Increased T-bet/GATA-3 and ROR-γt /Foxp3 Ratios in Cerebrospinal Fluid as Potential Criteria for Definite Neuro-Behçet’s Disease

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Abstract

When the central nervous system (CNS) is the primary affected site in an initial attack of Behçet’s disease (BD), the differential diagnosis is particularly challenging. Some cases remain unclassified or qualified as probable neuro-Behçet’s disease (NBD). Several cytokines are involved in the immunopathogenesis of this disease; however, studies establishing the differential cytokine pattern between probable and definite NBD are scarce. Twenty-eight parenchymal NBD patients, diagnosed according to the International Consensus Recommendation (ICR) criteria and classified into definite (D-NBD; n = 17) and probable (P-NBD; n = 11), were sampled at their first neurological symptoms, and compared with healthy control subjects (n = 20). Oligoclonal bands (OCB) of IgG were detected by isoelectric focusing on agarose, and immunoblotting of matched serum and cerebrospinal fluid (CSF) sample pairs. T cell cytokines (INF-γ, IL-4, IL-17, and IL-10) and transcription factors related to Th1, Th2, Th17, and T regulatory populations (respectively T-bet, GATA-3, ROR-γt, and Foxp3) were studied by quantitative RT-PCR in peripheral blood mononuclear cells (PBMCs) and CSF cells. Inflammatory cytokines such as IL-6, TNF-α, and IL-1β were also analyzed. CSF OCB pattern 2 was present in only 1 out of 28 neuro-Behçet’s patients who belonged to the P-NBD group. Two D-NBD patients had OCB in CSF showing pattern 4. In the D-NBD CSF samples, IL-17 and IL-10 expressions were significantly elevated compared to P-NBD. Moreover, D-NBD patients had increased levels of T-bet/GATA-3 and ROR-γt/Foxp3 ratios compared to P-NBD. Furthermore, a significant increase of CSF IL-6 in D-NBD, compared to P-NBD and the controls, was found. In addition to the increased IL-6 level, the data obtained suggest the existence in D-NBD patients of a significantly disrupted balance between Th17 effector and T regulatory cells, as reflected by the enhanced ROR-γt/Foxp3 ratio. This could be considered as an additional criterion for definite neuro-Behçet’s disease.

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Most cited references 43

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Neuro-Behçet's disease: epidemiology, clinical characteristics, and management.

Omar Araji, Joshua D. Kidd (2009)

Behçet's disease (BD) is a multisystem relapsing inflammatory disorder of unknown cause. In neuro-BD (NBD), the CNS can be involved in one or both of two ways: first, and most commonly, through the development of an immune-mediated meningoencephalitis, which predominantly involves the brainstem, but can also involve the basal ganglia, thalamus, cortex and white matter, spinal cord, or cranial nerves; and second, as a consequence of thrombosis within the dural venous sinuses. Headache is a common symptom in BD and does not necessarily indicate CNS involvement. Peripheral nervous system involvement is rare. New treatment options have recently become available, which have led to an improvement in morbidity after meningoencephalitis. Most of the reported studies on NBD are retrospective. Collaborative prospective studies of the natural history of the disease, particularly the nature and treatment of progressive neurological disease, and evidence-based studies of treatment are needed.

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Upregulated IL-23 and IL-17 in Behçet patients with active uveitis.

Wei Chi, Xuefei Zhu, Peizeng Yang … (2008)

Behçet disease (BD) is a systemic inflammatory disease presumably caused by an autoimmune response. The interleukin (IL)-23/IL-17 pathway has been demonstrated to be involved in the development and maintenance of certain inflammatory diseases. This study was designed to investigate the role of IL-23 and IL-17 in BD. IL-23p19 mRNA in peripheral blood mononuclear cells (PBMCs) was examined using RT-PCR. The levels of IL-23, IL-17, and IFN-gamma in sera or PBMCs were detected by ELISA. Flow cytometry was used to evaluate the frequencies of IL-17-producing and IFN-gamma-producing T cells and the expression of CD45RO. Results showed that the expression of IL-23p19 mRNA, IL-23, IL-17, and IFN-gamma was markedly elevated in BD patients with active uveitis. The frequencies of IL-17-producing and IFN-gamma-producing T cells from PBMCs were significantly upregulated in BD patients with active uveitis. The increased IL-17 (3.10% +/- 0.53%) in BD patients with active uveitis was primarily produced by CD45RO(+) memory T cells. Recombinant (r) IL-23 could upregulate IL-17 production by polyclonally stimulated PBMCs, whereas interferon (IFN)-gamma downregulated IL-17 production. These findings reveal that the levels of IL-23, IL-17, and IFN-gamma are elevated in BD patients with active uveitis, and they suggest that the IL-23/IL-17 pathway together with IFN-gamma is associated with the active intraocular inflammation in BD patients.