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Epidemiological, clinical, and immunological characteristics of neuromyelitis optica: A review

  • Wildéa Lice de Carvalho Jennings Pereira
    Affiliations
    Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Paraná 86038-440, Brazil

    Outpatient Clinic for Demyelinating Diseases, University Hospital, State University of Londrina, Londrina, Paraná 86061-335, Brazil
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  • Edna Maria Vissoci Reiche
    Correspondence
    Corresponding author at: Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, Londrina State University, Av. Robert Koch, 60, 86038-440 Londrina, Paraná, Brazil.
    Affiliations
    Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, State University of Londrina, Londrina, Paraná 86038-440, Brazil
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  • Ana Paula Kallaur
    Affiliations
    Health Sciences Postgraduate Program, Health Sciences Center, State University of Londrina, Londrina, Paraná 86038-440, Brazil
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  • Damacio Ramón Kaimen-Maciel
    Affiliations
    Outpatient Clinic for Demyelinating Diseases, University Hospital, State University of Londrina, Londrina, Paraná 86061-335, Brazil

    Department of Clinical Medicine, Health Sciences Center, State University of Londrina, Londrina, Paraná 86038-440, Brazil
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      Highlights

      • Neuromyelitis optica (NMO) most commonly affects the optic nerves and spinal cord.
      • The etiology of NMO involves interactions between genetic and environmental factors.
      • Various autoimmune diseases have been reported in up to 30% of patients with neuromyelitis optica.
      • Antibody against aquaporin 4 (anti-APQ4) is the major immunologic characteristic of NMO.
      • Antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity mediate the damage processes.

      Abstract

      The aim of this study was to review the epidemiological and clinical characteristics of neuromyelitis optica (NMO) and the immunopathological mechanisms involved in the neuronal damage. NMO is an inflammatory demyelinating autoimmune disease of the central nervous system that most commonly affects the optic nerves and spinal cord. NMO is thought to be more prevalent among non-Caucasians and where multiple sclerosis (MS) prevalence is low. NMO follows a relapsing course in more than 80–90% of cases, which is more commonly in women. It is a complex disease with an interaction between host genetic and environmental factors and the main immunological feature is the presence of anti-aquaporin 4 (AQP4) antibodies in a subset of patients. NMO is frequently associated with multiple other autoantibodies and there is a strong association between NMO with other systemic autoimmune diseases. AQP4-IgG can cause antibody-dependent cellular cytotoxicity (ADCC) when effector cells are present and complement-dependent cytotoxicity (CDC) when complement is present. Acute therapies, including corticosteroids and plasma exchange, are designed to minimize injury and accelerate recovery. Several aspects of NMO pathogenesis remain unclear. More advances in the understanding of NMO disease mechanisms are needed in order to identify more specific biomarkers to NMO diagnosis.

      Keywords

      1. Introduction

      Neuromyelitis optica (NMO), also known as Devic's disease or Devic's syndrome, is an inflammatory demyelinating autoimmune disease of the central nervous system (CNS) that most commonly affects the optic nerves and spinal cord [
      • Jacob A.
      • Matiello M.
      • Wingerchuk D.M.
      • Lucchinetti C.F.
      • Pittock S.J.
      • Weinshenker B.G.
      Neuromyelitis optica: changing concepts.
      ,
      • Matiello M.
      • Jacob A.
      • Wingerchuk D.
      • Weinshenker B.G.
      Neuromyelitis optica.
      ,
      • Kim W.
      • Kim S.H.
      • Kim H.J.
      New insights into neuromyelitis optica.
      ,
      • Jarius S.
      • Wildemann B.
      The history of neuromyelitis optica.
      ]. There has long been controversy as to whether Devic's disease is a peculiar variant of multiple sclerosis (MS) or a distinct disease [
      • Kim W.
      • Kim S.H.
      • Kim H.J.
      New insights into neuromyelitis optica.
      ,
      • Matà S.
      • Lolli F.
      Neuromyelitis optica: An update.
      ]. However, clinical, immunological, radiological, and pathological studies have established that NMO is distinct from MS. In 2004, the discovery of the specific autoantibody against aquaporin-4 (anti-AQP4) reinforced the later consideration [
      • Matiello M.
      • Jacob A.
      • Wingerchuk D.
      • Weinshenker B.G.
      Neuromyelitis optica.
      ,
      • Kim W.
      • Kim S.H.
      • Kim H.J.
      New insights into neuromyelitis optica.
      ].
      The epidemiology of NMO is not clearly established because the disease is frequently misdiagnosed as MS [
      • Mandler R.N.
      Neuromyelitis optica – Devic's syndrome, update.
      ]. Although cases of NMO have been reported in all continents, epidemiological studies of the disease are scarce [
      • Mealy M.A.
      • Wingerchuk D.M.
      • Greenberg B.M.
      • Levy M.
      Epidemiology of Neuromyelitis optica in the United States: a multicenter analysis.
      ] and its incidence and prevalence are poorly established [
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ,
      • Rivera J.F.
      • Kurtzke J.F.
      • Booth V.J.A.
      • Corona V, V.T.
      Characteristics of Devic's disease (neuromyelitis optica) in Mexico.
      ,
      • Wingerchuk D.M.
      Neuromyelitis optica: effect of gender.
      ,
      • Mealy M.A.
      • Wingerchuk D.M.
      • Greenberg B.M.
      • Levy M.
      Epidemiology of Neuromyelitis optica in the United States: a multicenter analysis.
      ]. Studies present incidence rates ranging from 0.053 to 0.4 per 100,000 individuals and prevalence rates ranging from 0.52 to 4.4 per 100.000 individuals [
      • Mealy M.A.
      • Wingerchuk D.M.
      • Greenberg B.M.
      • Levy M.
      Epidemiology of Neuromyelitis optica in the United States: a multicenter analysis.
      ,
      • Cossburn M.
      • Tackley G.
      • Baker K.
      • Ingram G.
      • Burtonwood M.
      • Malik G.
      • Pickersgill T.
      • Te Water Naude J.
      • Robertson N.
      The prevalence of neuromyelitis optica in South East Wales.
      ].
      NMO is thought to be more prevalent among non-Caucasians and where MS prevalence is low [
      • Rivera J.F.
      • Kurtzke J.F.
      • Booth V.J.A.
      • Corona V, V.T.
      Characteristics of Devic's disease (neuromyelitis optica) in Mexico.
      ,
      • Lana-Peixoto M.A.
      Devic's neuromyelitis optica: a critical review.
      ,
      • Mealy M.A.
      • Wingerchuk D.M.
      • Greenberg B.M.
      • Levy M.
      Epidemiology of neuromyelitis optica in the United States: a multicenter analysis.
      ,
      • Cossburn M.
      • Tackley G.
      • Baker K.
      • Ingram G.
      • Burtonwood M.
      • Malik G.
      • et al.
      The prevalence of neuromyelitis optica in South East Wales.
      ]. There have been many reports about the higher rate of NMO in Asian, Indian and Black populations than in Caucasians [
      • Matiello M.
      • Jacob A.
      • Wingerchuk D.
      • Weinshenker B.G.
      Neuromyelitis optica.
      ,
      • Lana-Peixoto M.A.
      Devic's neuromyelitis optica: a critical review.
      ]. On the other hand, NMO population enrolled in a French study was mainly Caucasians (87%) and, in a Danish study, all the patients with NMO except one were Caucasians, suggesting that the disease is more common in Caucasians than earlier believed [
      • Cabrera-Gómez J.A.
      • Kurtzke J.F.
      • González-Quevedo A.
      • Lara-Rodríguez R.
      An epidemiological study of neuromyelitis optica in Cuba.
      ,
      • Asgari N.
      • LIllevang S.T.
      • Skejoe H.P.
      • Falah M.
      • Stenager E.
      • Kyvik K.O.
      A population-based study of neuromyelitis optica in Caucasians.
      ].
      There is a female predominance in NMO [
      • Wingerchuk D.M.
      Neuromyelitis optica: effect of gender.
      ,
      • Cossburn M.
      • Tackley G.
      • Baker K.
      • Ingram G.
      • Burtonwood M.
      • Malik G.
      • et al.
      The prevalence of neuromyelitis optica in South East Wales.
      ]. An epidemiological report in a Cuban population showed a much higher rate in females (0.91) than in males (0.12) [
      • Mealy M.A.
      • Wingerchuk D.M.
      • Greenberg B.M.
      • Levy M.
      Epidemiology of neuromyelitis optica in the United States: a multicenter analysis.
      ]. In Iranian and French patients, the female to male ratio was 3:1 and in American patients it was 6.5:1 [
      • Mealy M.A.
      • Wingerchuk D.M.
      • Greenberg B.M.
      • Levy M.
      Epidemiology of Neuromyelitis optica in the United States: a multicenter analysis.
      ,
      • Cabrera-Gómez J.A.
      • Kurtzke J.F.
      • González-Quevedo A.
      • Lara-Rodríguez R.
      An epidemiological study of neuromyelitis optica in Cuba.
      ,
      • Sahraian M.A.
      • Moinfar Z.
      • Khorramnia S.
      • Ebrahim M.M.
      Relapsing neuromyelitis optica: demographic and clinical features in Iranian patients.
      ]. A Brazilian study revealed a female:male ratio of 5:1 [
      • Papais-Alvarenga R.M.
      • Miranda-Santos C.M.
      • Puccioni-Sohler M.
      • De Almeida A.M.
      • Oliveira S.
      • Basilio de Oliveira C.A.
      • et al.
      Optic neuromyelitis syndrome in Brazilian patients.
      ]. The female preponderance may suggest that sex hormones influence NMO susceptibility and activity. Gender may determine whether NMO follows a relapsing or monophasic course with an association between female and the relapsing course [
      • Wingerchuk D.M.
      Neuromyelitis optica: effect of gender.
      ].
      The age of onset ranges from childhood to adulthood but the disease affects mostly young adults with a mean age at onset higher than that of MS [
      • Kim W.
      • Kim S.H.
      • Kim H.J.
      New insights into neuromyelitis optica.
      ,
      • Lana-Peixoto M.A.
      Devic's neuromyelitis optica: a critical review.
      ]. In the United States, the average age at onset of NMO was 41.1 years; in Brazilian reports, the age at onset ranged from 14 to 55 years [
      • Mealy M.A.
      • Wingerchuk D.M.
      • Greenberg B.M.
      • Levy M.
      Epidemiology of Neuromyelitis optica in the United States: a multicenter analysis.
      ,
      • Papais-Alvarenga R.M.
      • Miranda-Santos C.M.
      • Puccioni-Sohler M.
      • De Almeida A.M.
      • Oliveira S.
      • Basilio de Oliveira C.A.
      • et al.
      Optic neuromyelitis syndrome in Brazilian patients.
      ]. NMO appears to be very rare in European pediatric population, but a cohort study with six pediatric patients with NMO from Germany showed that the age at the disease onset ranged from 5.0 to 14.0 years old [
      • Huppke P.
      • Blüthner M.
      • Bauer O.
      • Stark W.
      • Reinhardt K.
      • Huppke B.
      • et al.
      Neuromyelitis optica and NMO-IgG in European pediatric patients.
      ].

