Behçet's disease from the aspect of autoinflammatory disease

Beh?et's disease is a systemic inflammatory disease presented with recurrent oral aphtha, cutaneous manifestations, uveitis, and genital ulcer. The etiology of Beh?et's disease is still unknown, but both genetic background and environmental factors are thought to be important in the pathogenesis of Beh?et's disease. Beh?et's disease has long been regarded as a Th1 type autoimmune disease, because of the association with HLA-B51 and hyperreactivity against streptococcal antigen. However, it was recently found that Beh?et's disease and autoinflammatory diseases share several clinical features. Furthermore, increased activity of neutrophils and elevated levels of interleukin-1β are observed in both Beh?et's disease and autoinflammatory diseases. The relationship between Beh?et's disease and autoinflammatory diseases, especially Familial Mediterranean fever, is speculated, because both diseases are prevalent in the Mediterranean basin and treated with colchicine. Genetic researches on Beh?et's disease and FMF suggest that the MEFV gene mutated in Familial Mediterranean fever is a probable susceptibility gene for Beh?et's disease. Although many observations suggest that Beh?et's disease might be autoinflammatory, there is evidence implying autoimmune pathogenesis of Beh?et's disease. For example, some symptoms of Beh?et's disease is treated with T cell suppressing agents. Recent data suggest that a novel subset of T cells, Th17, plays a crucial role in pathogenesis of Beh?et's disease, and genome-wide association researches verified it. IL-17, which is the secreted from of Th17 activates neutrophils. Hence, IL-17 might cause the symptoms resembling autoinflammatory diseases. Recently, Anti-IL-1 treatment proved to be effective and other susceptibility genes are being investigated. These new findings will shed light on the long-sought pathogenesis of Beh?et's disease.     

The F response parameters in Behçet's disease

The F response parameters may provide a sensitive method for detection of mild neuropathy in patients with otherwise normal nerve conduction studies. We investigated conventional nerve conduction studies and F response parameters in patients with Beh?et's disease (BD), but without neurologic involvement. The results indicate that ulnar motor and sensory, tibial motor and sural sensory nerve conduction studies failed to differentiate the patients with BD and controls. In the ulnar nerve, the F response parameters were not significantly different for the populations. In the tibial nerve, the F response latency and chronodispersion were increased while F amplitude, duration, and persistence were all decreased in patients with BD. The results suggests that, (1) peripheral nerve dysfunction occurred especially in lower extremities in patients with Beh?et's disease. (2) The F response parameters were considered the most sensitive method for the detection of neuropathy in Beh?et's disease.     

The serum vitamin C levels in Behçet's disease

Beh?et's disease (BD) is a chronic inflammatory disorder of unknown aetiology, and recognised as a multi-system vasculitis. It has been postulated that an imbalance of the oxidant and antioxidant systems related to the disease are important in its pathogenesis. Previous publications have reported increased levels of enzymatic antioxidant defence systems in patients with BD. The non-enzymatic antioxidant systems, including vitamin C and uric acid, were looked for in the present study. For this aim, the serum malondialdehyde (MDA), an end product of lipid peroxidation, and vitamin C and uric acid, as endogenous antioxidants, were determined in 20 patients with BD (11 in active and 9 in inactive periods) and 20 healthy subjects. The MDA level was significantly higher in both the active and inactive period patients compared with the control group (p < 0.001, p < 0.05, respectively). The MDA level was also significantly higher in the active period patients compared with the inactive period patients (p < 0.05). The vitamin C levels were significantly lower in both the active and inactive period patients compared with the control group (p < 0.001, p < 0.05, respectively). There was no significant difference in the vitamin C level between the active and inactive period patients (p > 0.05). There was also no significant difference in uric acid levels between the groups (p > 0.05). In the patients group, a negative correlation was found between the levels of serum MDA and vitamin C (r=-0.517; p < 0.05). Our results indicate that decreased vitamin C and increased MDA levels reflect the increased levels of oxidative stress in BD patients, and this situation may be important in relation with its pathogenesis.     

