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.     

Epidemiology of neuromyelitis optica in the United States: a multicenter analysis

BACKGROUND Rare diseases require integrated multicenter clinical networks to facilitate clinical research. Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSDs) are uncommon neuroinflammatory syndromes that are distinct from multiple sclerosis and associated with NMO-IgG, a serologic antibody against aquaporin 4. OBJECTIVE To develop a national multicenter NMO clinical consortium and report initial demographic, clinical, and radiographic features of a cohort of patients with NMO/NMOSD in the United States. DESIGN Review of medical records from patients undergoing evaluation during a 5-year period. We used uniform diagnostic criteria and clinical, laboratory, and neuroimaging definitions to describe the cohort. SETTING Three academic medical centers. PATIENTS One hundred eighty-seven patients with NMO/NMOSD. RESULTS Of the 187 patients included in the analysis, 86 had NMO-IgG-seropositive NMO; 40, NMO-IgG-seronegative NMO; and 61, NMO-IgG-seropositive NMOSD. Altogether, 29.4% of our patients were initially misdiagnosed with multiple sclerosis. The average age at onset of NMO/NMOSD was 41.1 years with a strong female predilection, similar to other autoimmune disorders. Nonwhite patients constituted 52.4% of the cohort. The hallmark of NMO and NMOSD is recurrent longitudinally extensive transverse myelitis, but patients with NMO tend to initially present with optic neuritis. CONCLUSIONS A national multicenter consortium to study NMO/NMOSD is feasible and facilitates accurate clinical diagnosis. This network establishes a foundation for determining disease prevalence, translational research, and clinical trials.     

The IL-10-producing regulatory B cells (B10 cells) and regulatory T cell subsets in neuromyelitis optica spectrum disorder

B cells contribute to the pathogenesis of neuromyelitis optica (NMO) by producing Aquaporin 4-specific autoantibodies (AQP4-ab); on the other hand, there are certain B cells that suppress immune responses by producing regulatory cytokines, such as IL-10. In this study, we investigated the presence of IL-10-producing Breg cells among lymphocyte subsets. Twenty-two seropositive NMO spectrum disorder (NMOSD) patients (29 samples) and 13 healthy controls (HCs) (14 samples) were enrolled. All NMOSD patients have received one or more immunosuppressive drugs. The phenotype and frequency of B cell and T cell subsets in the peripheral blood were measured by flow cytometry. We defined Breg cells as IL-10-producing B (B10) cells, which are CD19⁺CD39⁺CD1d⁺IL-10⁺. The potential relations were evaluated between specific lymphocyte subsets and AQP4-ab intensity measured by the cell-based indirect immunofluorescence assay. The frequency of B10 cells was higher in patients with NMOSD regardless of the disease status than that in HCs (attack samples; p?=?0.009 and remission samples; p?<?0.001, respectively). In addition, the frequency of IL-17⁺ Treg cells among Treg cells was higher during remission than during an attack (uncorrected p?=?0.032). Among the lymphocyte subsets, B10 cells alone showed a positive correlation with the intensity of AQP4-ab positivity (ρ [rho]?=?0.402 and p?=?0.031). It was suggested that the suppressive subsets including B10 and IL-17⁺ Treg cells might have important roles in controlling disease status in NMOSD. Further functional studies may help to elucidate the immunological role of B10 and IL-17⁺ Treg cells in NMOSD.     

A clinical and radiological profile of neuromyelitis optica and spectrum disorders in an Indian cohort

Background:

There is insufficient data on the clinical and radiological features of neuromyelitis optica (NMO) and neuromyelitis optica spectrum disorders (NMOSD) from India.

Objective:

The objective of the following study is to examine the clinico-radiological features of NMO and NMOSD in an Indian cohort.

Materials and Methods:

This retrospective study included 44 consecutive patients who (1) satisfied the 2006 Wingerchuk criteria for NMO (16 seropositive and 7 seronegative); or (2) had isolated or recurrent optic neuritis (ON) with seropositivity (n = 4); or (3) had isolated or recurrent myelitis with seropositivity (n = 17).