      2. Classification

      The disease can follow a monophasic or relapsing course [
      • Matà S.
      • Lolli F.
      Neuromyelitis optica: An update.
      ]. Eugène Devic and Fernand Gault characterized NMO as an acute monophasic disorder of transverse myelitis (TM) and optic neuritis (ON) occurring simultaneously or in rapid succession. This definition is called Devic's classical syndrome. A relapsing form of NMO was later reported, recognizing the existence of two NMO subtypes. Studies suggest that classical Devic's syndrome occurs only in a minority of cases, with women and men equally affected. In more than 80–90% of cases, NMO follows a relapsing course, which is more commonly found in women and associated with older age at onset, longer time interval between index events, less severe motor impairment with the first myelitis attack, and with the presence of systemic autoimmunity [
      • Matà S.
      • Lolli F.
      Neuromyelitis optica: An update.
      ,
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ] (Table 1).
      Table 1Classification of neuromyelitis optica (NMO) clinical forms.
      Clinical formsCharacteristics
      Monophasic1 — Transverse myelitis and optic neuritis occurring simultaneously or in rapid succession

      2 — Affects equally men and women

      3 — Minority of cases

      4 — Devic's classical syndrome
      Relapsing1 — Transverse myelitis

      2 — Optical neuritis

      3 — Relapsing attacks

      4 — Affects more frequently women

      5 — 80–90% of cases
      NMO spectrum disorders (NMOSD): anti-aquaporin 4 (AQP4) seropositivity status in addition to limited forms of NMO1 — Idiopathic single or recurrent events of longitudinally extensive myelitis

      2 — Optical neuritis simultaneous bilateral or recurrent

      3 — Asian optic-spinal multiple sclerosis

      4 — Optic neuritis or longitudinally extensive myelitis associated with systemic autoimmune disease

      5 — Optic neuritis or myelitis association with brain lesions typical of NMO
      NMO spectrum disorders (NMOSD) is a proposed term to classify patients who do not meet the 2006 diagnostic criteria [
      • Wingerchuk D.M.
      • Lennon V.A.
      • Pittock S.J.
      • Lucchinetti C.F.
      • Weinshenker B.G.
      Revised diagnostic criteria for neuromyelitis optica.
      ]. This condition is characterized by anti-AQP4 seropositivity status in addition to limited forms of NMO, including idiopathic single or recurrent events of longitudinally extensive myelitis, ON simultaneous bilateral or recurrent; Asian optic-spinal MS; ON or longitudinally extensive myelitis associated with systemic autoimmune disease; ON or myelitis associated with brain lesions typical of NMO (brainstem, hypothalamic, periventricular and corpus callosal) [
      • Fujihara K.
      • Misu T.
      • Nakashima I.
      • Takahashi T.
      • Bradl M.
      • Lassmann H.
      • et al.
      Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease.
      ].

      3. Diagnostic criteria of NMO

      The first diagnostic criteria for NMO were proposed in 1999 but they were reviewed in 2006 and the authors proposed criteria that remove the restriction on CNS involvement beyond the optic nerves and spinal cord and included anti-AQP4 seropositivity. The revised diagnostic criteria are acute myelitis, ON and, at least, two of three supportive criteria: contiguous spinal cord MRI lesion extending over ≥3 vertebral segments, brain MRI not meeting diagnostic criteria for MS and anti-AQP4 seropositive status [
      • Wingerchuk D.M.
      • Lennon V.A.
      • Pittock S.J.
      • Lucchinetti C.F.
      • Weinshenker B.G.
      Revised diagnostic criteria for neuromyelitis optica.
      ] (Table 2).
      Table 2Diagnostic criteria for neuromyelitis optica (NMO).
      1 — Acute myelitis
      2 — Optic neuritis
      3 — At least two of three supportive criteria:

      • Contiguous spinal cord magnetic resonance imaging (MRI) lesion over ≥3 vertebral segments
      • Brain MRI not meeting diagnostic criteria for multiple sclerosis
      • Anti-aquaporin 4 (anti-AQP4) seropositive status

      4. Clinical features

      Devic's disease was described in 1870 by Thomas Clifford Allbutt who reported, firstly, the association between unilateral optic nerve disorder and myelitis. In 1894, Eugène Devic and his student Fernand Gault described 16 patients who had lost vision bilaterally or unilaterally and within weeks developed loss of sphincter control, spastic tetraparesis or paraparesis and loss of sensation [
      • Jacob A.
      • Matiello M.
      • Wingerchuk D.M.
      • Lucchinetti C.F.
      • Pittock S.J.
      • Weinshenker B.G.
      Neuromyelitis optica: changing concepts.
      ,
      • Kim W.
      • Kim S.H.
      • Kim H.J.
      New insights into neuromyelitis optica.
      ,
      • Jarius S.
      • Wildemann B.
      The history of neuromyelitis optica.
      ,
      • Matà S.
      • Lolli F.
      Neuromyelitis optica: An update.
      ,
      • Mandler R.N.
      Neuromyelitis optica – Devic's syndrome, update.
      ,
      • Sahraian M.A.
      • Moinfar Z.
      • Khorramnia S.
      • Ebrahim M.M.
      Relapsing neuromyelitis optica: demographic and clinical features in Iranian patients.
      ].
      Some hypothalamic symptoms, such as hypothermia, fever, hypotension, bradycardia, narcolepsy, anorexia, hyperphagia and syndrome of inappropriate secretion of antidiuretic hormone have been described associated with NMOSD. Intractable vomiting, nausea and hiccough, typically associated with lesions in the area postrema, are the most frequent brain symptoms in NMO [
      • Lana-Peixoto M.A.
      • Callegaro D.
      The expanded spectrum of neuromyelitis optica — evidences for a new definition.
      ]. Hyponatremia and posterior reversible encephalopathy syndrome (PRES) are other uncommon complications in patients with NMO [
      • Lana-Peixoto M.A.
      • Callegaro D.
      The expanded spectrum of neuromyelitis optica — evidences for a new definition.
      ,
      • Weinshenker B.G.
      Clinical spectrum of neuromyelitis optica 2013.
      ].
      Various autoimmune diseases have been reported in up to 30% of patients with NMO, suggesting that individuals with this condition might have a genetic predisposition to aberrant autoimmunity [
      • Mandler R.N.
      Neuromyelitis optica – Devic's syndrome, update.
      ,
      • Iyer A.
      • Elsone L.
      • Appleton R.
      • Jacob A.
      A review of the current literature and a guide to the early diagnosis of autoimmune disorders associated with neuromyelitis optica.
      ]. There is a strong recognized association between NMO with other systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), Sjögren syndrome (SS), myasthenia gravis (MG), anticardiolipin syndrome, ANCA-associated diseases, Hashimoto thyroiditis, pernicious anemia, ulcerative colitis, idiopathic thrombocytopenic purpura, primary sclerosing cholangitis, and sarcoidosis [
      • Iyer A.
      • Elsone L.
      • Appleton R.
      • Jacob A.
      A review of the current literature and a guide to the early diagnosis of autoimmune disorders associated with neuromyelitis optica.
      ,
      • Sergio P.
      • Mariana B.
      • Alberto O.
      • Claudia U.
      • Oscar R.
      • Pablo M.
      • et al.
      Association of neuromyelitis optic (NMO) with autoimmune disorders: report of two cases and review of the literature.
      ,
      • Fujihara K.
      Neuromyelitis optica and astrocytic damage in its pathogenesis.
      ,
      • Leite M.I.
      • Coutinho E.
      • Lana-Peixoto M.
      • Apostolos S.
      • Waters P.
      • Sato D.
      • et al.
      Myasthenia gravis and neuromyelitis optica spectrum disorder: a multicenter study of 16 patients.
      ,
      • Maruta K.
      • Sonoda Y.
      • Uchida Y.
      • Takahashi T.
      • Fukunaga H.
      A case of neuromyelitis optica associated with anti-aquaporin 4 antibody and other autoantibodies.
      ,
      • Wingerchuk D.M.
      • Weinshenker B.G.
      The emerging relationship between neuromyelitis optica and systemic rheumatologic autoimmune disease.
      ,
      • Freitas E.
      • Guimarães J.
      Neuromyelitis optica spectrum disorders associated with other autoimmune diseases.
      ,
      • Jarius S.
      • Paul F.
      • Franciotta D.
      • De Seze J.
      • Münch C.
      • Salvetti M.
      • et al.
      Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature.
      ].
      In many cases, NMO is frequently associated with multiple other autoantibodies, including specific antibodies against for a panel of extracellular and intracellular antigens, such as antinuclear antibodies (ANA), antibodies against double-stranded DNA (anti-dsDNA), extractable nuclear antigen (anti-ENA), tireoperoxidase (anti-TPO), tireoglobulin (anti-Tg), acetylcholine receptor (AChR-Ab), and celiac disease-related antibodies, such as deamidated gliadin and tissue transglutaminase antibodies. Other autoantibodies found in NMO patients are anti-myelin oligodendrocyte glycoprotein (anti-MOG) and anti-myelin basic protein [
      • Wingerchuk D.M.
      • Weinshenker B.G.
      The emerging relationship between neuromyelitis optica and systemic rheumatologic autoimmune disease.
      ,
      • Sato D.K.
      • Lana-Peixoto M.
      • Fujihara K.
      • De Seze J.
      Clinical spectrum and treatment of neuromyelitis optica spectrum disorders: evolution and current status.
      ].
      Some other syndromes are recently recognized to be in association with NMO, such as opsoclonus-myoclonus, cognitive decline, acute myopathy with hyperCKemia, hearing loss, and lumbar myeloradiculitis [
      • Weinshenker B.G.
      Clinical spectrum of neuromyelitis optica 2013.
      ].

