Yongqiang Dai

Interleukin-17-secreting T cells in neuromyelitis optica and multiple sclerosis during relapse

Growing evidence suggests that interleukin (IL)-17 and IL-17-secreting CD4(+)T (Th17) cells are involved in the pathogenic mechanisms of multiple sclerosis (MS). IL-17-secreting CD8(+)T cells were recently identified as a novel subset of CD8(+)T cells. We aimed to analyze the role of Th17 and IL-17 secreting CD8(+)T cells in the pathogenesis of neuromyelitis optica (NMO) as well as MS. Fourteen patients with NMO, 20 with MS and 16 control participants (CTL) were enrolled between November 2008 and December 2009. The proportion of Th17 cells and IL-17 secreting CD8(+)T cells were counted using flow cytometry, and serum levels of IL-6, IL-17, IL-21, IL-23, and transforming growth factor-beta (TGF-β) were measured by enzyme-linked immunosorbent assay. Patients with NMO had a larger proportion of Th17 cells than patients with MS (3.72% versus [vs.] 2.58%, p=0.02) and CTL (3.72% vs. 1.36%, p<0.001). The proportion of Th17 cells in patients with MS was also markedly higher than in the CTL (2.58% vs. 1.36%, p<0.001). IL-17-secreting CD8(+)T cell counts in NMO patients were markedly higher than in MS patients (1.61% vs. 1.09%, p=0.036) and CTLs (1.61% vs. 0.58%, p<0.001). The proportion of IL-17-secreting CD8(+)T cells in MS patients was also higher than in CTLs (1.09% vs. 0.58%, p=0.002). Serum IL-17 and IL-23 levels were increased in patients with NMO and MS, while serum IL-21 concentration was higher only in NMO patients compared to CTL. We concluded that Th17 cells were highly activated in patients with NMO. IL-17-secreting CD8(+)T cells were increased in patients with NMO and MS during relapse and have an important role in the pathological mechanism of NMO and MS.

Soluble egg antigen from Schistosoma japonicum modulates the progression of chronic progressive experimental autoimmune encephalomyelitis via Th2-shift response

Soluble egg antigen (SEA) is strongly antigenic and inherently induces Th2-biased immune responses. In this study, we tested whether SEA from Schistosoma japonicum is able to prevent experimental autoimmune encephalomyelitis (EAE) induced by MOG(35-55) peptide, an established animal model of multiple sclerosis (MS). Intraperitoneal administration with SEA before EAE induction and in the preclinical phase after EAE induction successfully ameliorated the severity and progression of EAE on mice compared with phosphate buffered saline (PBS) controls, while no protective effect was shown when SEA immunization began after disease onset. This effect was associated with reduced interferon gamma (IFN-gamma) production and/or increased interleukin 4 (IL-4) production in spleen and central nervous system (CNS) even at the chronic stage. Similarly, we observed reduced inflammation and demyelination in spinal cords of SEA pretreated EAE mice compared with controls. Our data indicate that immunization with SEA from S. japonicum induces a preestablished Th2-biased microenvironment that provides preventive immune-modulating effects on EAE progression. This study may have important implications for its promising therapeutic use in MS and other autoimmune diseases.

HLA-DPB1 0501 is associated with susceptibility to anti-aquaporin-4 antibodies positive neuromyelitis optica in southern Han Chinese.

OBJECTIVES To analyze the role of HLA-DRB1 and -DPB1 alleles in the pathogenesis of neuromyelitis optica (NMO) and multiple sclerosis in Southern Han Chinese. METHODS Thirty serum anti-aquaporin 4 antibodies (AQP4-Ab)-positive NMO patients, 53 conventional multiple sclerosis (C-MS) patients, and 93 controls (CTLs) were enrolled. The HLA-DRB1 and -DPB1 alleles of the subjects were determined by sequencing-based typing (SBT). RESULTS The frequency of the DRB1 0901 was lower in NMO patients than in CTLs (P(uncorr)=0.022, OR: 0.194, 95% CI: 0.043-0.876), and DRB1 1602 was higher in NMO patients than in C-MS (P(uncorr)=0.038, OR: 3.491, 95% CI: 1.024-11.896) and CTLs (P(uncorr)=0.051, OR: 2.711, 95% CI: 0.971-7.556). The frequency of DPB1 0501 was significant higher in NMO patients than in C-MS (P(uncorr)=0.018, OR: 4.629, 95% CI: 1.235-17.350) and CTLs (P(uncorr)=0.001, P(corr)=0.022, OR: 7.096, 95% CI: 2.011-25.044). CONCLUSIONS DPB1 0501 correlates with risk of AQP4-Ab positive NMO in Southern Han Chinese.

