD patients. Additionally, therapeutic agent screening identified potential drugs targeting the four hub genes. This study employed a systematic approach to identify four potential hub genes (E2F1, GATA3, HDAC5, and MSH2) and construct a nomogram for VTE diagnosis in BD. Immune cell infiltration analysis revealed dysregulation, suggesting potential macrophage involvement in VTE development. ssGSEA provided insights into potential mechanisms underlying BD-induced VTE, and potential therapeutic agents were identified.

Asunto(s)

Síndrome de Behçet , Biomarcadores , Biología Computacional , Perfilación de la Expresión Génica , Mapas de Interacción de Proteínas , Humanos , Síndrome de Behçet/genética , Síndrome de Behçet/complicaciones , Síndrome de Behçet/diagnóstico , Biología Computacional/métodos , Mapas de Interacción de Proteínas/genética , Biomarcadores/sangre , Redes Reguladoras de Genes , Trombosis de la Vena/genética , Trombosis de la Vena/etiología , Trombosis de la Vena/diagnóstico , Tromboembolia Venosa/genética , Tromboembolia Venosa/etiología , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/sangre , Factor de Transcripción GATA3/genética , Curva ROC , Histona Desacetilasas/genética , Aprendizaje Automático

RESUMEN

Behçet's disease (BD) is a complex autoimmune disorder impacting several organ systems. Although the involvement of abdominal aortic aneurysm (AAA) in BD is rare, it can be associated with severe consequences. In the present study, we identified diagnostic biomarkers in patients with BD having AAA. Mendelian randomization (MR) analysis was initially used to explore the potential causal association between BD and AAA. The Limma package, WGCNA, PPI and machine learning algorithms were employed to identify potential diagnostic genes. A receiver operating characteristic curve (ROC) for the nomogram was constructed to ascertain the diagnostic value of AAA in patients with BD. Finally, immune cell infiltration analyses and single-sample gene set enrichment analysis (ssGSEA) were conducted. The MR analysis indicated a suggestive association between BD and the risk of AAA (odds ratio [OR]: 1.0384, 95% confidence interval [CI]: 1.0081-1.0696, p = 0.0126). Three hub genes (CD247, CD2 and CCR7) were identified using the integrated bioinformatics analyses, which were subsequently utilised to construct a nomogram (area under the curve [AUC]: 0.982, 95% CI: 0.944-1.000). Finally, the immune cell infiltration assay revealed that dysregulation immune cells were positively correlated with the three hub genes. Our MR analyses revealed a higher susceptibility of patients with BD to AAA. We used a systematic approach to identify three potential hub genes (CD247, CD2 and CCR7) and developed a nomogram to assist in the diagnosis of AAA among patients with BD. In addition, immune cell infiltration analysis indicated the dysregulation in immune cell proportions.

Asunto(s)

Aneurisma de la Aorta Abdominal , Síndrome de Behçet , Biomarcadores , Biología Computacional , Análisis de la Aleatorización Mendeliana , Humanos , Síndrome de Behçet/genética , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/complicaciones , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/diagnóstico , Biología Computacional/métodos , Curva ROC , Redes Reguladoras de Genes , Predisposición Genética a la Enfermedad , Mapas de Interacción de Proteínas/genética , Nomogramas , Receptores CCR7

RESUMEN

Inflammatory signals from immunological cells may cause damage to intestinal epithelial cells (IECs), resulting in intestinal inflammation and tissue impairment. Interferon-γ-inducible protein 16 (IFI16) was reported to be involved in the pathogenesis of Behçet's syndrome (BS). This study aimed to investigate how inflammatory cytokines released by immunological cells and IFI16 participate in the pathogenesis of intestinal BS. RNA sequencing and real-time quantitative PCR (qPCR) showed that the positive regulation of tumor necrosis factor-α (TNF-α) production in peripheral blood mononuclear cells (PBMCs) of intestinal BS patients may be related to the upregulation of polo like kinase 1 (PLK1) in PBMCs (P = 0.012). The plasma TNF-α protein level in intestinal BS was significantly higher than in healthy controls (HCs; P = 0.009). PBMCs of intestinal BS patients and HCs were co-cultured with human normal IECs (NCM460) to explore the interaction between immunological cells and IECs. Using IFI16 knockdown, PBMC-NCM460 co-culture, TNF-α neutralizing monoclonal antibody (mAb), stimulator of interferon genes (STING) agonist 2'3'-cGAMP, and the PLK1 inhibitor SBE 13 HCL, we found that PLK1 promotes the secretion of TNF-α from PBMCs of intestinal BS patients, which causes overexpression of IFI16 and induces apoptosis of IECs via the STING-TBK1 pathway. The expressions of IFI16, TNF-α, cleaved caspase 3, phosphorylated STING (pSTING) and phosphorylated tank binding kinase 1 (pTBK1) in the intestinal ulcer tissue of BS patients were significantly higher than that of HCs (all P < 0.05). PLK1 in PBMCs of intestinal BS patients increased TNF-α secretion, inducing IEC apoptosis via activation of the IFI16-STING-TBK1 pathway. PLK1 and the IFI16-STING-TBK1 pathway may be new therapeutic targets for intestinal BS.