      5. Pathogenesis

      NMO is a complex disease with an interaction between host genetic and environmental factors. The major immunologic characteristic of the NMO is the presence of antibodies against aquaporin 4 (anti-AQP4), the main water channel in the brain. However, the lack of anti-AQP4 seropositivity in a subset of NMO patients suggests that the myelitis and ON can be caused by other mechanisms, such as connective tissue disorders, paraneoplastic disorders [
      • Jarius S.
      • Paul F.
      • Franciotta D.
      • De Seze J.
      • Münch C.
      • Salvetti M.
      • et al.
      Neuromyelitis optica spectrum disorders in patients with myasthenia gravis: ten new aquaporin-4 antibody positive cases and a review of the literature.
      ], or infectious diseases [
      • Sellner J.
      • Hemmer B.
      • Mühlau M.
      The clinical spectrum and immunobiology of parainfectious neuromyelitis optica (Devic) syndromes.
      ], providing strong evidence in favor of the hypothesis of NMO being etiopathogenetically heterogeneous [
      • Jarius S.
      • Wildemann B.
      The history of neuromyelitis optica.
      ].

      5.1 Human leukocyte antigen (HLA) genetic factor

      The genetic factor most extensively studied is the HLA. In a Chinese report, the frequency of HLA-DPB1*0501 allele was significant higher in NMO than in MS and the -DPB1*0501 allele was correlated with risk of NMO with anti-AQP4 positive in the Southern Han Chinese population [
      • Wang H.
      • Dai Y.
      • Qiu W.
      • Zhong X.
      • Wu A.
      • Wang Y.
      • et al.
      HLA-DPB1*0501 is associated with susceptibility to anti-aquaporin-4 antibodies positive neuromyelitis optica in Southern Han Chinese.
      ].
      Blanco et al. demonstrated that NMO is associated with increased frequency of HLA-DRB1*10 allele compared with MS and with increased frequency of HLA-DRB1*03 allele compared with healthy controls [
      • Blanco Y.
      • Ercilla-González G.
      • Llufriu S.
      • Casanova-Estruch B.
      • Magraner M.J.
      • Ramió-Torrentá L.
      • et al.
      HLA-DRB1 typing in Caucasians patients with neuromyelitis optica.
      ]. Among French Afro-Caribbean patients with NMO the HLA-DRB1 allele distribution showed an increased frequency of -DRB1*03 alleles [
      • Deschamps R.
      • Paturel L.
      • Jeannin S.
      • Chausson N.
      • Olindo S.
      • Béra O.
      • et al.
      Different HLA class II (DRB1 and DQB1) alleles determine either susceptibility or resistance to NMO and multiple sclerosis among the French Afro-Caribbean population.
      ] and in Afro-Brazilian patients, the -DRB1*03 was also more frequent, especially in the subgroup presenting extensive spinal cord lesion [
      • Brum D.G.
      • Barreira A.A.
      • Dos Santos A.C.
      • Kaimen-Maciel D.R.
      • Matiello M.
      • Costa R.M.
      • et al.
      HLA-DRB association in neuromyelitis optica is different from that observed in multiple sclerosis.
      ]. The HLA-DRB1*03 allele is related to anti-AQP4 seropositivity in Caucasians with NMO [
      • Blanco Y.
      • Ercilla-González G.
      • Llufriu S.
      • Casanova-Estruch B.
      • Magraner M.J.
      • Ramió-Torrentá L.
      • et al.
      HLA-DRB1 typing in Caucasians patients with neuromyelitis optica.
      ].
      Even though some studies have reported associations between HLA alleles and NMO, others have found no association [
      • Zephir H.
      • Fajardy I.
      • Outteryck O.
      • Blanc F.
      • Roger N.
      • Fleury M.
      • et al.
      Is neuromyelitis optica associated with human leukocyte antigen?.
      ], suggesting a multifactorial and complex genetic susceptibility, with only 3% of NMO patients having relatives with this condition [
      • Mandler R.N.
      Neuromyelitis optica – Devic's syndrome, update.
      ,
      • Matiello M.
      • Kim H.J.
      • Kim W.
      • Brum D.G.
      • Barreira A.A.
      • Kingsbury D.J.
      • et al.
      Familial neuromyelitis optica.
      ].