Results:

The female:male ratio was 7.8:1 with median age of onset 26.5 (range 8-72). Annualized relapse rate (ARR) was comparable across all groups (F [3, 40] = 0.938 and P = 0.431). Various presentations other than ON and myelitis were noted. All 40 patients with myelitis had spinal cord lesions involving ≥3 vertebral segments during the course of the disease. Cervicomedullary involvement was seen in 32.5% (13/40) patients. Brain magnetic resonance imaging was available for 40 patients; eight of these (20%) had brain lesions in locations described in multiple sclerosis (MS), 27.5% (11/40) had lesions at sites unusual for MS and 52.5% (21/40) had normal brain imaging.

Conclusion:

NMO and NMOSD patients in this cohort have comparable ARR regardless of clinical presentation, supporting the emerging trend of treating all patients with immunotherapeutic agents at an early stage. Varied presentations seen in NMO and NMOSD highlight the need for a high index of suspicion for NMO in demyelinating episodes not classical for MS.     

Neuromyelitis optica spectrum disorder in a patient with systemic lupus erythematosus and anti-phospholipid antibody syndrome

Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system characterized by severe episodes of optic nerve and spinal cord inflammation. NMO-IgG (anti-aquaporin-4) has been recently described as a sensitive and specific marker for NMO. As there have been prior published reports of an association between NMO and systemic autoimmune diseases, the prognostic value of the antibody test in these cases is uncertain. We describe a 47-year old woman with recurrent transverse myelitis and a long-standing history of systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APLS). While she did not have a history of optic neuritis, serological testing for the NMO-IgG was positive when she was admitted for her second episode of transverse myelitis. Testing for the NMO-IgG in cases of isolated or recurrent transverse myelitis attributed to current SLE and APLS may help clarify the diagnosis of a distinct disease process likely to cause recurrent and severe disability, warranting more aggressive immunotherapy.     

Idiopathic severe recurrent transverse myelitis: a restricted variant of neuromyelitis optica

Recurrent idiopathic transverse myelitis occur in multiple sclerosis (MS) and neuromyelitis optica (NMO). In NMO, acute optic neuritis and myelitis occur, either monophasic or relapsing, without clinical manifestations of involvement of other parts of the central nervous system (CNS). Recent evidence suggests that NMO is different from multiple sclerosis. The authors reported two patients having severe recurrent transverse myelitis sparing the optic nerves and cerebral hemispheres. Both patients had longitudinally extensive myelitis in some attacks with poor neurological outcome despite aggressive immunomodulatory therapy. One patient had prominent clinical features of brainstem injury with radiological and histological confirmation of brainstem involvement, and the other patient had trigeminal neuralgia suggestive of possible brainstem dysfunction. Histologically, prominent necrosis and neutrophilic infiltration of spinal cord tissue without eosinophils or hyalinized vessels were observed, and oligoclonal bands were absent in their cerebrospinal fluid. It is likely to be a distinct idiopathic inflammatory demyelinating disorder restricted to the spinal cord and brainstem different from MS, but within the spectrum of NMO with probably an autoimmune basis.     

2015年视神经脊髓炎谱系疾病诊断标准国际共识解读

（aquaporin-4,AQP4）抗体的发现,加深了人们对 NMO 的认识,并扩展了 NMO 谱系疾sclerosis,MS）的一种中枢神经系统特发性炎性疾病。NMO 高度特异性的水通道蛋白4视神经脊髓炎（neuromyelitis optica,NMO）是不同于多发性硬化（multiple （International Panel for NMO Diagnosis,IPND）对 NMOSD 诊断标准进行了修订,并达病（neuromyelitis optica spectrum disorders,NMOSD）的定义。NMO 诊断国际专家组成2015年 NMOSD 诊断标准国际共识。该诊断标准取消了 NMO 的个别定义,而将 NMO归入 NMOSD。同时,根据 AQP4抗体表达状态,分为 AQP4抗体阳性和 AQP4抗体阴性NMOSD。AQP4抗体阳性 NMOSD 的诊断要求具备6项核心症状之一;AQP4抗体阴性或无法进行 AQP4抗体检测的 NMOSD 的诊断,要求则更为严格,必须有特征性的 MRI 表现。本文即对2015年 NMOSD 诊断标准国际共识中的要点进行解读和评论。     

