H. Houman

Expression of Th-17 and RORgammat mRNA in Behçet’s Disease

Summary Background To investigate plasma IL-17 level and the expression of Th17 cell transcription factor RORγt in the pathogenesis of Behçet’s Disease (BD). Material/Methods Blood samples were collected from 73 patients with BD (45 patients were in active stage), 20 systemic lupus erythematosus (SLE) and 12 multiple sclerosis patients (MS). Twelve patients with BD were investigated both in their active and remission stages. Samples were processed to detect IL-17A level in plasma by enzyme-linked immunosorbent assay (ELISA). Related gene expression was assessed by real-time reverse transcription polymerase chain reaction. Function of Th17 cells in active BD patients with erythema nodosum (EN)-like eruption was studied in relation to human umbilical vein endothelial cells (HUVECs). Results We demonstrated the presence of Th17 cells and RORγt among the peripheral blood mononuclear cells (PBMC). The percentage of circulating Th17 cells and the ability to produce interleukin-17A (IL-17A) were increased in samples derived from patients with active BD, MS and SLE patients. We observed that IL-17A from patients with active BD could induce adhesion molecule messenger RNA expression in HUVECs. Conclusions RORγt determined Th17 cell might be involved with increased IL-17A in BD. Our results indicate that IL-17 contributes to the active proinflammatory pattern that is characteristic of inflammatory diseases and patients with active BD.

RORC and Foxp3 axis in cerebrospinal fluid of patients with Neuro-Behçet's Disease

Neurological manifestations are present in 5% to 30% of patients with Behçets disease (BD). Neuro-Behçets Disease (NBD) is hypothetically caused by T helper (Th) cells, which development is dependent on the expression of lineage-specific transcription factors. Cerebrospinal fluid (CSF) mRNA expression of TBX21, GATA3, RORC, FOXP3 and EBI3 were assessed in 18 NBD patients and 26 controls disease [16 noninflammatory neurological disease (NIND) and 10 headache attributed to Behçets disease (HaBD)]. Expression of TBX21 (Th1), RORC (Th17) and Foxp3 (Treg) were increased in NBD patients compared to HaBD and NIND patients. EBI3 and Th2-associated GATA3 expressions were found to be decreased (P<0.0001 and P<0.0001) in NBD patients. Analysis of transcription factor ratios, revealed an increase in the RORC/FOXP3 and TBX21/GATA3 ratios in NBD patients (P<0.0001; P<0.0003). Our findings indicate that both Th1 and Th17 mRNA expressions involving a possible impairment of Treg cells. This might play a role in CSF-NBD inflammation, permitting activation of harmful T cell subpopulations. The TBX21/GATA3 and RORC/FOXP3 ratios dysregulations in NBD are consistent with those reported in other inflammatory diseases and indicating the plasticity existing between Th1, Th17 and Treg cells during inflammation.

Associations of vitamin D receptor gene polymorphisms FokI and BsmI with susceptibility to rheumatoid arthritis and Behçet's disease in Tunisians

OBJECTIVES Reports of immunomodulating effects of vitamin D suggest a need for examining allele and genotype frequencies of the vitamin D nuclear receptor gene (VDR) in patients with autoimmune diseases. T-helper-1 (Th1) counts in peripheral blood are increased in both rheumatoid arthritis (RA) and Behçets disease (BD). We studied VDR polymorphisms in patients with these two diseases in Tunisia. METHODS In 108 patients with RA, 131 patients with BD, and 152 controls, we studied FokI and BsmI VDR polymorphisms, using the restriction fragment length polymorphism technique. RESULTS The FokI polymorphism alleles and genotype were significantly more common in the RA group than in the controls (P=0.001 and P=0.005, respectively). The FokI F allele and F/F genotype were significantly associated with BD (P=0.0003 and P=0.002, respectively). Furthermore, in the group with BD, the FokI polymorphism was significantly associated with the presence of vascular manifestations (P=0.006). In patients with RA, the FokI polymorphism was significantly associated with female gender (P=0.003). No significant associations were found between the Bsm1 polymorphism and RA or BD. CONCLUSION The VDR F allele is associated with RA and BD in Tunisians.