      5.2 Non-HLA genetic factors

      Several studies have suggested relationships between chemokines and their receptors and the development of inflammatory demyelinating diseases, such as MS and NMO [
      • Namgoong S.
      • Bae J.S.
      • Cheong H.S.
      • Kim J.H.
      • Kim J.Y.
      • Kim L.H.
      • et al.
      No association between CCL2 gene polymorphisms and risk of inflammatory demyelinating diseases in a Korean population.
      ,
      • Szczucinski A.
      • Losy J.
      Chemokines and chemokine receptors in multiple sclerosis. Potential targets for new therapies.
      ,
      • Ransohoff R.M.
      The chemokine system in neuroinflammation: an update.
      ,
      • Sorensen T.L.
      • Sellebjerg F.
      Distinct chemokine receptor and cytokine expression profile in secondary progressive MS.
      ]. The CCL family is the largest chemokine subgroup which attracts leukocytes in the inflammatory response [
      • Bruserud O.
      • Kittang A.O.
      The chemokine system in experimental and clinical hematology.
      ] and the chemokine ligand 2 (CCL2/MCP-1) is considered a significant player in the recruitment and activation of myelin-degrading phagocytes. CCL-2 is known to be an important contributor to the progression or development of inflammatory demyelinating diseases [
      • Van Der Voorn P.
      • Tekstra J.
      • Beelen R.H.
      • Tensen C.P.
      • Van Der Valk P.
      • De Groot C.J.
      Expression of MCP-1 by reactive astrocytes in demyelinating multiple sclerosis lesions.
      ,
      • Mahad D.J.
      • Ransohoff R.M.
      The role of MCP-1 (CCL2) and CCR2 in multiple sclerosis and experimental autoimmune encephalomyelitis (EAE).
      ]. It is a mediator for infiltration and migration of monocytes, basophils, dendritic cells, and memory T cells [
      • Charo I.F.
      • Ransohoff R.M.
      The many roles of chemokines and chemokine receptors in inflammation.
      ].
      Several studies have focused on the association between the polymorphism rs1024611 of the CCL2 with the risk of autoimmune diseases and MS [
      • Namgoong S.
      • Bae J.S.
      • Cheong H.S.
      • Kim J.H.
      • Kim J.Y.
      • Kim L.H.
      • et al.
      No association between CCL2 gene polymorphisms and risk of inflammatory demyelinating diseases in a Korean population.
      ,
      • Kroner A.
      • Mäurer M.
      • Loserth S.
      • Kleinschnitz C.
      • Hemmer B.
      • Rosche B.
      • et al.
      Analysis of the monocyte chemoattractant protein 1–2518 promoter polymorphism in patients with multiple sclerosis.
      ,
      • Messadi A.
      • Fekih-Mrissa N.
      • Kallel A.
      • Bouguerra C.
      • Sediri Y.
      • Zaweli J.
      • et al.
      Lack of association between monocyte protein-1 (MCP-1)-2518 A>G chemoattractant and C–C chemokine receptor 2 (CCR2) Val64Ile polymorphisms and multiple sclerosis in a Tunisian population.
      ,
      • Hou S.
      • Yang P.
      • Xie L.
      • Du L.
      • Zhou H.
      • Jiang Z.
      Monocyte chemoattractant protein (MCP)-1-2518 A/G SNP in Chinese Han patients with VKH syndrome.
      ,
      • González-Escribano M.F.
      • Torres B.
      • Aguilar F.
      • Rodríguez R.
      • García A.
      • Valenzuela A.
      • et al.
      MCP-1 promoter polymorphism in Spanish patients with rheumatoid arthritis.
      ]. Seven polymorphisms of CCL2 were evaluated (rs1024611, rs2857656, rs4586, rs13900, rs28730833, rs3917887, and rs2857657) and none of these variants revealed any association with inflammatory demyelinating diseases, as well as MS or NMO in a Korean population [
      • Namgoong S.
      • Bae J.S.
      • Cheong H.S.
      • Kim J.H.
      • Kim J.Y.
      • Kim L.H.
      • et al.
      No association between CCL2 gene polymorphisms and risk of inflammatory demyelinating diseases in a Korean population.
      ].
      A genome-wide association study (GWAS) for NMO and MS showed that the polymorphism risks for MS and NMO were different from each other [
      • Kim H.J.
      • Park H.Y.
      • Kim E.
      • Lee K.S.
      • Kim K.K.
      • Choi B.O.
      • et al.
      Common CYP7A1 promoter polymorphism associated with risk of neuromyelitis optica.
      ]. The single nucleotide polymorphisms (SNPs) in cluster of differentiation 6 (CD6) and tumor necrosis factor receptor superfamily member 1 A (TNFRSF1A) genes were associated with NMO [
      • Park T.J.
      • Kim H.J.
      • Kim J.H.
      • Bae J.S.
      • Cheong H.S.
      • Park B.L.
      • et al.
      Associations of CD6, TNFRSF1A, and IRF8 polymorphisms with risk of inflammatory demyelinating diseases.
      ].
      Cluster of differentiation 58 (CD58), also known as lymphocyte function-associated antigen 3 (LFA-3), is one of cell adhesion expressed on antigen presenting cells (APCs) [
      • Barbosa J.A.
      • Mentzer S.J.
      • Kamarck M.E.
      • Hart J.
      • Biro P.A.
      • Strominger J.L.
      • et al.
      Gene mapping and somatic cell hybrid analysis of the role of human lymphocyte function-associated antigen-3 (LFA-3) in CTL-target cell interactions.
      ]. Many association studies were conducted to evaluate the relationship between inflammatory demyelinating diseases and CD58 [
      • Hafler D.A.
      • Compston A.
      • Sawcer S.
      • Lander E.S.
      • Daly M.J.
      • De Jager P.L.
      • et al.
      Risk alleles for multiple sclerosis identified by a genomewide study.
      ,
      • Kim J.Y.
      • Bae J.S.
      • Kim H.J.
      • Shin H.D.
      CD58 polymorphisms associated with the risk of neuromyelitis optica in a Korean population.
      ]. An association analysis between NMO and CD58 polymorphisms carried out in a Korean population revealed that four SNPs of CD58 (rs2300747, rs1335532, rs12044852, and rs1016140) and 2 haplotypes (CD58_ht1 and CD58_ht3) were significantly associated with the increased risk of NMO [
      • Kim J.Y.
      • Bae J.S.
      • Kim H.J.
      • Shin H.D.
      CD58 polymorphisms associated with the risk of neuromyelitis optica in a Korean population.
      ].
      Interleukin 17 (IL-17) A and IL-17F are known to play an important role in many autoimmune diseases including NMO [
      • Wang H.
      • Zhong X.
      • Wang K.
      • Qiu W.
      • Li J.
      • Dai Y.
      • et al.
      Interleukin 17 gene polymorphism is associated with anti-aquaporin 4 antibody-positive neuromyelitis optica in the Southern Han Chinese—a case control study.
      ]. Polymorphisms in IL17A and IL17F have been associated with autoimmune disorders [
      • Wang H.
      • Zhong X.
      • Wang K.
      • Qiu W.
      • Li J.
      • Dai Y.
      • et al.
      Interleukin 17 gene polymorphism is associated with anti-aquaporin 4 antibody-positive neuromyelitis optica in the Southern Han Chinese—a case control study.
      ,
      • Kawaguchi M.
      • Takahashi D.
      • Hizawa N.
      • Suzuki S.
      • Matsukura S.
      • Kokubu F.
      • et al.
      IL-17F sequence variant (His161Arg) is associated with protection against asthma and antagonizes wild-type IL-17F activity.
      ,
      • Arisawa T.
      • Tahara T.
      • Shibata T.
      • Nagasaka M.
      • Nakamura M.
      • Kamiya Y.
      • et al.
      The influence of polymorphisms of interleukin-17A and interleukin-17F genes on the susceptibility to ulcerative colitis.
      ,
      • Nordang G.B.
      • Viken M.K.
      • Hollis-Moffatt J.E.
      • Merriman T.R.
      • Førre Ø.T.
      • Helgetveit K.
      • et al.
      Association analysis of the interleukin 17A gene in Caucasian rheumatoid arthritis patients from Norway and New Zealand.
      ]. An association study between 2 SNPs in the IL17 gene with NMO and MS carried out in the Southern Han Chinese population demonstrated that the frequencies of T allele and TT genotype of rs763780 were dramatically higher in NMO patients than controls, suggesting that rs763780 may be a susceptibility locus for autoimmune diseases. Moreover, increased levels of serum IL-17 and IL-17 secreting T cells were found in NMO patients, suggesting that IL17 may be a candidate gene in the pathogenesis of NMO [
      • Wang H.
      • Zhong X.
      • Wang K.
      • Qiu W.
      • Li J.
      • Dai Y.
      • et al.
      Interleukin 17 gene polymorphism is associated with anti-aquaporin 4 antibody-positive neuromyelitis optica in the Southern Han Chinese—a case control study.
      ].

      5.3 Infectious diseases as environmental factors

      NMO has been associated with bacterial, fungal, and viral infections. Pulmonary tuberculosis, paracoccidioidomycosis, and infections caused by human immunodeficiency virus type 1 (HIV-1), hepatitis A virus, dengue virus, human T lymphotropic virus type 1 (HTLV-1), human herpes virus type 3 (HHV-3) or varicella-zoster virus (VZV), human herpes virus type 4 (HHV-4) or Epstein–Barr virus (EBV), and human herpes virus type 5 (HHV-5) or cytomegalovirus (CMV) have been reported in patients with NMO [
      • Sellner J.
      • Hemmer B.
      • Mühlau M.
      The clinical spectrum and immunobiology of parainfectious neuromyelitis optica (Devic) syndromes.
      ,
      • De Sousa A.M.
      • Puccioni-Sohler M.
      • Borges A.D.
      • Fernandes Adorno L.
      • Papais Alvarenga M.
      • Papais Alvarenga R.M.
      Post-dengue neuromyelitis optica: case report of a Japanese-descendent Brazilian child.
      ,
      • Olindo S.
      • Bonnan M.
      • Merle H.
      • Signate A.
      • Smadja D.
      • Cabre P.
      Neuromyelitis optica associated with subacute human T-lymphotropic virus type 1 infection.
      ,
      • Brum D.G.
      • Donadi E.A.
      • Dos Santos A.C.
      • Takayanagui O.M.
      • Marques W.J.R.
      • Barreira A.A.
      Seropositive antiaquaporin-4 antibody associated with multisegmental myelitis in a patient with paracoccidioidomycosis.
      ,
      • Zatjirua V.
      • Butler J.
      • Carr J.
      • Henning F.
      Neuromyelitis optica and pulmonary tuberculosis: a case–control study.
      ,
      • Feyissa A.M.
      • Singh P.
      • Smith R.G.
      Neuromyelitis optica in patients with coexisting human immunodeficiency virus infections.
      ].
      The temporal relationship between NMO and systemic infections are known but not completely clear. Molecular mimicry, bystander activation, and exacerbation of a pre-existing CNS disorder by a systemic infection are some immune mechanisms involved in parainfectious NMO. Microbial infections cause injury of AQP4-rich tissue, tissue destruction, increase self-antigen presentation, e.g., AQP4, and activate T- and B-cells. Activation of B cells produces antibodies, which recognize self and microbial epitopes. Pro-inflammatory cytokines are secreted during systemic infections and trigger exposition of AQP4 and other neuroantigens [
      • Sellner J.
      • Hemmer B.
      • Mühlau M.
      The clinical spectrum and immunobiology of parainfectious neuromyelitis optica (Devic) syndromes.
      ].