The emerging relationship between neuromyelitis optica and systemic rheumatologic autoimmune disease

Neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSD) are associated with autoantibodies that target aquaporin-4 and, in many cases, multiple other autoantibodies, including antinuclear antibody and antibodies to extractable nuclear antigens. The clinical syndromes that define NMO and NMOSD, especially longitudinally extensive transverse myelitis and optic neuritis, can also occur in the context of established rheumatologic diseases such as systemic lupus erythematosus and Sj?gren syndrome and other organ-specific autoimmune diseases. These observations raise questions fundamental to both clinical practice and etiologic research. For example, they could suggest that NMO is one manifestation of a genetic tendency toward humoral autoimmunity. Alternatively, they might indicate that NMO is a central nervous system complication of a multisystem rheumatologic disease. We describe the historical background of this controversy, summarize the current evidence that addresses NMO-systemic autoimmunity relationships, and discuss the practical implications for clinical management.     

Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica

Neuromyelitis optica (NMO) is a rare CNS inflammatory disorder that predominantly affects the optic nerves and spinal cord. Recent serological findings strongly suggest that NMO is a distinct disease rather than a subtype of multiple sclerosis. In NMO, serum antibodies, collectively known as NMO-IgG, characteristically bind to cerebral microvessels, pia mater and Virchow-Robin spaces. The main target antigen for this immunoreactivity has been identified as aquaporin-4 (AQP4). The antibodies are highly specific for NMO, and they are also found in patients with longitudinally extensive transverse myelitis without optic neuritis, which is thought to be a precursor to NMO in some cases. An antibody-mediated pathogenesis for NMO is supported by several observations, including the characteristics of the AQP4 antibodies, the distinct NMO pathology--which includes IgG and complement deposition and loss of AQP4 from spinal cord lesions--and emerging evidence of the beneficial effects of B-cell depletion and plasma exchange. Many aspects of the pathogenesis, however, remain unclear.     

Dopamine favors expansion of glucocorticoid-resistant IL-17-producing T cells in multiple sclerosis

Dopamine (DA) is a neurotransmitter produced mainly in the central nervous system (CNS) that has immunomodulatory actions on T cells. As the multiple sclerosis (MS) has long been regarded as an autoimmune disease of CNS mediated by T cells, the objective of this study was to evaluate the impact of DA on in vitro functional status of T cells from relapsing–remitting (RR)–MS patients. Peripheral T-cells from RR–MS patients were activated by mitogens and cell proliferation and cytokine production were assayed by [³H]-thymidine uptake and ELISA, respectively. Our results demonstrated that DA enhanced in vitro T cell proliferation and Th17-related cytokines in MS-derived cell cultures. In addition, this catecholamine reduced Treg-related cytokines (IL-10 and TGF-β) release by activated CD4⁺ T cells. These DA-induced effects on T cells were mainly dependent on IL-6 production by both polyclonally-activated CD4⁺ T cells and LPS-stimulated monocytes. Furthermore, the production of IL-17 and IL-6 by MS-derived T cells was directly related with neurological disability (EDSS score), and the release of these cytokines was less sensitive to glucocorticoid inhibition in MS patients than in control group, mainly after DA addition. In conclusion, our data suggest that DA amplifies glucocorticoid-resistant Th17 phenotype in MS patients, and this phenomenon could be, at least in part, due to its ability to induce IL-6 production by monocytes and CD4⁺ T cells.     