Asunto(s)

Apoptosis , Síndrome de Behçet , Proteínas de Ciclo Celular , Proteínas de la Membrana , Fosfoproteínas , Quinasa Tipo Polo 1 , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Transducción de Señal , Humanos , Síndrome de Behçet/patología , Síndrome de Behçet/metabolismo , Síndrome de Behçet/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genética , Masculino , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Femenino , Adulto , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/patología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Factor de Necrosis Tumoral alfa/genética , Mucosa Intestinal/patología , Mucosa Intestinal/metabolismo , Persona de Mediana Edad

RESUMEN

The etiological complexity of Behçet disease (BD), an immune-mediated rare form of vasculitis characterized by multi-organ involvement, is still elusive due to an incomplete understanding of the synergy between genetic susceptibility, environmental triggers, and an abnormal immune response. The diagnosis of BD relies on clinical symptoms. Lung inflammatory disorders are severe conditions of patients with BD, here we focus on the expression of biomarkers in BD patients with pulmonary manifestations. Aiming to identify additional discriminating biomarker patterns, we measured and compared protein and gene expression of IL-38 and a broad panel of selected genes in bronchoalveolar cells of patients suffering from BD with and without pulmonary involvement compared to controls. ELISA and RT-PCR analysis were applied. The first principal analysis highlighted decreased IL-38 level in BD patients compared to Rheumatoid Arthritis (RA) patients and controls: BD patients expressed lower IL-38 levels, particularly in cases with pulmonary involvement. The area under the curve (AUC) of the receiver-operating characteristic curve showed that IL-38 may be an eventual biomarker for BD. Co-cultured recombinant IL-38 and stimulated memory PBMCs of active BD, were able to suppress IL-17 and NLRP3 inflammasome and ameliorate the secretion of IL-10 and TGFß. Transcription factors of the IL-1 family (IL-1ß, IL-18, IL-32, IL-33 and IL-37) along with IFN-γ, IL-17, RORγt, Foxp3, TGFß, IL-10 and NLRP3 inflammasome were the parameters that are the main contributor to the segregation between BD with and without lung involvement. Our results indicate that IL-38 might be involved in the pathogenesis of BD and the combined gene expression in BAL suggests distinct mechanisms governing the inflammatory disorders in the lung.

Asunto(s)

Síndrome de Behçet , Enfermedades Pulmonares , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Interleucina-17/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR , Interleucina-10/genética , Inflamasomas , Lavado Broncoalveolar , Biomarcadores , Factor de Crecimiento Transformador beta/genética , Expresión Génica , Interleucinas/genética