      5.4 Immunopathological mechanisms of NMO

      Typical NMO lesions are cavitary, necrotic and infiltrated with macrophages and granulocytes [
      • Fujihara K.
      Neuromyelitis optica and astrocytic damage in its pathogenesis.
      ,
      • Zhang H.
      • Verkman A.S.
      Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica.
      ]. Serological evidence of B cell autoimmunity has been described in patients with NMO [
      • Lucchinetti C.F.
      • Mandler R.N.
      • McGavern D.
      • Bruck W.
      • Gleich G.
      • Ransohoff R.M.
      • et al.
      A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica.
      ]. Immunopathological studies demonstrated a pronounced loss of immunoreactivities to astrocytic proteins, glial fibrillary acidic protein (GFAP) and aquaporin-4, especially in the perivascular regions with deposition of activated complements and immunoglobulins [
      • Fujihara K.
      Neuromyelitis optica and astrocytic damage in its pathogenesis.
      ]. Co-injection of immunoglobulin G from NMO patients with human complement into mouse brain produced lesions with characteristic histological features of human NMO lesions [
      • Saadoun S.
      • Waters P.
      • Bell B.A.
      • Vincent A.
      • Verkman A.S.
      • Papadopoulos M.C.
      Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice.
      ]. Some authors have proposed that NMO should be classified as an astrocytopathic disease rather than a demyelinating disease because the astrocytic damage in NMO is much more severe than myelin and neuron damage [
      • Fujihara K.
      • Misu T.
      • Nakashima I.
      • Takahashi T.
      • Bradl M.
      • Lassmann H.
      • et al.
      Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease.
      ].
      Although typical NMO lesions are localized at sites where AQP4 expression is normally the highest, the reasons why pathological damages commonly occur in spinal cord and optic nerves are still unclear [
      • Wingerchuk D.M.
      • Lennon V.A.
      • LucchinettI C.F.
      • Pittock S.J.
      • Weinshenker B.G.
      The spectrum of neuromyelitis optica.
      ,
      • Papadopoulos M.C.
      • Verkman A.S.
      Aquaporin 4 and neuromyelitis optica.
      ]. It was demonstrated that during NMOSD relapses interleukin-6 (IL-6) and GFAP are elevated in cerebrospinal fluid (CSF) [
      • Uzawa A.
      • Mori M.
      • Sawai S.
      • Masuda S.
      • Muto M.
      • Uchida T.
      • et al.
      Cerebrospinal fluid interleukin-6 and glial fibrillary acidic protein levels are increased during initial neuromyelitis optics attacks.
      ] and that GFAP levels in patients with ON with NMO are higher than those with MS [
      • Storoni M.
      • Petzold A.
      • Plant G.T.
      The use of serum glial fibrillary acidic protein measurements in the diagnosis of neuromyelitis optica spectrum optic neuritis.
      ]. The anti-aquaporin-1 (anti-AQP1) antibody, against other aquaporin present in the CNS, can be an alternative biomarker in seronegative patients for anti-AQP4 [
      • Tzartos J.S.
      • Stergiou C.
      • Kilidireas K.
      • Zisimopoulou P.
      • Thomaidis T.
      • Tzartos S.J.
      Anti-aquaporin-1 autoantibodies in patients with neuromyelitis optica spectrum disorders.
      ].

      5.4.1 Anti-AQP4

      The main water channel in the brain is AQP4. It is also responsible for glutamate and potassium regulation in the blood–brain barrier, synapses, and paranodes adjacent to the nodes of Ranvier. AQP4 is a transmembrane protein expressed in the feet expansions of the astrocytes and regulates water movement between blood, brain, and CSF [
      • Freitas E.
      • Guimarães J.
      Neuromyelitis optica spectrum disorders associated with other autoimmune diseases.
      ,
      • Waters P.
      • Vincent A.
      Detection of anti-aquaporin-4 antibodies in Neuromyelitis optica: current status of the assays.
      ,
      • González C.
      • González-Buitrago J.M.
      • Izquierdo G.
      Aquaporins, anti-aquaporin-4 autoantibodies and neuromyelitis optica.
      ,
      • Bonnan M.
      • Cabre P.
      Plasma exchange in severe attacks of neuromyelitis optica.
      ].
      In 2004, Lennon et al. identified the anti-AQP4 using indirect immunofluorescence assay, which is an IgG autoantibody specific for NMO and distinguishes NMO from MS. The specificity and sensibility of the detection of serum anti-AQP4 for NMO are more than 90.0% and approximately 70.0%, respectively [
      • Lennon V.A.
      • Wingerchuk D.M.
      • Kryzer T.J.
      • Pittock S.J.
      • Lucchinetti C.F.
      • Fujihara K.
      • et al.
      A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis.
      ]. In a Brazilian sample of 28 patients with NMO, 18 (64. 3%) were seropositive for anti-AQP4 [
      • Adoni T.
      • Lino A.M.
      • Marchiori P.E.
      • Kok F.
      • Callegaro D.
      Seroprevalence of NMO-IgG antibody in Brazilian patients with neuromyelitis optica.
      ]. This serum biomarker indicates high risk for myelitis or recurrent ON. Titers show to be higher in association with disease activity and decline after immunosuppressive therapy. Therefore, previously seronegative patients should be retested during new relapses [
      • Fujihara K.
      • Misu T.
      • Nakashima I.
      • Takahashi T.
      • Bradl M.
      • Lassmann H.
      • et al.
      Neuromyelitis optica should be classified as an astrocytopathic disease rather than a demyelinating disease.
      ,
      • Papadopoulos M.C.
      • Verkman A.S.
      Aquaporin 4 and neuromyelitis optica.
      ,
      • Matiello M.
      • Lennon V.A.
      • Jacob A.
      • Pittock S.J.
      • Lucchinetti C.F.
      • Wingerchuk D.M.
      • et al.
      NMO-IgG predicts the outcome of recurrent optic neuritis.
      ,
      • Akman-Demir G.
      • Tüzün E.
      • Waters P.
      • Içöz S.
      • Kürtüncü M.
      • Jarius S.
      • et al.
      Prognostic implications of aquaporin-4 antibody status in neuromyelitis optica patients.
      ].
      Anti-AQP4 is very specific and if it is positive in other autoimmune diseases with CNS injury, concurrent NMOSD is probable [
      • Dellavance A.
      • Alvarenga R.R.
      • Rodrigues S.H.
      • Kok F.
      • De Souza A.W.
      • Andrade L.E.
      Anti-aquaporin-4 antibodies in the context of assorted immune-mediated diseases.
      ]. Laboratory methods include indirect immunofluorescence, enzyme-linked immunosorbent assay (ELISA), which is the most widely available test, cell-based assays (CBA) and immunoprecipitation. All these assays demonstrate strong specificity, but the CBA has the highest sensitivity [
      • Waters P.
      • Vincent A.
      Detection of anti-aquaporin-4 antibodies in Neuromyelitis optica: current status of the assays.
      ,
      • Waters P.J.
      • McKeon A.
      • Leite M.I.
      • Rajasekharan S.
      • Lennon V.A.
      • Villalobos A.
      • et al.
      Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays.
      ].

      5.4.2 Anti-myelin oligodendrocyte glycoprotein (MOG)

      Experimental studies have demonstrated that MOG, a glycoprotein localized on the outer surface of the myelin sheath and oligodendrocytes, might be a target antigen in MS, acute disseminated encephalomyelitis (ADEM) and NMO, especially in anti-AQP4 seronegative patients [
      • Di Pauli F.
      • Mader S.
      • Rostasy K.
      • Schanda K.
      • Bajer-Kornek B.
      • Ehling R.
      • et al.
      Temporal dynamics of anti-MOG antibodies in CNS demyelinating diseases.
      ]. The autoimmune response to MOG can induce NMO-like disease in experimental animal models. Since anti-AQP4 is absent in approximately 5.0 to 40.0% of NMO patients, the anti-MOG is of relevance for the NMO diagnosis [
      • Mader S.
      • Gredler V.
      • Schanda K.
      • Rostasy K.
      • Dujmovic I.
      • Pfaller K.
      • et al.
      Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders.
      ]. Experiments performed with injected IgG in mouse brain demonstrated that anti-MOG IgG antibodies cause myelin changes and alter the expression of axonal proteins but do not produce axonal loss, inflammation, neuronal or astrocyte death, with recovery within two weeks. On the other hand, anti-AQP4 IgG antibodies produce complement-mediated myelin loss, and astrocyte and neuronal death with limited recovery at two weeks [
      • Saadoun S.
      • Waters P.
      • Owens G.P.
      • Bennett J.L.
      • Vincent A.
      • Papadopoulos M.C.
      Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain.
      ]. Seronegative patients for anti-AQP4 and positive for anti-MOG seem to have more favorable clinical prognosis [
      • Kitley J.
      • Woodhall M.
      • Waters P.
      • Leite M.I.
      • Devenney E.
      • Craig J.
      • et al.
      Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype.
      ]. When compared to patients seropositive for anti-AQP4 or seronegative for anti-MOG and anti-AQP4, NMO patients who are positive for anti-MOG present distinct clinical features, including fewer relapses and better recovery [
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Waters P.J.
      • De Haidar Jorge F.M.
      • et al.
      Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders.
      ].
      Further studies are needed to understand the pathogenesis of seronegative anti-AQP4 NMO, and to determine whether MOG-IgG positive NMO is pathologically related to or is a phenocopy of seropositive anti-AQP4 NMO [
      • Mandler R.N.
      Neuromyelitis optica – Devic's syndrome, update.
      ].