New insights into the pathogenesis of Behçet's disease

Behçet's disease (BD) is a recurrent systemic inflammatory disorder of unknown origin characterized by oral and genital mucous ulcer, uveitis, and skin lesions. Involvement of large vessels, central nervous system (CNS), gastrointestinal tract and thrombotic events are less frequent but can be life threatening. The aim of this review is to provide new insights into the pathogenesis of BD. Over the past year substantial advances have been done in the understanding of the genetic [1,2] and immunology [3] of BD. BD is at the crossroad between autoimmune and autoinflammatory syndromes. In common with autoimmune diseases BD shares class I MHC association. However, in contrast to autoimmune disorders, BD has clinical features that seem to be mostly autoinflammatory. The pathogenesis of BD is still unknown, but major determinants of the genetic and immune system abnormalities have been reported recently. Triggering infectious factors are supposed to participate in the outbreak of BD in genetically predisposed patients. Two recent large genome-wide association study (GWAS) conducted in Turkey and Japan reported association between single nucleotide polymorphism (SNP) of interleukin (IL)-10 and IL-23R/IL-12RB2 genes and BD. New insights into the perturbations of T cell homeostasis of BD recently emerged. We have recently demonstrated the promotion of Th17 responses and the suppression of regulatory T cells (Tregs) that were driven by interleukin (IL)-21 production and that correlates with BD activity. Inflammatory cells within BD inflammatory lesions included mostly neutrophils, Th1 and Th17 cells, and cytotoxic CD8+ and γδ T cells. Altogether, the recent progresses in the knowledge of BD pathogenesis pave the way for innovative therapy.     

HLA-B*27 allele associated to Behçet's disease and to anterior uveitis in Moroccan patients

Human leukocyte antigen HLA-B51 is the most strongly associated gene with Beh?et disease (BD) in different ethnic populations. We analyze the influence of HLA-B alleles in BD predisposition in Moroccan population and its association with clinical manifestations. The HLA-B phenotype frequencies were analyzed by serologic HLA class I typing and by polymerase chain reaction sequence-specific oligonucleotide (PCR-SSO) reverse dot blot hybridization in 120 unrelated Moroccan patients: all of whom fulfilled the international study group criteria for Beh?et's disease, and in 112 ethnically matched healthy controls. Besides HLA-B*51 allele (20%), a significant increased frequency of the HLA-B*27 allele was found in Moroccans patients with Beh?et's disease when compared to controls (13.3% of patients versus 2.7% of controls, chi square =?8.75, OR =?5.59, 95% IC [1.58-19.75] and particularly in the patients who presented an anterior uveitis (25% vs. 5.5%, p 相似文献   

New insights in the clinical understanding of Behçet's disease

Behçet''s disease is a chronic relapsing multisystemic inflammatory disorder characterized by four major symptoms (oral aphthous ulcers, genital ulcers, skin lesions, and ocular lesions) and occasionally by five minor symptoms (arthritis, gastrointestinal ulcers, epididymitis, vascular lesions, and central nervous system symptoms). Although the etiology of Behçet''s disease is still unknown, there have been recent advances in immunopathogenic studies, genome-wide association studies, animal models, diagnostic markers, and new biological agents. These advances have improved the clinical understanding of Behçet''s disease and have enabled us to develop new treatment strategies for this intractable disease, which remains one of the leading causes of blindness.     

Anti-cyclic citrullinated peptide antibodies and joint involvement in Behçet's disease

Purpose

We aimed to determine the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in a large group of Korean patients with Behçet''s disease (BD), with and without joint involvement, and to compare these findings with the prevalences of anti-CCP antibodies in patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).

Materials and Methods

We tested 189 patients with BD, 105 with RA, and 36 with SLE for anti-CCP antibodies and IgM rheumatoid factor in serum. We reviewed the medical records of patients with BD to investigate their personal and clinical characteristics as well as their laboratory test results.