RESUMEN

OBJECTIVES: HLA molecules play a crucial role in transplantation. The best treatment modality in patients with end-stage renal disease is renal transplant. HLA mismatches between patients and donors can prolong time for renal transplant therapy, reduce graft survival, and increase mortality. HLA region is the most polymorphic genetic region and is essential for antigen presentation. The main target of the recipient's immune system is HLA molecules on the surface of donor cells. HLA-B*51 is associated with Behcet disease, a rare multisystemic disease characterized by autoimmunity and inflammatory processes. In transplant recipients, inflammation and vasculitis are immunologic mechanisms that are responsible for damage of graft tissue. In this retrospective study, we aimed to investigate the frequency of HLA-B*51 in patients diagnosed with end-stage renal disease and in controls and to investigate correlations with rejection episodes. MATERIALS AND METHODS: Patients who applied to Baskent University Adana Dr. Turgut Noyan Research and Medical Center (between 2010 and 2022) with end-stage renal disease (n = 1732) and a control group (n = 5277) received HLA typing for class I (HLA-A, HLA-B). Sequence-specific primers or sequencespecific oligonucleotides were used. Among patients diagnosed with end-stage renal disease, 321 had kidney transplant. RESULTS: Frequency of HLA-B*51 was 25.92% in patients and 25.22% in controls. No significant differences were found between patients and controls in the frequency of HLA-B*51. Among kidney transplant recipients with HLA-B*51 (n = 72), 38.89% had rejection episodes and 61.11% had no rejection. No significant association was found between HLA-B*51 allele positivity and rejection. CONCLUSIONS: No significant relationship was shown between patients diagnosed with end-stage renal disease and HLA-B*51 positivity. Previous studies support frequency of the HLA-B*51 allele in the control group. Although Behçet disease is known to cause renal vasculitis, HLA-B*51 positivity alone was not associated with vasculitis or inflammation.

Asunto(s)

Síndrome de Behçet , Antígeno HLA-B51 , Fallo Renal Crónico , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Rechazo de Injerto , Supervivencia de Injerto , Prueba de Histocompatibilidad , Inflamación , Fallo Renal Crónico/diagnóstico , Fallo Renal Crónico/genética , Fallo Renal Crónico/cirugía , Estudios Retrospectivos , Donantes de Tejidos , Antígeno HLA-B51/genética

RESUMEN

Defining monogenic drivers of autoinflammatory syndromes elucidates mechanisms of disease in patients with these inborn errors of immunity and can facilitate targeted therapeutic interventions. Here, we describe a cohort of patients with a Behçet's- and inflammatory bowel disease (IBD)-like disorder termed "deficiency in ELF4, X-linked" (DEX) affecting males with loss-of-function variants in the ELF4 transcription factor gene located on the X chromosome. An international cohort of fourteen DEX patients was assessed to identify unifying clinical manifestations and diagnostic criteria as well as collate findings informing therapeutic responses. DEX patients exhibit a heterogeneous clinical phenotype including weight loss, oral and gastrointestinal aphthous ulcers, fevers, skin inflammation, gastrointestinal symptoms, arthritis, arthralgia, and myalgia, with findings of increased inflammatory markers, anemia, neutrophilic leukocytosis, thrombocytosis, intermittently low natural killer and class-switched memory B cells, and increased inflammatory cytokines in the serum. Patients have been predominantly treated with anti-inflammatory agents, with the majority of DEX patients treated with biologics targeting TNFα.

Asunto(s)

Artritis , Síndrome de Behçet , Productos Biológicos , Enfermedades Inflamatorias del Intestino , Masculino , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Enfermedades Inflamatorias del Intestino/diagnóstico , Enfermedades Inflamatorias del Intestino/genética , Artralgia , Proteínas de Unión al ADN , Factores de Transcripción/genética

RESUMEN

PURPOSE: To explore the association of the polymorphisms in PTPN6 and LncRNA C1RL-AS1 genes with ocular BD in Han Chinese patients. METHODS: Correlation study was performed using the iPLEX system on a cohort of ocular BD patients andcontrols. The genotyping of 7 SNPs for LncRNA C1RL-AS1 and PTPN6 genes in ocular BD patients was performed using the iPLEX Gold genotype. RESULTS: The frequencies of rs4013722 AG genotype/A allele in LncRNA C1RL-AS1 were significantly decreased in BD patients, and the frequency of GG genotype was significantly increased in BD patients. The rs4013722 was associated with ocular BD in male patients, but not in female patients. The AG and GG genotype of rs4013722 were associated with skin lesions in male patients. The gene polymorphisms of PTPN6 were not associated with BD patients. CONCLUSIONS: The LncRNA C1RL-AS1/rs4013722 polymorphism conferred susceptibility to ocular BD in Han Chinese patients, which was influenced by sex.Abbreviations: LncRNA: Long Non-coding RNA; BD: Behcet's disease; SNP: single nucleotide polymorphism; PBMCs: peripheral blood mononuclear cells; PTPs: Protein tyrosine phosphatases; PTPN6: protein tyrosine phosphatase non-receptor 6; GWAS: genome-wide association study; HWE: Hardy-Weinberg equilibrium; LD: linkage disequilibrium; OR: odds ratio; CI: confidence interval; eQTL: expression quantitative trait loci; IBD: inflammatory bowel disease; RA: rheumatoid arthritis; Padj: Bonferroni corrected P value; NS: non-significant.