IL-22 secreting CD4 + T cells in the patients with neuromyelitis optica and multiple sclerosis

Interleukin (IL)-22 secreting CD4(+) T (Th22) cells and IL-22 are involved in the pathogenesis of autoimmune disease, but their role in neuromyelitis optica (NMO) and multiple sclerosis (MS) is unclear. We measured the proportion of Th22, Th17, CD4(+)IL-22(+)IL-17A(+) T cells and serum IL-22 in NMO and MS patients. The proportion of Th22 cells, Th17 cells and serum IL-22 were increased in patients with NMO and MS. Our findings suggest that increased Th22 cells may play an important role in the pathogenesis of NMO and MS.

Interleukin 17 gene polymorphism is associated with anti-aquaporin 4 antibody-positive neuromyelitis optica in the Southern Han Chinese — A case control study

BACKGROUND Interleukin 17 (IL-17) plays an important role in many autoimmune diseases including neuromyelitis optica (NMO) and multiple sclerosis (MS), which are inflammatory demyelinating diseases of the central nervous system. A large number of non-HLA single nucleotide polymorphisms have been reported to increase the risk of MS. However, their effects on NMO have been less well studied. METHODS Fifty-two anti-aquaporin 4 antibody-positive NMO patients, 69 anti-aquaporin 4 antibody-negative conventional MS patients, and 131 controls were genotyped for the IL-17A rs2275913 and IL-17F rs763780 single nucleotide polymorphisms by DNA sequencing. RESULTS Significantly higher frequencies of the rs763780 T allele (p(uncorr)=0.011) and TT genotype (p(uncorr)=0.007, p(corr)=0.042) were observed in NMO patients versus controls. CONCLUSIONS The rs763780 T allele and TT genotype may increase susceptibility to NMO in the Southern Han Chinese.

Cerebrospinal Fluid BAFF and APRIL Levels in Neuromyelitis Optica and Multiple Sclerosis Patients During Relapse

BackgroundBAFF (B-cell activating factor of the tumor necrosis factor family) and APRIL (a proliferation-inducing ligand) are two of the major survival factors for B cells. Many studies have shown that BAFF levels were elevated in MS patients. However, whether the levels of CSF BAFF/APRIL increased in NMO patients was still unclear.ObjectiveTo measure the CSF BAFF and APRIL concentration of in NMO patients, and explore their relationship with disease activity in NMO.MethodsCSF BAFF and APRIL was measured by an enzyme-linked immunosorbent assay (ELISA) in NMO (n = 22), MS (n = 18) patients and controls (n = 14).ResultsConcentration of BAFF and APRIL in NMO patients were significantly higher than MS and controls. CSF BAFF and APRIL levels in controls were also lower than MS. Both NMO and MS revealed an increased disease disability with increased CSF BAFF. CSF APRIL was associated with EDSS scores in NMO, but not found in MS.ConclusionsBAFF/APRIL system considered important for aggressive B cells and T-cell responses, and may stimulates B cells and T cell activation in acute relapse of NMO and MS. In NMO patients, CSF BAFF and APRIL may be key factors of B cell immune response and reflect disease severity.

Notable Increased Cerebrospinal Fluid Levels of Soluble Interleukin-6 Receptors in Neuromyelitis Optica

Background: IL-6 is a proinflammatory cytokine which is involved in the maintenance of the humoral response in various autoimmune disorders. Cerebrospinal fluid (CSF) IL-6 has shown to be increased in neuromyelitis optica (NMO). The soluble form of IL-6 receptor (sIL-6R), which links to IL-6, can activate biological responses in cells. Whether or not sIL-6R is altered in NMO has not been clarified. Objective: To measure CSF IL-6 and sIL-6R in NMO and multiple sclerosis (MS) patients, and investigate whether IL-6 and sIL-6R have possible uses as sensitive biomarkers for diseases activity. Methods: CSF concentrations of IL-6 and sIL-6R were measured by an ELISA in NMO (n = 22) and MS (n = 18) patients, as well as control subjects (n = 14). Results: The concentration of IL-6 levels were higher in NMO compared to MS (p = 0.032) and the controls (p = 0.023). The levels of sIL-6R were also higher in NMO compared to MS (p = 0.002) and the controls (p < 0.001). CSF sIL-6R was associated with an Expanded Disability Status Scale score in NMO (p = 0.005) but not in MS (p = 0.891). In the MS subgroup, sIL-6R concentrations were associated with CSF white blood cells (p = 0.034). Conclusions: Our study revealed that CSF sIL-6R was increased in NMO patients, and correlated with clinical presentations.