Hyperhomocysteinaemia is associated with uveitis but not with deep venous thrombosis in Behçet's disease

Abstract Plasma homocysteine was assessed in Behçets disease (BD) patients in order to determine the prevalence of hyperhomocysteinaemia in BD and to test its association with clinical manifestations of the disease. The study included 59 patients with BD and 118 age- and sex-matched healthy subjects. Plasma homocysteine, vitamin B12 and folate were assessed by automated immunoassay methods. Hyperhomo-cysteinaemia was defined as plasma homocysteine >15μmol/l. Plasma homocysteine concentrations and the prevalence of hyperhomocysteinaemia were significantly higher in BD patients than in controls [median (5th–95th percentile), 11.3 (6.6–28.1) vs. 10.6 (6.6–17.1)μmol/l, and 25.4% vs. 9.3%, respectively]. In BD patients, hyperhomocysteinaemia was related to male gender, disease severity and uveitis [odds ratio (OR), 5.32; 95% confidence interval (CI), 1.43–21.61; p=0.008], but not to age, smoking, disease activity, deep venous thrombosis, arthritis or neurological involvement. The association between uveitis and hyperhomocysteinaemia persisted (multi-adjusted OR, 7.46; 95% CI, 1.03–54.3; p=0.05) after adjusting for gender, age, disease activity and duration, smoking, deep venous thrombosis, and serum concentrations of creatinine, vitamin B12 and folate. Plasma homocysteine should be measured in patients with BD, and the effect of B-vitamin supplementation should be tested in those with hyperhomo-cysteinaemia.

BAFF is up-regulated in central nervous system of neuro-Behçet's disease.

We report that B cell-activating factor of the tumor necrosis factor family (BAFF) is expressed in central nervous system (CNS) of neuro-Behçets disease (NBD). This study investigated BAFF and BAFF-R (BAFF receptor) in NBD, compared to multiple sclerosis (MS) and to non inflammatory neurological diseases (NIND). Cerebrospinal fluid (CSF) was used to determine the level of BAFF messenger RNA (mRNA) and the level of BAFF-R mRNA in unfractionated cells. A sandwich ELISA was used to quantify soluble BAFF protein levels in serum and in CSF. BAFF and BAFF-R expression in CSF were increased in NBD and MS patients compared to NIND patients. RNA levels of BAFF and BAFF-R were significantly correlated in NBD and MS patients. Serum sBAFF levels were increased in NBD and MS patients, but did not correlate with BAFF expression in CSF. CNS-produced BAFF may support inflammatory cell survival in NBD.

Endothelial nitric oxide synthase gene polymorphism is associated with Behçet's disease in Tunisian population

Nitric oxide (NO) is a molecule that plays a key role in many physiologic and pathologic processes. It is produced in vivo from the aminoacid l-arginine by a family of nitric oxide synthases (NOS). Endothelial NOS (eNOS) is a constitutively expressed isoform of NOS. The eNOS gene entails several polymorphisms, of which certain were investigated in Behçets disease (BD). We sought to establish the association of eNOS gene Glu298Asp polymorphism in exon 7 with susceptibility to BD. In this study, 135 Tunisian patients with BD and 157 healthy blood donor controls from the same geographic area were genotyped by polymerase chain reaction technique for eNOS polymorphism in exon 7. Our results showed that the distribution of the Glu298Asp genotype differed between BD patients and controls but did not reach statistical significance (p = 0.06). Allele Asp298 was significantly more frequent in healthy controls than in BD patients (p = 0.037, chi(2) = 4.33, OR = 1.01, 95% CI = 1.41-1.99). A significant difference was found (p = 0.004, OR = 1.26, 95% CI = 2.13-3.62) between BD patients with skin lesions and patients without this manifestation. Our findings suggest that Glu298Asp polymorphism of eNOS gene is associated with BD susceptibility as well as skin lesions.