Asunto(s)

Síndrome de Behçet , ARN Largo no Codificante , Humanos , Masculino , Femenino , ARN Largo no Codificante/genética , Síndrome de Behçet/genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Leucocitos Mononucleares , Genotipo , Polimorfismo de Nucleótido Simple , China/epidemiología , Frecuencia de los Genes , Estudios de Casos y Controles , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , Serina Endopeptidasas/genética

RESUMEN

PURPOSE OF REVIEW: The purpose of this review was to comprehensively summarize recent phenotype research findings in Behçet's syndrome. RECENT FINDINGS: Cluster analysis has recently been employed as a phenotype research tool in Behçet's syndrome. Studies reported different clustering patterns caused by biological variation and some degree of artificial heterogeneity. However, some clusters were more consistent than others: 1) oral ulcers, genital ulcers, and skin lesions 2) oral ulcers, genital ulcers, skin lesions, and arthritis 3) oral ulcers, genital ulcers, skin lesions, and uveitis 4) oral ulcers, genital ulcers, skin lesions, and gastrointestinal involvement. A number of loci suggestive of differential risk for individual disease manifestations were proposed. Peripheral blood gene expression profile and plasma proteome exhibited significant differences in patients with different organ involvements and were able to differentiate between disease phenotypes. However, these observations require further validation and functional studies. SUMMARY: Clustering patterns in Behçet's syndrome is highly heterogeneous. Artificial heterogeneity might obscure the true biological variation of disease expression. Preliminary genetic, transcriptomic and proteomic data suggest that different pathogenetic mechanisms may operate in different phenotypes of Behçet's syndrome.

Asunto(s)

Síndrome de Behçet , Úlceras Bucales , Úlcera Cutánea , Uveítis , Humanos , Síndrome de Behçet/genética , Síndrome de Behçet/complicaciones , Úlceras Bucales/complicaciones , Proteómica , Uveítis/etiología , Úlcera Cutánea/complicaciones

RESUMEN

BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

Asunto(s)

Síndrome de Behçet , Periodontitis , Femenino , Humanos , Fibrinolisina , Síndrome de Behçet/complicaciones , Síndrome de Behçet/genética , Enfermedades Raras/complicaciones , Periodontitis/complicaciones , Periodontitis/genética , Plasminógeno/genética , Fibrina

RESUMEN

Behçet's syndrome is a recurring inflammatory multiorgan disorder affecting the skin, mucosa, eyes, joints, stomach, and central nervous system. Behçet's syndrome epidemiology varies greatly among populations (0.64-420/100,000), and Behçet's syndrome has gained increasing international acclaim in the recent 50 years due to raising awareness of the syndrome, although it is rare in most population. In addition to the unclear etiology of the syndrome, the diagnosis of Behçet's syndrome is complicated by a vague clinical presentation, phenotypic heterogeneity and/or incomplete representation, and the lack of any specific laboratory, radiographic, or histological findings. There exists a dire need to elucidate factors that contribute to disease pathogenesis and/or are associated with clinical features of Behçet's syndrome and the classification of different forms of the syndrome. The identification of such molecular, cellular, and/or clinical factors are crucial for timely diagnosis and efficacious management of Behçet's syndrome. We discuss recent advances in the clinical diagnosis of Behçet's syndrome and related contributions of genetics, epigenetics, microbiome, inflammasomes, and autoantibodies to the improved diagnosis, management, and understanding of Behçet's syndrome.