Human T-lymphotropic virus type I or II (HTLV-I/II) associated with recurrent longitudinally extensive transverse myelitis (LETM): two case reports

We describe two patients with recurrent longitudinally extensive transverse myelitis (LETM) associated with human T-lymphotropic virus type I or II (HTLV-I/II) exposure, and with neuromyelitis optica (NMO) immunoglobulin G (IgG) antibody in one case. HTLV-I/II are well known retroviral agents of myelopathy and B-cell dysfunction in humans. NMO is an autoimmune, demyelinating disorder of the central nervous system (CNS), also linked to B-cell dysfunction. Therefore, the immunopathogenesis of NMO may in some cases be linked to human HTLV exposure. Awareness of a possible association with human retroviral exposure will contribute to the optimal diagnosis and management of patients presenting with LETM or NMO.     

MG患者外周血Th17细胞与AChR抗体产生的关系研究

目的探讨重症肌无力(MG)患者外周血中Th17细胞及相关细胞因子白细胞介素17(IL-17)在MG发病中的作用。方法收集40例MG患者和10名健康人(对照组)外周血标本,采用流式细胞术检测外周血单个核细胞(PBMCs)中Th17细胞比例,反转录酶-聚合酶链锁反应(RT-PCR)检测PBMCs中维甲酸受体相关孤儿受体γt(RORγt)mRNA水平,ELISA检测血清中IL-17水平,放射免疫沉淀法检测血清中抗乙酰胆碱受体抗体(AChR-Ab)滴度;分离PBMCs中CD4~+T细胞和CD19~+B细胞与金黄色葡萄球菌肠毒素B(SEB)进行共培养,培养系统中加入人IL-17和(或)IL-21中和抗体,放射免疫测定法检测培养液中AChR-Ab滴度。采用MG评分(quantitative MG scoring system,QMGs)对MG的严重程度进行评估,并对MG患者的Th17细胞比例、RORγt mRNA和IL-17水平与病情QMGs的相关性,以及MG患者抗AChR-Ab滴度与PBMCs中Th17细胞比例的相关性进行分析。结果 MG患者PBMCs中Th17细胞比例[1.11%(0.90%,1.34%)]高于健康对照组Th17细胞比例[0.26%(0.08%,0.36%)](z=5.494,P0.001),且与疾病严重程度呈正相关(r=0.4394,P=0.0046);血清中IL-17水平和PBMCs中RORγt mRNA相对表达[分别71.46(53.91,104.76)pg/mL、2.63(1.94,3.12)]均较健康对照组[分别18.82(12.73,29.80)pg/mL、1.13(0.98,1.28)]显著增高(均P0.001);MG患者血清中抗AChR-Ab滴度[2.34(1.19,3.60)nmol/L]较健康对照组[-0.08(-0.24,-0.03)nmol/L]显著增高(z=4.662,P0.001),且与Th17细胞比例呈正相关(r=0.7066,P=0.0001)。MG患者外周血T、B细胞与SEB共培养后抗AChR-Ab水平高于未加入SEB时及健康对照(均P0.01);加入抗人IL-21或IL-17中和抗体后,两者AChR-Ab滴度与未加入抗体时AChR-Ab滴度比较均降低(均P0.05),且均仍高于MG患者未加入SEB时及健康对照(P0.01);在培养上清中同时加入抗人IL-21和IL-17中和抗体时AChR-Ab滴度明显低于加入单种抗体时,而与未加入SEB时及健康对照差异无统计学意义(均P0.05)。结论 MG患者外周血中Th17细胞可能通过IL-17促进AChR-Ab产生,参与疾病的病理过程。     

Perivascular Enhancement in a Patient with Neuromyelitis Optica Spectrum Disease during an Optic Neuritis Attack

We present a case with neuromyelitis optica spectrum disease (NMOSD) who had perivascular enhancement during an optic neuritis attack. Cloud‐like enhancement, pencil‐thin enhancement, and leptomeningeal enhancement have been defined as specific enhancement patterns to neuromyelitis optica (NMO). Perivascular enhancement has not been described before in NMO/NMOSD. This finding suggests that perivascular enhancement may also be seen in NMO/NMOSD patients.     