Tc1/Tc2 ratio in the inflammatory process in patients with Behçet's disease

BACKGROUND: Peripheral blood CD8+ T cells expressing interferon gamma and interleukin-4 (IL-4), and lacking CD28 molecules, were responsible for the dynamic interplay between peripheral blood and inflammatory sites. INTRODUCTION: The aim of the current study was to define in Behçets disease (BD), CD8+ T-cell subsets using CD28 and CD11b monoclonal antibodies, and the characterization of the Tc1/Tc2 ratio and perforin expression. METHODS: Flow cytometry was used for intracytoplasmic cytokines and perforin expression. Effector cells were investigated by adhesion of CD8+ T cells to human microvascular endothelial cells and by chemotaxis using beta-chemokine. RESULTS: Interferon-gamma-producing CD8+ T cells in active and remission BD patients were increased, which induce a significant increase of the Tc1:Tc2 ratio in BD. CD8(+)CD28(-)CD11b+ T cells were found to be more expanded in BD patients than in age-matched healthy controls. The expression of CD11b molecules in active BD allowed to CD8(+)CD28+/CD8(+)CD28- subsets to adhere to human microvascular endothelial cells, with more efficiency in BD. Using MIP-1alpha, we observed that the migratory process of CD28(-)CD11b(+) is more important in BD. CD28(-)CD11b+ exhibited an increased perforin expression in BD patients. CONCLUSION: Taken together these results suggest the presence of immune activation, probably in response to a profound inflammation affecting BD patients. The physiopathological significance of these results were toward autoimmune diseases and/or infectious process.

MICA Transmembrane Region Polymorphism and HLA B51 in Tunisian Behçeťs Disease Patients

None of MICA microsatellite alleles was significantly increased in Tunisian BD patients. Only HLA-B51 was primarily associated to BD in this population. These data, similar to those found in other ethnics6,9, further support the hypothesis that the amino-acids, common to all HLA-B51 encoding alleles and absent in other HLA-B antigens, probably confer high affinity binding for peptides that may contribute to BD development. However, the possibility that HLA-B contributes to the pathogenesis as an additional or complementary risk factor cannot be excluded.

Pellagra in a patient with primary Sjögren's syndrome.

A 27-year-old woman presented with persistent dryness of the mouth and eyes. She presented with permanent photodistributed rash involving the face and distal extremities. Laboratory tests showed positive Sjögrens syndrome (SS)-A and SS-B antibodies. Histological examination of minor salivary gland biopsy revealed inflammatory infiltration grade 4 according to Chisholms classification. Skin biopsy showed acanthosis, hyperkeratosis in the epidermis and little inflammatory infiltrate in the dermis. There was an infiltration of CD4 T lymphocytes in the dermis. Based on the characteristics of the dermatitis and on a rapid response to niacin replacement, the diagnosis of pellagra was carried out. A complete resolution of the dermatological signs was obtained within 2 months. To the best of our knowledge, the association between primary SS and pellagra has never been reported. We emphasise the possible mechanisms of this association.

Un cas exceptionnel de sarcoïdose systémique suivie par une maladie de Crohn : une association fortuite ou lien étiopathogénique ?

La maladie de Crohn (MC) est une maladie inflammatoire chronique de l’intestin caractérisée sur le plan anatomopathologique par la présence de granulomes épithéloïdes et gigantocellulaires sans nécrose caséeuse. Il est bien établi que des manifestations extra-intestinales très diverses peuvent compliquer la MC voire même la précéder sans toutefois que leur étiopathogénie ne soit bien élucidée. Il peut s’agir, en particulier, de localisations granulomateuses extra-intestinales, en l’occurrence hépatiques, pulmonaires ou cutanées. Néanmoins, l’association d’une MC à une sarcoïdose systémique, granulomatose systémique d’origine indéterminée et qui touche avec prédilection la région médiastinopulmonaire, est exceptionnellement rapportée. À notre connaissance, seuls 10 cas ont déjà été publiés [1–8]. De par son extrême rareté, l’association entre ces 2 maladies est souvent considérée comme fortuite. Nous rapportons un nouveau cas d’une telle association et nous discutons son caractère, fortuit ou non, à travers des données nosologiques et étiopathogéniques récentes.