      5.4.3 Cellular immune response

      The events initiating anti-AQP4 production, its access to the CNS, the precise mechanisms by which the inflammatory cascade in NMO produces oligodendrocyte injury and demyelination remain unclear [
      • Mandler R.N.
      Neuromyelitis optica – Devic's syndrome, update.
      ]. The presence of AQP4-specific antibodies alone is not sufficient to provoke inflammatory disease in the CNS; indeed, some patients show persistently high titers of anti-AQP4 antibodies despite clinical remission. It is clear that AQP4-specific T cells are required in the peripheral immune compartment to help the production of anti-AQP4, a class-switched antibody, from B cells [
      • Mitsdoerffer M.
      • Kuchroo V.
      • Korn T.
      Immunology of neuromyelitis optica: a T cell-B cell collaboration.
      ].
      Activated-antigen specific T cells can enter the brain and cause disruption of the blood–brain barrier (BBB) for autoimmune diseases of the CNS [
      • Graber D.J.
      • Levy M.
      • Kerr D.
      • Wade W.F.
      Neuromyelitis optica pathogenesis and aquaporin 4.
      ]. Reports showed that certain amino acid sequence of AQP4 is immunogenic to induce AQP4-specific T cells in animal strains [
      • Kalluri S.R.
      • Rothhammer V.
      • Staszewski O.
      • Srivastava R.
      • Petermann F.
      • Prinz M.
      • et al.
      Functional characterization of aquaporin-4 specific T cells: towards a model for NEUROMYELITIS OPTICA.
      ,
      • Pohl M.
      • Fischer M.T.
      • Mader S.
      • Schanda K.
      • Kitic M.
      • Sharma R.
      • et al.
      Pathogenic T cell responses against aquaporin 4.
      ,
      • Kinoshita M.
      • Nakatsuji Y.
      Where do AQP4 antibodies fit in the pathogenesis of NMO?.
      ]. NMO patients harbour activated T cells specific for AQP4 in the periphery. There is an increase in Th1 and Th17 subsets in the periphery of patients with NMOSD [
      • Kinoshita M.
      • Nakatsuji Y.
      Where do AQP4 antibodies fit in the pathogenesis of NMO?.
      ,
      • Li Y.
      • Wang H.
      • Long Y.
      • Lu Z.
      • Hu X.
      Increased memory Th17 cells in patients with neuromyelitis optica and multiple sclerosis.
      ]. Pathogenic T cells against AQP4 may exist in the periphery of patients with NMO and might accelerate the disease activity once they find the target antigen in the CNS [
      • Kinoshita M.
      • Nakatsuji Y.
      Where do AQP4 antibodies fit in the pathogenesis of NMO?.
      ].
      T cells might play a significant role in deciding the location of lesions in CNS. Authors reported that Th1 and Th17 cells induce distinct phenotypes of inflammation in experimental autoimmune encephalomyelitis (EAE) models [
      • Goverman J.
      Autoimmune T, cell responses in the central nervous system.
      ,
      • Domingues H.S.
      • Mues M.
      • Lassmann H.
      • Wekerle H.
      • Krishnamoorthy G.
      Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis.
      ]. There is a hypothesis that the balance between Th1 and Th17 cells affects the clinical presentation of NMO because patients with opticospinal involvement show increase in the production of IL-17 within the CNS. This hypothesis might explain why some patients with typical NMO presentation turn out to be seronegative for anti-AQP4 [
      • Wingerchuk D.M.
      • Lennon V.A.
      • LucchinettI C.F.
      • Pittock S.J.
      • Weinshenker B.G.
      The spectrum of neuromyelitis optica.
      ,
      • Kinoshita M.
      • Nakatsuji Y.
      Where do AQP4 antibodies fit in the pathogenesis of NMO?.
      ].
      T cells are implicated in NMO pathogenesis because AQP4 IgG is a T-cell-dependent immunoglobulin subclass (IgG1). T cells are probably involved in the peripheral immune response, including breaking tolerance and antibody production [
      • Papadopoulos M.C.
      • Verkman A.S.
      Aquaporin 4 and neuromyelitis optica.
      ]. Bradl et al. [
      • Bradl M.
      • Misu T.
      • Takahashi T.
      • Watanabe M.
      • Mader S.
      • Reindl M.
      • et al.
      Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo.
      ] induced acute T-cell-mediated EAE in rats and confronted them with an application of immunoglobulins from AQP4 antibody positive and negative NMO patients. The authors concluded that human anti-AQP-4 antibodies are not only important in the diagnosis of the disease but also induce NMO-like lesions in animals with T-cell-mediated brain inflammation [
      • Bradl M.
      • Misu T.
      • Takahashi T.
      • Watanabe M.
      • Mader S.
      • Reindl M.
      • et al.
      Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo.
      ].
      There is increasing evidence of extensive cross-talk between Th17 and B cells. It is possible that B cells, which can serve as antigen presenting cells (APCs) in the context of NMO and are an excellent source of IL-6, might skew T cells towards a Th17 response [
      • Mitsdoerffer M.
      • Kuchroo V.
      • Korn T.
      Immunology of neuromyelitis optica: a T cell-B cell collaboration.
      ].
      Fig. 1, Fig. 2 illustrate the NMO pathogenic mechanisms mediated by innate and adaptive immune response.
      Figure thumbnail gr1
      Fig. 1Neuromyelitis optica (NMO) pathogenic mechanisms mediated by innate and adaptive immune response. In the periphery, pathogens are recognized by cells of the innate immune response, such as dendritic cells, which present the antigens to the Th1 and Th2 specific lymphocytes through the major histocompatibility complex (MHC) class II, initiating the adaptive immune response. Th1 cells (CD4+CCR5+CXCR3+ T cells) secrete interferon gamma (IFN-γ) and interleukin 6 (IL-6) while Th2 cells (CD4+CCR4+CCR8+ T cells) secrete interleukin 10 (IL-10) among others. Moreover, activated Th17 cells (CD4+CCR6+ T cells) secrete interleukin 17 (IL-17). IL-6-stimulated B cells differentiate into plasmablasts to produce antibodies against foreign and autoantigens that shared epitopes with pathogens, such as aquaporin 4 (anti-AQP4). 1: These Th cells and other inflammatory cells, such as neutrophils, eosinophils, macrophages, and natural killers cross the blood–brain barrier that is disrupted by the inflammatory response and reach the central nervous system (CNS). In this site, cytotoxicity mechanisms mediated by complement and anti-AQP4 are responsible for the astrocyte lesions. 2: In the CNS, microglia cells present either microbial or self-antigens to the T lymphocytes, a cross-presentation mechanism that contributes to the autoimmunity in the NMO.
      Figure thumbnail gr2
      Fig. 2Neuromyelitis optica pathogenesis mechanisms mediated by inflammatory cytokines and chemokines. In the periphery, environmental factors, such as virus and bacteria, induce an innate immune response. The activated microglia presents antigens to the adaptive immune response with activation of T helper (Th) 1, Th2, and Th17 lymphocytes. The Th1 and Th17 cells secrete inflammatory cytokines, such as interferon gamma (IFN-γ) and IL-17, respectively, which activate other inflammatory cells and amplify the innate immune response. The Th2 cells secrete IL-10, an anti-inflammatory cytokine that modulates the Th1 cells. Moreover, these cells express different chemokine receptors that contribute to the recruitment of other inflammatory cells to the central nervous system.
      Peripheral blood samples from MS and NMO patients treated with interferon (IFN)-β1b, which has effects on the Th1/Th2 balance and is known to be not effective in NMO treatment due to different immune responses demonstrated that the percentage of CD4+CCR5+ and CD4+CXCR3+ T cells, representative of Th1 response, was decreased in NMO patients after treatment; and that the percentage of CD4+CCR4+ T cells, representative of Th2 response, was significantly increased compared with the pretreatment levels, suggesting that Th2 predominance is involved in the pathogenesis of NMO [
      • Nakajima H.
      • Hosokawa T.
      • Doi Y.
      • Ikemoto T.
      • Ishida S.
      • Kimura F.
      • et al.
      Interferon-β1b increases Th2 response in neuromyelitis optica.
      ].
      MS and NMO patients in the relapsing phase showed a significantly increased CD4+CXCR3+/CD4+CCR4+ ratio and CD8+CXCR3+/CD8+CCR4+ ratio compared with patients in the remission phase, suggesting that CD8+CXCR3+ T cells might play a role in the NMO pathogenesis. Moreover, the CD4+CXCR3+/CD4+CCR4+ ratio and CD8+CXCR3+/CD8+CCR4+ ratio were significantly higher in NMO patients in the relapsing phase than in MS patients in the relapsing phase, reflecting a more remarkable immune and inflammatory activities in NMO patients than in MS [
      • Shimizu Y.
      • Ota K.
      • Kubo S.
      • Kabasawa C.
      • Kobayashi M.
      • Ohashi T.
      • et al.
      Association of Th1/Th2-related chemokine receptors in peripheral T cells with disease activity in patients with multiple sclerosis and neuromyelitis optica.
      ].