Espectro de neuromielitis óptica: ¿seropositivo para la anticuaporina es una entidad diferente de los pacientes que son seronegativos? Una perspectiva de Colombia

IntroductionNeuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterised by attacks of optic neuritis and longitudinally extensive transverse myelitis. The discovery of anti–aquaporin-4 (anti-AQP4) antibodies and specific brain MRI findings as diagnostic biomarkers have enabled the recognition of a broader and more detailed clinical phenotype, known as neuromyelitis optica spectrum disorder (NMOSD).ObjectiveThis study aimed to determine the demographic and clinical characteristics of patients with NMO/NMOSD with and without seropositivity for anti-AQP4 antibodies, in 2 quaternary-level hospitals in Bogotá.MethodsOur study included patients > 18 years of age and diagnosed with NMO/NMOSD and for whom imaging and serology results were available, assessed between 2013 and 2017 at the neurology departments of hospitals providing highly complex care. Demographic, clinical, and imaging data were gathered and compared in patients with and without seropositivity for anti-AQP4 antibodies.ResultsThe sample included 35 patients with NMO/NMOSD; the median age of onset was 46.5 years (P25-P75, 34.2-54.0); most patients had sensory (n = 25) and motor manifestations (n = 26), and a concomitant autoimmune disease was identified in 6. Twenty patients were seropositive for anti-AQP4 antibodies. Only age and presence of optic nerve involvement showed statistically significant differences between groups (p = .03).ConclusionsClinical, imaging, and laboratory variables showed no major differences between patients with and without anti-AQP4 antibodies, with the exception of age of onset and presence of optic nerve involvement (uni- or bilateral); these factors should be studied in greater detail in larger populations.     

Neuromyelitis optica and non organ-specific autoimmunity

BACKGROUND: Neuromyelitis optica (NMO) is often associated with other clinical or serological markers of non-organ-specific autoimmunity. OBJECTIVE: To evaluate the relationship between NMO spectrum disorders (NMOSDs), including NMO, longitudinally extensive transverse myelitis, and recurrent optic neuritis, and autoimmune disease. We concentrated on the association with systemic lupus erythematosus (SLE), Sj?gren syndrome (SS), or serological evidence of these disorders, which commonly is a source of diagnostic confusion. DESIGN: Retrospective blinded serological survey. SETTING: Mayo Clinic College of Medicine, Rochester, and Centre Hospitalier Régional Universitaire de Lille. METHODS: Group 1 included 153 US patients with NMOSDs (78 with NMO and 75 with longitudinally extensive transverse myelitis) and 33 control subjects with SS/SLE. Group 2 included 30 French patients with SS/SLE, 14 with NMOSDs (6 with NMO, 6 with longitudinally extensive transverse myelitis, and 2 with recurrent optic neuritis), 16 without NMOSDs, and 4 with NMO without SS/SLE. RESULTS: For group 1, NMO-IgG was detected in 66.7%, antinuclear antibodies in 43.8%, and Sj?gren syndrome A (SSA) antibodies in 15.7% of patients with NMO and longitudinally extensive transverse myelitis. Five NMO-IgG-seropositive patients with NMOSDs had coexisting SLE, SS, or both. Antinuclear antibodies and SSA antibodies were more frequent in NMO-IgG-seropositive patients than in NMO-IgG-seronegative patients (P= .001). For group 2, NMO-IgG was detected in 5 of 14 patients (35.7%) with NMOSDs and SS/SLE and in 2 of 4 patients (50.0%) with NMO without SS/SLE (P= .59). We detected NMO-IgG only in patients with NMOSDs and not in 49 controls with SS/SLE but without optic neuritis or myelitis from the 2 cohorts (P= .01). CONCLUSION: Neuromyelitis optica spectrum disorders with seropositive findings for NMO-IgG occurring with SS/SLE or non-organ-specific autoantibodies is an indication of coexisting NMO rather than a vasculopathic or other complication of SS/SLE.     