Azathioprine plus corticosteroid treatment in Chinese patients with neuromyelitis optica

We investigated the efficacy of azathioprine (AZA) plus long-term low dose corticosteroids in Chinese patients with neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) at the Center for Demyelinating Diseases, South China. We prospectively enrolled patients between June 2010 and June 2014. Annualized relapse rate (ARR), expanded disability status scale (EDSS) score and modified Rankin Scale (mRS) were analyzed retrospectively. Of 77 patients with NMO/NMOSD (four males, 73 females; age range: 4-69 years), median disease duration before initiation of AZA was 32.0 months (range: 2.0-197.0). Median post-treatment follow-up was 23 months (range: 6-58) and 44 patients (57.1%) were relapse-free at median follow-up 19 months (range: 6-51). Pre-treatment ARR was 0.923, and post-treatment ARR was 0 (p < 0.0001). Survival analysis indicated a significantly lower risk of relapse (hazard ratio 0.522; 95% confidence interval 0.377-0.722; p < 0.0001). Significant improvements were shown in the EDSS (3.0 versus 1.0; p < 0.0001) and mRS (2.0 versus 1.0; p < 0.0001). Our study provides evidence supporting the use of AZA plus a low dose corticosteroid as an effective and safe strategy which is associated with a reduction in the risk of relapse in Chinese patients with NMO.

Raloxifene suppresses experimental autoimmune encephalomyelitis and NF-κB-dependent CCL20 expression in reactive astrocytes.

Recent clinical data have led to the consideration of sexual steroids as new potential therapeutic tools for multiple sclerosis. Selective estrogen receptor modulators can exhibit neuroprotective effects like estrogen, with fewer systemic estrogen side effects than estrogen, offering a more promising therapeutic modality for multiple sclerosis. The important role of astrocytes in a proinflammatory effect mediated by CCL20 signaling on inflammatory cells has been documented. Their potential contribution to selective estrogen receptor modulator-mediated protection is still unknown. Using a mouse model of chronic neuroinflammation, we report that raloxifene, a selective estrogen receptor modulator, alleviated experimental autoimmune encephalomyelitis–an animal model of multiple sclerosis–and decreased astrocytic production of CCL20. Enzyme-linked immunosorbent assay, immunohistochemistry imaging and transwell migration assays revealed that reactive astrocytes express CCL20, which promotes Th17 cell migration. In cultured rodent astrocytes, raloxifene inhibited IL-1β-induced CCL20 expression and chemotaxis ability for Th17 migration, whereas the estrogen receptor antagonist ICI 182,780 blocked this effect. Western blotting further indicated that raloxifene suppresses IL-1β-induced NF-κB activation (phosphorylation of p65) and translocation but does not affect phosphorylation of IκB. In conclusion, these data demonstrate that raloxifene provides robust neuroprotection against experimental autoimmune encephalomyelitis, partially via an inhibitory action on CCL20 expression and NF-κB pathways in reactive astrocytes. Our results contribute to a better understanding of the critical roles of raloxifene in treating experimental autoimmune encephalomyelitis and uncover reactive astrocytes as a new target for the inhibitory action of estrogen receptors on chemokine CCL20 expression.

Clinical, radiographic characteristics and immunomodulating changes in neuromyelitis optica with extensive brain lesions

BackgroundNeuromyelitis optica (NMO) shows various brain magnetic resonance imaging (MRI) abnormalities with recurrent central nervous system (CNS) attacks, although predominantly affecting the spinal cord and optic nerve. However, NMO with extensive involvement of the brain has infrequently been studied. We investigated the clinical, radiographic features and immunomodulating changes of NMO patients with extensive brain lesions (EBLs) in China.MethodsNMO patients (including 16 NMO patients with EBLs and 53 NMO patients without EBLs) hospitalized during January 2006 and February 2010 were recruited and analyzed retrospectively. Data of clinical characteristics, magnetic resonance imaging (MRI) features, laboratory abnormalities, treatment details and outcomes were analyzed. All the patients received the follow-up visits for two years.ResultsEBLs in NMO were classified into four categories according to their respective MRI characteristics: 1) Tumefactive-like lesions (n=4, 25%); 2) Acute disseminated encephalomyelitis (ADEM)-like lesions (n=6, 37.5%); 3) Multiple sclerosis (MS)-like lesions (n=5, 31.25%); 4) Posterior reversible encephalopathy syndrome (PRES)-like lesions (n=1, 6.25%). NMO patients with EBLs had higher rates of encephalopathy symptoms (37.5% vs. 5.6%, p = 0.004), homonymous hemianopia (18.8% vs. 0%, p = 0.011) and AQP4 seropositivity (100% vs. 69.8%, p = 0.008) than NMO patients without EBLs (NEBLs). Immunomodulating changes (including the levels of C3, C4, ESR and CRP) were significantly higher in patients with EBLs than those without EBLs. The relapse times in EBLs during the follow-up period were more frequent than those happened in NEBLs (1.88 ± 0.30 vs. 1.23 ± 0.14, p = 0.04). The EDSS scores in EBLs patients were also much higher than those in NEBLs throughout all the whole visits of follow-up.ConclusionsThe presence of EBLs in NMO may indicate a higher diseases activity and portend a worse prognosis. CRP is a useful marker in monitoring diseases activity. Systemic inflammation may be crucial to the formation of EBLs in NMO.