Results

Anti-CCP antibodies were detected in seven of the 189 BD patients (3.7%), at a mean titer of 30.6±44.4 U/mL, in 86 of the 105 RA patients (81.9%) with a mean titer of 198.8±205.7 U/mL, and in nine of the 36 SLE patients (25%) with a mean titer of 180.4±113.9 U/mL. One of the seven anti-CCP-positive BD patients fulfilled the diagnostic criteria for both BD and RA. Five of the seven anti-CCP-positive BD patients (71.4%) had polyarticular joint involvement, and the other two patients (28.6%) had oligoarticular involvement.

Conclusion

We determined the prevalence of anti-CCP antibodies in a large group of Korean BD patients with and without joint involvement. Negative anti-CCP test in patients with BD may help to differentiate BD from RA and SLE, all of which present with similar clinical features.     

The Clinical Feature of Beh?et's Disease in Northeastern China

Purpose

Behçet''s disease (BD) is a chronic, relapsing, multi-system vasculitis of unknown aetiology with complicated and diversified clinical features predominantly involving oral and genital ulcers, and ocular and cutaneous lesions. The clinical features of this disease have been described to be different according to geographical areas and gender. We investigated the specific clinical features of BD patients in Northeastern China.

Materials and Methods

116 patients involved in this study fulfilled the classification criteria of the International Study Group for BD. The clinical manifestations and results of laboratory tests of BD were recorded in each patient.

Results

The onset was typically between 20-39 years with a slight female predominance. Oral ulcers were the most common manifestation, followed by skin lesions, positive pathergy reaction/genital ulcers, and ocular lesions. Vascular lesion and epididymitis were rare in patients with BD. The frequency of erythema nodosum-like lesion and articular involvement were significantly higher in females, while gastrointestinal involvement was significantly higher in males. The results of laboratory tests showed that the human leukocyte antigen (HLA)-B*51 alleles were positive in 30.9% of patients and the immunological abnormities were present in some patients.

Conclusion

The clinical features of BD showed geographical and gender difference. Genetic and immune factors might participate in aetiopathogenesis of BD.     

The link between the epidemics of obesity and allergic diseases: does obesity induce decreased immune tolerance?

There is increasing epidemiological evidence that obesity increases the risk of asthma, atopic, and autoimmune diseases. We hypothesize that the increase in these diseases is caused, at least in part, by decreased immunological tolerance as a consequence of immunological changes induced by adipokines (e.g. leptin and adiponectin) and cytokines [e.g. interleukin 6 (IL6) and tumor necrosis factor alpha (TNFalpha)] secreted by white adipose tissue. The increasing body weight increases the levels of circulating IL6, leptin, and TNFalpha. IL6 and leptin down-regulate the activity of regulatory T-lymphocytes (Tregs). Additionally, adiponectin, which decreases with increasing obesity, down-regulates the secretion of IL10 from macrophages and adipocytes. These changes in IL6, leptin, and IL10 decrease the regulatory effect of Tregs resulting in decreased immunological tolerance to antigens. In pregnant women, these obesity-induced immunological changes might be transmitted to the fetus by epigenetic inheritance thereby increasing the risk of atopic disease. We propose that obesity results in immunological changes resulting in decreased immunological tolerance to antigens and skewing of the immune system towards a Th2 cytokine profile increasing the risk of allergy and other immune-mediated diseases. Furthermore, this hypothesis offers a unifying explanation for the observation that older siblings appear to confer protection against atopic diseases, preeclampsia, and certain autoimmune diseases. More studies are definitely needed to explore further the immunological effects of obesity and its possible effects on allergic disease.     