Neuromyelitis optica: a distinct demyelinating disease of the central nervous system

Objectives – We review and discuss the pathogenesis, epidemiology, diagnosis as well as recent advances in the treatment of NMO. We also highlight areas of future research. Methods – A review was carried out on reports drawn from MEDLINE until 2007. Results – Neuromyelitis optica (NMO) is a relative uncommon demyelinating disease of the central nervous system (CNS) that preferentially affects the optic nerves and spinal cord. NMO follows an unpredictable course, being either monophasic or relapsing. The relapsing form of NMO primarily affects women with onset varying from childhood to adults in their 40s or elderly. Until recently, NMO was considered to be a variant of multiple sclerosis. However, in contrast to multiple sclerosis, NMO attacks are not mediated by T cells but rather by B cells and NMO‐immunoglobulin G antibodies that target aquaporin‐4. Humoral immune mechanisms, including complement activation plays an important role in the pathogenesis of NMO. At present, parenteral corticosteroids are widely employed as first‐line treatment of optic neuritis and myelitis attacks, whereas therapeutic plasmapheresis is applied in the case of corticosteroids failure. Various strategies for the prevention of NMO relapses have been employed in small case series with modest activity. Conclusion – Recent advances in the clinical, neuroimaging, laboratory and pathological hallmarks have established that NMO is a distinct demyelinating disease of the CNS.     

Neuromyelitis optica IgG status in acute partial transverse myelitis

BACKGROUND: Neuromyelitis optica (NMO) IgG is a specific marker for NMO. Furthermore, a high proportion of patients with longitudinally extensive transverse myelitis (characterized by spinal cord lesions extending 3 vertebral segments or more on magnetic resonance imaging) are seropositive for NMO-IgG and are considered to have a limited form of NMO. The NMO-IgG status in mild cases of acute partial transverse myelitis asociated with minimal magnetic resonance imaging abnormalities (spinal cord lesions <2 vertebral segments on magnetic resonance imaging) is unknown. OBJECTIVE: To investigate the NMO-IgG status of patients with acute partial transverse myelitis and a normal cerebral magnetic resonance image. DESIGN: Observational, retrospective consecutive case series with longitudinal follow-up. SETTING: Allegheny Multiple Sclerosis Treatment Center. PATIENTS: Three groups of patients were tested for NMO-IgG. Group 1 consisted of 22 patients with acute partial transverse myelitis, group 2 consisted of 4 patients with definite NMO (by 1999 criteria of Wingerchuk et al), and group 3 consisted of 6 patients with definite multiple sclerosis. MAIN OUTCOME MEASURE: NMO-IgG status. A commercially available assay for NMO antibodies was performed at the Mayo Clinic. Testing was performed during the convalescent stage of the illness. RESULTS: Of the 22 patients with acute partial transverse myelitis, only 1 was seropositive for NMO-IgG at presentation. This patient subsequently developed recurrent episodes of longitudinally extensive transverse myelitis that are typicaly seen in association with NMO-IgG. Three of the 4 patients meeting criteria for NMO were seropositive. None of the patients with multiple sclerosis had NMO-IgG detected. CONCLUSION: NMO-IgG is rarely encountered in patients with acute partial transverse myelitis, which is in sharp contrast to the high frequency of this antibody in patients with NMO and longitudinally extensive transverse myelitis.     