      5.4.4 Complement system, CDC, ADCC, glutamate excitotoxicity

      NMO pathogenesis involves binding of anti-AQP4 to AQP4 on astrocyte end-feet, which activates complement, leading to formation of membrane attack complex (MAC) and astrocyte injury. This event is followed by recruitment of inflammatory cells, first neutrophils and eosinophils (granulocytes); and then macrophages, which further disrupt the BBB. Astrocyte injury and an inflammatory reaction are thought to damage oligodendrocytes and neurons secondarily [
      • Ratelade J.
      • Verkman A.S.
      Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies.
      ].
      Anti-AQP4 can cause antibody-dependent cellular cytotoxicity (ADCC) when effector cells are present and complement-dependent cytotoxicity (CDC) when complement is present [
      • Ratelade J.
      • Verkman A.S.
      Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies.
      ,
      • Vincent T.
      • Saikali P.
      • Cayrol R.
      • Roth A.D.
      • Bar-Or A.
      • Prat A.
      • et al.
      Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood–brain barrier permeability and granulocyte recruitment.
      ]. The ability of AQP4-bound AQP4-IgG to cause CDC and ADCC is explained by the fact that IgG Fc region binds complement protein C1q and effector cell receptor FcR. AQP4-IgG of the subtype IgG1 is the predominant subtype in NMO, which strongly activates complement and binds all classes of Fc receptors involved in ADCC [
      • Ratelade J.
      • Verkman A.S.
      Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies.
      ,
      • Vincent T.
      • Saikali P.
      • Cayrol R.
      • Roth A.D.
      • Bar-Or A.
      • Prat A.
      • et al.
      Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood–brain barrier permeability and granulocyte recruitment.
      ,
      • Capel P.J.
      • Van De Winkel J.G.
      • Van Den Herik-Oudijk I.E.
      • Verbeek J.S.
      Heterogeneity of human IgG Fc receptors.
      ].
      Measurements of complement protein binding suggested a mechanism for the enhanced CDC involving C1q binding to AQP4-IgG when clustered on AQP4 orthogonal arrays particles (OAPs). OAP formation by AQP4 enhances CDC at two levels: C1q binding to clustered AQP4-IgG; and AQP4-IgG binding affinity to AQP4 [
      • Kitazawa Y.
      • Warabi Y.
      • Bandoh M.
      • Takahashi T.
      • Matsubara S.
      Elderly-onset neuromyelitis optica which developed after the diagnosis of prostate adenocarcinoma and relapsed after a 23-valent pneumococcal polysaccharide vaccination.
      ]. Kitazawa et al. reported a case of elderly-onset NMO, which developed after the diagnosis of prostate adenocarcinoma and relapsed after a 23-valent pneumococcal polysaccharide vaccination [
      • Kitazawa Y.
      • Warabi Y.
      • Bandoh M.
      • Takahashi T.
      • Matsubara S.
      Elderly-onset neuromyelitis optica which developed after the diagnosis of prostate adenocarcinoma and relapsed after a 23-valent pneumococcal polysaccharide vaccination.
      ], suggesting that activation of the immune system by complement activation induced by vaccination could be involved in the onset and relapses of NMO [
      • González C.
      • González-Buitrago J.M.
      • Izquierdo G.
      Aquaporins, anti-aquaporin-4 autoantibodies and neuromyelitis optica.
      ].
      AQP4-IgG binds with greater affinity to M23-AQP4 than to M1-AQP4, contributing to the bivalent binding of IgG [
      • González C.
      • González-Buitrago J.M.
      • Izquierdo G.
      Aquaporins, anti-aquaporin-4 autoantibodies and neuromyelitis optica.
      ]. Hinson and co-workers proposed that M1-AQP4 is rapidly internalized by astrocytes upon AQP4-IgG exposure, resulting in increased OAP size and enhanced CDC, whereas M23-AQP4 resists internalization [
      • Hinson S.R.
      • Romero M.F.
      • Popescu B.F.
      • Lucchinetti C.F.
      • Fryer J.P.
      • Wolburg H.
      • et al.
      Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes.
      ]. However, Phuan et al. found that reduced CDC for M1-AQP4 is not due to preferential internalization of M1-AQP4 versus M23-AQP4, but to assembly of M23-AQP4 in OAPs and multivalent binding of C1q to clustered AQP4-IgG [
      • Phuan P.W.
      • Ratelade J.
      • Rossi A.
      • Tradtrantip L.
      • Verkman A.S.
      Complement-dependent cytotoxicity in neuromyelitis optica requires aquaporin-4 protein assembly in orthogonal arrays.
      ], suggesting that preferential internalization of M1-AQP4 is not involved in NMO pathogenesis.
      Although CDC is probably the major initiating mechanism in NMO, other pathogenic mechanisms triggered by AQP4-IgG have been proposed, such as ADCC and glutamate excitotoxicity [
      • Ratelade J.
      • Verkman A.S.
      Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies.
      ]. Several leukocyte types besides natural-killer (NK) cells express Fc receptors and can mediate ADCC, including macrophages, neutrophils and eosinophils, which are found, abundantly, in NMO lesions. AQP4-IgG together with NK cells can cause death of AQP4-transfected cells and astrocyte cultures. Binding of NK cells to the Fc region of AQP4-IgG leads to their degranulation causing astrocyte injury [
      • Ratelade J.
      • Verkman A.S.
      Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies.
      ]. Zhang et al. found in spinal cord slice cultures that neutrophils and macrophages exacerbate NMO lesions caused by submaximal AQP4-IgG and complement, which most likely involves an ADCC mechanism [
      • Zhang H.
      • Bennett J.L.
      • Verkman A.S.
      Ex vivo spinal cord slice model of neuromyelitis optica reveals novel immunopathogenic mechanisms.
      ].
      It was found that there is decreased glutamate uptake in astrocytes exposed to human NMO serum and internalization of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) together with AQP4 in transfected HEK-293 cells following exposure to NMO serum. Hinson et al. proposed that NMO pathogenesis involves glutamate excitotoxicity by a mechanism involving AQP4-IgG-induced internalization of EEAT2 on astrocytes and consequent injury in glutamate uptake from the extracellular space following neuroexcitation, leading to oligodendrocyte impairment and myelin loss [
      • Ratelade J.
      • Verkman A.S.
      Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies.
      ,
      • Hinson S.R.
      • Roemer S.F.
      • Lucchinetti C.F.
      • Fryer J.P.
      • Kryzer T.J.
      • Chamberlain J.L.
      • et al.
      Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2.
      ]. Ceftriaxone, which upregulates EEAT2 [
      • Rothstein J.D.
      • Patel S.
      • Regan M.R.
      • Haenggeli C.
      • Huang Y.H.
      • Bergles D.E.
      • et al.
      Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression.
      ], was proposed as a therapy for NMO [
      • Ratelade J.
      • Verkman A.S.
      Neuromyelitis optica: aquaporin-4 based pathogenesis mechanisms and new therapies.
      ].
      On the other hand, Ratelade et al. [
      • Ratelade J.
      • Bennett J.L.
      • Verkman A.S.
      Evidence against cellular internalization in vivo of NMO-IgG, aquaporin-4, and excitatory amino acid transporter 2 in neuromyelitis optica.
      ] found no significant internalization of EAAT2 in astrocytes after exposure to high concentrations of AQP4-IgG and no reduced glutamate uptake. The authors concluded that glutamate excitotoxicity is not involved in NMO pathogenesis and that ceftriaxone would not be useful in the NMO treatment [
      • Ratelade J.
      • Bennett J.L.
      • Verkman A.S.
      Evidence against cellular internalization in vivo of NMO-IgG, aquaporin-4, and excitatory amino acid transporter 2 in neuromyelitis optica.
      ].
      Fig. 3, Fig. 4 illustrate the NMO pathogenic mechanisms mediated by CDC, ADCC, and glutamate excitotoxicity.
      Figure thumbnail gr3
      Fig. 3Neuromyelitis optica (NMO) pathogenic mechanisms mediated by complement system. NMO pathogenesis involves binding of anti-aquaporin 4 (AQP4) to AQP4 on astrocyte end-feet, which activates complement, leading to formation of membrane attack complex (MAC) and astrocyte injury. This event is followed by recruitment of inflammatory cells, first neutrophils and eosinophils (granulocytes), and then macrophages, which further disrupt the blood–brain barrier (BBB). Astrocyte injury and an inflammatory reaction are thought to damage oligodendrocytes and neurons secondarily. Anti-AQP4 can cause antibody-dependent cellular cytotoxicity (ADCC) when effector cells are present, such as neutrophils, eosinophils, and natural killer (NK) cells, and complement-dependent cytotoxicity (CDC) when complement is present. The ability of AQP4-bound anti-AQP4 IgG to cause CDC and ADCC is explained by the fact that IgG Fc region binds to complement protein C1q and to effector cell receptor FcR. IgG1 subtype of anti-AQP4 IgG is the predominant antibody in NMO, which strongly activates complement and binds all classes of FcR involved in ADCC.
      Figure thumbnail gr4
      Fig. 4Neuromyelitis optica (NMO) pathogenic mechanisms mediated by complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC), and glutamate excitotoxicity. In the normal central nervous system, AQP4 is expressed at astrocyte end-feet facing the blood–brain barrier (BBB) formed by endothelial cells connected by tight junctions. In NMO, by unknown mechanisms, circulating anti-AQP4 IgG crosses the BBB and binds to AQP4 on astrocytes. This event leads to recruitment and activation of complement system proteins and deposition of the membrane attack complex (MAC), producing astrocyte damage by CDC. Complement activation and cytokine secretion by astrocytes recruit inflammatory cells, such as eosinophils, neutrophils, and macrophages, which further disrupt the BBB, allowing more entry of anti-AQP4 IgG. Degranulating inflammatory cells and astrocytes damage secondarily cause oligodendrocytes injury, myelin loss, and axon damage by ADCC. The presence of anti-AQP4 in the oligodendrocyte decreases glutamate uptake in astrocytes and internalization of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) together with AQP4. NMO pathogenesis involves glutamate excitotoxicity by a mechanism involving anti-AQP4 IgG-induced internalization of EEAT2 on astrocytes and consequent injury in glutamate uptake from the extracellular space following neuroexcitation, leading to oligodendrocyte impairment and myelin loss.