Asunto(s)

Síndrome de Behçet , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiología , Síndrome de Behçet/genética , Piel/patología

RESUMEN

Behect's disease is a chronic vasculitis characterized by complex multi-organ immune aberrations. However, a comprehensive understanding of the gene-regulatory profile of peripheral autoimmunity and the diverse immune responses across distinct cell types in Behcet's disease (BD) is still lacking. Here, we present a multi-omic single-cell study of 424,817 cells in BD patients and non-BD individuals. This study maps chromatin accessibility and gene expression in the same biological samples, unraveling vast cellular heterogeneity. We identify widespread cell-type-specific, disease-associated active and pro-inflammatory immunity in both transcript and epigenomic aspects. Notably, integrative multi-omic analysis reveals putative TF regulators that might contribute to chromatin accessibility and gene expression in BD. Moreover, we predicted gene-regulatory networks within nominated TF activators, including AP-1, NF-kB, and ETS transcript factor families, which may regulate cellular interaction and govern inflammation. Our study illustrates the epigenetic and transcriptional landscape in BD peripheral blood and expands understanding of potential epigenomic immunopathology in this disease.

Asunto(s)

Síndrome de Behçet , Vasculitis , Humanos , Síndrome de Behçet/genética , Transcriptoma , Cromatina/genética , Perfilación de la Expresión Génica

RESUMEN

The symptoms of Behçet's disease (BD), a multisystemic condition with autoimmune and inflammation as hallmarks, include arthritis, recurring oral and vaginal ulcers, skin rashes and lesions, and involvement of the nervous, gastrointestinal, and vascular systems. Non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), may be important regulators of inflammation and autoimmune disease. These ncRNAs are essential to the physiological and pathophysiological disease course, and miRNA in particular has received significant attention for its role and function in BD and its potential use as a diagnostic biomarker in recent years. Although promising as therapeutic targets, miRNAs must be studied further to fully comprehend how miRNAs in BD act biologically.

Asunto(s)

Enfermedades Autoinmunes , Síndrome de Behçet , MicroARNs , ARN Largo no Codificante , Femenino , Humanos , MicroARNs/genética , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Inflamación , ARN Largo no Codificante/genética

RESUMEN

Mitochondrial DNA (mtDNA) leakage into the cytoplasm can occur when cells are exposed to noxious stimuli. Specific sensors recognize cytoplasmic mtDNA to promote cytokine production. Cytoplasmic mtDNA can also be secreted extracellularly, leading to sterile inflammation. However, the mode of secretion of mtDNA out of cells upon noxious stimuli and its relevance to human disease remain unclear. Here, we show that pyroptotic cells secrete mtDNA encapsulated within exosomes. Activation of caspase-1 leads to mtDNA leakage from the mitochondria into the cytoplasm via gasdermin-D. Caspase-1 also induces intraluminal membrane vesicle formation, allowing for cellular mtDNA to be taken up and secreted as exosomes. Encapsulation of mtDNA within exosomes promotes a strong inflammatory response that is ameliorated upon exosome biosynthesis inhibition in vivo. We further show that monocytes derived from patients with Behçet's syndrome (BS), a chronic systemic inflammatory disorder, show enhanced caspase-1 activation, leading to exosome-mediated mtDNA secretion and similar inflammation pathology as seen in BS patients. Collectively, our findings support that mtDNA-containing exosomes promote inflammation, providing new insights into the propagation and exacerbation of inflammation in human inflammatory diseases.

Asunto(s)

Síndrome de Behçet , Exosomas , Humanos , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Síndrome de Behçet/genética , Síndrome de Behçet/metabolismo , Exosomas/genética , Mitocondrias/genética , Inflamación/metabolismo , Caspasas/metabolismo

RESUMEN

OBJECTIVE: To describe the demographic and clinical features, as well as the frequency of the HLA-B*51 allele in Behçet disease (BD) patients in Latin American countries. METHODS: A systematic literature review of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines was conducted without performing a meta-analysis. We included observational studies (cross-sectional or cohort) of BD patients fulfilling the International Study Group for BD classification criteria and reported the demographic, clinical, and laboratory features of the disease in adult patients. RESULTS: Twelve studies were included in the SLR. Information from 532 patients across 5 Latin American countries was included for the analysis. Mean age at disease diagnosis was 33 years, 58.3% were female and 41.7% male; most patients were non-Caucasian. The most common clinical manifestations were recurrent oral ulcers and genital ulcers, followed by skin, eye, joint, neurological, gastrointestinal, vascular, and cardiac involvement. The prevalence of BD was described in 2 studies, 1 conducted in Brazil that reported a prevalence of .3/100,000 inhabitants, and another in Colombia with a prevalence of 1.1/100,000 inhabitants. The frequency of HLA-B*51 allele in BD patients was 38%, 30.1%, and 9% in Argentina, Brazil, and Mexico, respectively. CONCLUSIONS: The prevalence of BD in the Latin American countries seems to be low, as well as the frequency of HLA-B*51 allele. However, the strength of association between HLA-B*51 and BD remains high in our population. The key clinical features of BD are like those reported in countries/regions where BD is endemic.