New Insights into Neuromyelitis Optica

Neuromyelitis optica (NMO) is an idiopathic inflammatory disorder of the central nervous system (CNS) that preferentially affects the optic nerves and spinal cord. In Asia, NMO has long been considered a subtype of multiple sclerosis (MS). However, recent clinical, pathological, immunological, and imaging studies have suggested that NMO is distinct from MS. This reconsideration of NMO was initially prompted by the discovery of a specific antibody for NMO (NMO-IgG) in 2004. NMO-IgG is an autoantibody that targets aquaporin-4 (AQP4), the most abundant water channel in the CNS; hence, it was named anti-AQP4 antibody. Since it demonstrated reasonable sensitivity and high specificity, anti-AQP4 antibody was incorporated into new diagnostic criteria for NMO.The spectrum of NMO is now known to be wider than was previously recognized and includes a proportion of patients with recurrent, isolated, longitudinally extensive myelitis or optic neuritis, and longitudinally extensive myelitis or optic neuritis associated with systemic autoimmune disease or with brain lesions typical of NMO. In this context, a new concept of "NMO spectrum disorders" was recently introduced. Furthermore, seropositivity for NMO-IgG predicts future relapses and is recognized as a prognostic marker for NMO spectrum disorders. Humoral immune mechanisms, including the activation of B-cells and the complement pathway, are considered to play important roles in NMO pathogenesis. This notion is supported by recent studies showing the potential pathogenic role of NMO-IgG as an initiator of NMO lesions. However, a demonstration of the involvement of NMO-IgG by the development of active immunization and passive transfer in animal models is still needed. This review focuses on the new concepts of NMO based on its pathophysiology and clinical characteristics. Potential management strategies for NMO in light of its pathomechanism are also discussed.     

Infiltration of Th1 and Th17 cells and activation of microglia in the CNS during the course of experimental autoimmune encephalomyelitis

Experimental autoimmune encephalomyelitis (EAE) is a mouse model for multiple sclerosis, where disease is mediated by autoantigen-specific T cells. Although there is evidence linking CD4⁺ T cells that secrete IL-17, termed Th17 cells, and IFN-γ-secreting Th1 cells with the pathogenesis of EAE, the precise contribution of these T cell subtypes or their associated cytokines is still unclear. We have investigated the infiltration of CD4⁺ T cells that secrete IFN-γ, IL-17 or both cytokines into CNS during development of EAE and have examined the role of T cells in microglial activation. Our findings demonstrate that Th17 cells and CD4⁺ T cells that produce both IFN-γ and IL-17, which we have called Th1/Th17 cells, infiltrate the brain prior to the development of clinical symptoms of EAE and that this coincides with activation of CD11b⁺ microglia and local production of IL-1β, TNF-α and IL-6 in the CNS. In contrast, significant infiltration of Th1 cells was only detected after the development of clinical disease. Co-culture experiments, using mixed glia and MOG-specific T cells, revealed that T cells that secreted IFN-γ and IL-17 were potent activators of pro-inflammatory cytokines but T cells that secrete IFN-γ, but not IL-17, were less effective. In contrast both Th1 and Th1/Th17 cells enhanced MHC-class II and co-stimulatory molecule expression on microglia. Our findings suggest that T cells which secrete IL-17 or IL-17 and IFN-γ infiltrate the CNS prior to the onset of clinical symptoms of EAE, where they may mediate CNS inflammation, in part, through microglial activation.     

Interferon beta inhibits the Th17 cell-mediated autoimmune response in patients with relapsing–remitting multiple sclerosis

Interferon (IFN)β has been used over the past decades as an effective first-line therapy against relapsing–remitting multiple sclerosis (RR MS), however its in vivo operative mechanisms of action are not fully understood. Current advances in our understanding of the development of the autoimmune response, including its induction by a recently discovered Th17 cell lineage, may allow us to identify the biomarkers of this effective therapy. Our in vitro human studies have characterized IFNβ’s immunoregulatory effects on Th17 cell differentiation. IFNβ inhibited IL-1β, IL-23 and transforming growth factor (TGF)-β (which induce Th17 cell differentiation), and induced IL-27, IL-12p35 and IL-10 (which suppress it) in dendritic cells (DCs) and B-cells. The effect on IL-1β, IL-23 and IL-27 production in DCs was mediated by the up-regulation of Toll-like receptor (TLR)7 and its downstream signaling molecules. IFNβ’s direct effect on naïve T-cells suppressed in vitro Th17 differentiation by inhibiting Th17 cell lineage markers (retinoic acid-related orphan nuclear hormone receptor (ROR)c, IL-17A, IL-23R and CCR6), and by inducing IL-10 production by CD4 cells, which constrains Th17 cell expansion. Our results have identified novel therapeutic mechanisms of IFNβ, which inhibit Th17 cell differentiation in the context of the autoimmune response in MS.