HLA-B phenotype modifies the course of Behçet's disease in Moroccan patients

In Moroccan patients, predisposition to Beh?et's disease is associated with HLA-B*51, mostly in males with young age at disease onset. In addition, the disease is associated with B*15 both in females and in males with late disease onset. We analyzed the clinical presentation, the severity and the course of the disease in 86 Moroccan patients according to their HLA-B phenotype. The presence of the B*51 or B*15 did not predispose to a particular clinical manifestation, nor to a more severe presentation of the disease. By contrast, outcome of the disease significantly differed depending on HLA-B phenotype, with an increase of symptoms in most B*51+ patients and in half of B*15 patients, and a remission or a decrease of symptoms in all B*51-B*15- patients. This variable course was mostly observed for ocular lesions, skin lesions, articular symptoms, and neurological symptoms. These data may suggest that treatment should be given early in the course of the disease in B*51 or B*15-positive patients in order to stabilize the inflammatory process.     

HLA-B*51 and B*15 alleles confer predisposition to Behçet's disease in Moroccan patients

HLA class I polymorphism in Moroccan patients with Beh?et's disease has not been investigated so far. In this study, HLA-B* phenotype frequencies were analyzed in 86 unrelated Moroccan patients (45 males, 41 females) and 111 ethnically matched healthy controls. The predisposing effect of the B*51 was confirmed (30.2% in patients and 15.3% in controls, OR = 2.39, 95% CI [1.2-4.8], p = 0.015). It was mostly observed in males with young age at disease onset (OR= 5.5 [1.9-15.9], p = 0.002 compared to controls). The Moroccan BD group also presented a previously unknown association with HLA-B*15 (25.6% of patients versus 11.7% of controls, OR = 2.59 [1.2-5.5], p = 0.014), both in females and in males with late-onset of the disease. Altogether, the B*15 and/or B*51 alleles were expressed in 55.8% of patients compared to 27% of controls (OR = 3.4 [1.9-6.2], p < 10-4, Pc = 0.003). Our data indicate HLA-B effects on BD pathogenesis should be considered separately for men and women.     

The response of the host microcirculation to bacterial sepsis: does the pathogen matter?

Sepsis results from the interaction between a host and an invading pathogen. The microcirculatory dysfunction is now considered central in the development of the often deadly multiple organ dysfunction syndrome in septic shock patients. The microcirculatory flow shutdown and flow shunting leading to oxygen demand and supply mismatch at the cellular level and the local activation of inflammatory pathways resulting from the leukocyte–endothelium interactions are both features of the sepsis-induced microcirculatory dysfunction. Although the host response through the inflammatory and immunologic response appears to be critical, there are also evidences that Gram-positive and Gram-negative bacteria can exert different effects at the microcirculatory level. In this review we discuss available data on the potential bacterial-specific microcirculatory alterations observed during sepsis.     

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 Beh?et'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% 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.     

Gene expression profiling and association studies implicate the neuregulin signaling pathway in Behçet's disease susceptibility

Behçet's disease (BD) is a complex disease with genetic and environmental risk factors implicated in its etiology; however, its pathophysiology is poorly understood. To decipher BD's genetic underpinnings, we combined gene expression profiling with pathway analysis and association studies. We compared the gene expression profiles in peripheral blood mononuclear cells (PBMCs) of 15 patients and 14 matched controls using Affymetrix microarrays and found that the neuregulin signaling pathway was over-represented among the differentially expressed genes. The Epiregulin (EREG), Amphiregulin (AREG), and Neuregulin-1 (NRG1) genes of this pathway stand out as they are also among the top differentially expressed genes. Twelve haplotype tagging SNPs at the EREG-AREG locus and 15 SNPs in NRG1 found associated in at least one published BD genome-wide association study were tested for association with BD in a dataset of 976 Iranian patients and 839 controls. We found a novel association with BD for the rs6845297 SNP located downstream of EREG, and replicated three associations at NRG1 (rs4489285, rs383632, and rs1462891). Multifactor dimensionality reduction analysis indicated the existence of epistatic interactions between EREG and NRG1 variants. EREG-AREG and NRG1, which are members of the epidermal growth factor (EGF) family, seem to modulate BD susceptibility through main effects and gene–gene interactions. These association findings support a role for the EGF/ErbB signaling pathway in BD pathogenesis that warrants further investigation and highlight the importance of combining genetic and genomic approaches to dissect the genetic architecture of complex diseases.