Asunto(s)

Síndrome de Behçet , Adulto , Humanos , Masculino , Femenino , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/epidemiología , Síndrome de Behçet/genética , Estudios Transversales , América Latina/epidemiología , Antígenos HLA-B/genética , Prevalencia

RESUMEN

This study aimed to investigate the roles of α9ß1 integrin and its ligands in Behçet's disease (BD) by examining serum levels and gene expressions. 15 healthy controls and 30 BD patients (14 active and 16 inactive) were included in the study. Serum levels of ITGA9, ITGB1, TNC, OPN, VCAM-1, VEGF, TSP1, TGM2, Emilin-1, and vWF, were measured by ELISA. Gene expressions of α9ß1 (ITGA9 and ITGB1) and its ligands (TNC and SPP1) were evaluated by RT-PCR. Laboratory findings (CRP, ESR, HGB, WBC, RBC, neutrophil, lymphocyte, PLT, RDW, MPV, PCT, and HLA-B51) were obtained from the electronic database. Active BD patients had higher serum levels of α9ß1 integrin and its ligands than inactive patients and healthy controls. No significant difference was observed between healthy controls and inactive patients. Gene expressions of ITGB1 and SPP1 were increased in both patient groups compared to healthy controls. ITGA9 and TNC gene expression levels were lower in the active group than in the inactive group. No noticeable differences were found in ITGB1 and SPP1 gene expressions between the patient groups. BD patients exhibited elevated CRP, ESR, WBC, neutrophil, PLT, and PCT levels, while HGB, RBC, and RDW values were lower than healthy controls. Active patients had higher CRP, ESR, WBC, neutrophil, and PLT levels. Significant positive correlations were found between CRP, ESR, WBC, neutrophil, PLT, PCT and serum levels of α9ß1 integrin and its ligands. Increased release of α9ß1 integrin and its ligands is associated with BD, suggesting their potential as markers for disease severity.

Asunto(s)

Síndrome de Behçet , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Biomarcadores , Estudios de Casos y Controles , Linfocitos , Integrinas

RESUMEN

OBJECTIVE: The aim of this study was to analyze HLA alleles in patients with Behçet disease (BD) and their correlation with ophthalmic manifestations (OMs) in a multiethnic Brazilian population. METHODS: This case-control study compared 72 BD patients with or without OM who underwent a thorough ophthalmologic evaluation, including best-corrected visual acuity, bino-ophthalmoscopy, and HLA analysis, with 144 matched healthy controls. Fluorescein angiography was also performed in the patients with BD and OM. HLA class I (A, B, and C) and II (DRB1, DQB1, and DQA1) typing were performed using PCR-SSO. RESULTS: Of 72 patients with BD, 42 (58%) had OM. The HLA-B*51 and -A*26 alleles were more frequent in patients with BD than in controls (23.6% vs 14.6% and 12.5% vs 4.3%, respectively), but could not differentiate OM risk. The HLA alleles of BD patients that differentiated those with and without OM were HLA-B*15 (40.5% vs 20.7%; odds ratio [OR], 2.59; p = 0.0059), HLA-C*02 (33.3% vs 13.4%; OR, 3.20; p = 0.0024), and HLA-DQB1*03 (64.3% vs 45.7%, p = 0.017), whereas HLA-A*03 (0.0% vs 13.3%, p = 0.006) and HLA-DRB1*15 (4.8% vs 19.5%; OR, 0.21; p = 0.0121) were protective against OM. CONCLUSIONS: In this study of a Brazilian multiethnic BD population, alleles were similar between groups of BD patients with and without OM. We described HLA-B*15, -C*02, and -DQB1*03 as risk factors and -A*03 and -DRB1*15 as protective factors for OM in BD, which could function as biomarkers for predicting disease phenotypes.

Asunto(s)

Síndrome de Behçet , Humanos , Síndrome de Behçet/diagnóstico , Síndrome de Behçet/genética , Alelos , Estudios de Casos y Controles , Factores de Riesgo , Brasil/epidemiología