      6. Treatment strategies

      It is important that NMO treatment starts as early as possible to control inflammatory damage, and to prevent further relapses and disability [
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Fujihara K.
      Brazilian committee for treatment and research in multiple sclerosis. Treatment of neuromyelitis optica: an evidence based review.
      ]. Acute therapies are designed to minimize injury and accelerate recovery, whereas preventative therapies are focused on reducing relapse frequency and severity [
      • Mandler R.N.
      Neuromyelitis optica – Devic's syndrome, update.
      ].
      The maintenance treatment is based on low doses of corticosteroids and immunosuppressive therapy; and the treatment in acute attacks is based on high doses of intravenous corticosteroids and plasma exchange (PE). In both acute and maintenance phases of the treatment, corticosteroids are the major therapy for NMO [
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Fujihara K.
      Brazilian committee for treatment and research in multiple sclerosis. Treatment of neuromyelitis optica: an evidence based review.
      ]. Watanabe et al. observed that the annual relapse rate was dramatically lower under use of corticosteroids than the period without the drug and it was also observed that the odds ratio for the period with 10 mg/day or less was 8.71 compared with more than 10 mg/day [
      • Watanabe S.
      • Misu T.
      • Miyazawa I.
      • Nakashima I.
      • Shiga Y.
      • Fujihara K.
      • et al.
      Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis.
      ]. The elevated levels of Th17 cytokines such as IL-17A, IL-6 and IL-23p, which are elevated during NMO exacerbations, are downregulated by corticosteroids [
      • Muls N.
      • Jnaoui K.
      • Dang H.A.
      • Wauters A.
      • Van Snick J.
      • Sindic C.J.
      • et al.
      Upregulation of IL-17, but not of IL-9, in circulating cells of CIS and relapsing MS patients. Impact of corticosteroid therapy on the cytokine network.
      ].
      NMO is sometimes unresponsive to steroid treatment and PE is an effective rescue therapy when high-dose steroid treatment fails in acute relapses of NMO. This therapy is an extracorporeal blood purification, which removes circulant molecules of complement, antibodies, and cytokines from the plasma. PE is an appropriate technique in severe NMO relapses because of the strong humoral response underlying NMO and there is evidence that NMO is an autoantibody-mediated disorder with complement activation. Clinical improvement can occur early in the course of PE [
      • Bonnan M.
      • Cabre P.
      Plasma exchange in severe attacks of neuromyelitis optica.
      ,
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Fujihara K.
      Brazilian committee for treatment and research in multiple sclerosis. Treatment of neuromyelitis optica: an evidence based review.
      ,
      • Khatri B.O.
      • Kramer J.
      • Dukic M.
      • Palencia M.
      • Verre W.
      Maintenance plasma exchange therapy for steroid-refractory neuromyelitis optica.
      ,
      • Wang K.C.
      • Wang S.J.
      • Lee C.L.
      • Chen S.Y.
      • Tsai C.P.
      The rescue effect of plasma exchange for neuromyelitis optica.
      ]. This therapy is most effective when prescribed associated with immunosuppressive drugs and at least five sessions are required to achieve a sufficient removal of antibodies and other substances [
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Fujihara K.
      Brazilian committee for treatment and research in multiple sclerosis. Treatment of neuromyelitis optica: an evidence based review.
      ]. Intravenous methylprednisolone and PE are the standard treatments for acute disease exacerbations in NMO [
      • Mandler R.N.
      Neuromyelitis optica – Devic's syndrome, update.
      ].
      Even though PE is not usually prescribed as a maintenance therapy for NMO, a retrospective study showed that maintenance PE therapy has a potential beneficial therapeutic role in steroid-refractory seropositive NMO patients. The patients underwent PE three times per week for two weeks, then twice a week for two weeks, then once a week for three to five weeks. The frequency of the sessions was tapered according to the clinical condition of the patients. The authors also suggested that maintenance of PE could become a disease-modifying therapy for NMO [
      • Khatri B.O.
      • Kramer J.
      • Dukic M.
      • Palencia M.
      • Verre W.
      Maintenance plasma exchange therapy for steroid-refractory neuromyelitis optica.
      ].
      Although retrospective studies and case series have reported marked improvement in neurological and visual functions in patients with NMO following PE, improvement was independent of anti-AQP4 seropositivity [
      • Mandler R.N.
      Neuromyelitis optica – Devic's syndrome, update.
      ,
      • Bonnan M.
      • Valentino R.
      • Olindo S.
      • Mehdaoui H.
      • Smadja D.
      • Cabre P.
      Plasma exchange in severe spinal attacks associated with neuromyelitis optica spectrum disorder.
      ].
      Due to the high morbidity associated with NMO exacerbations, immunosuppressive therapy is prescribed, typically, after the first attack. Immunosuppressive drugs, such as azathioprine, mycophenolate mofetil, and mitoxantrone can be used in combination with oral corticosteroids or alone as maintenance treatment for NMO. Azathioprine is a DNA synthesis inhibitor, which restrains cellular proliferation, in particular lymphocytes and there are positive results in NMO patients with long-term combination of azathioprine and corticosteroids [
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Fujihara K.
      Brazilian committee for treatment and research in multiple sclerosis. Treatment of neuromyelitis optica: an evidence based review.
      ,
      • Watanabe S.
      • Misu T.
      • Miyazawa I.
      • Nakashima I.
      • Shiga Y.
      • Fujihara K.
      • et al.
      Low-dose corticosteroids reduce relapses in neuromyelitis optica: a retrospective analysis.
      ]. The interruption of azathioprine was followed by increase in anti-AQP4 titers and clinical relapses in some patients [
      • Jarius S.
      • Aboul-Enein F.
      • Waters P.
      • Kuenz B.
      • Hauser A.
      • Berger T.
      • et al.
      Antibody to aquaporin-4 in the long-term course of neuromyelitis optica.
      ]. A Brazilian study, which analyzed patients treated with azathioprine alone or in combination with corticosteroids demonstrated that there was similarity in findings of relapse rates and reduction in disability of NMO patients [
      • Bichuetti D.B.
      • Lobato de Oliveira E.M.
      • Oliveira D.M.
      • Amorin de Souza N.
      • Gabbai A.A.
      Neuromyelitis optica treatment: analysis of 36 patients.
      ]. Mycophenolate mofetil inhibits inosine monophophosphate dehydrogenase, which is required for proliferation of B and T lymphocytes. In a retrospective study, it was observed that patients treated with mycophenolate mofetil exhibited reduction in relapse rates and 91.0% exhibited improvement or stabilization of disability [
      • Jacob A.
      • Matiello M.
      • Weinshenker B.G.
      • Wingerchuk D.M.
      • Lucchinetti C.
      • Shuster E.
      • et al.
      Treatment of neuromyelitis optica with mycophenolate mofetil: retrospective analysis of 24 patients.
      ].
      Methotrexate inhibits purine metabolism and interferes with interleukin-1 beta (IL-1β) binding to IL-1 receptors and interferes with T cell adhesion [
      • Ramanathan R.S.
      • Malhotra K.
      • Scott T.
      Treatment of neuromyelitis optica/neuromyelitis optica spectrum disorders with methotrexate.
      ]. The combined methotrexate and oral corticosteroids therapy resulted in disability stabilization in patients with NMO [
      • Minagar A.
      • Sheremara W.
      Treatment of Devic's disease with methotrexate and prednisone.
      ]. Mitoxantrone is an antineoplastic drug that reduces progression in MS patients with failure in other treatment choices. It has been used in patients with NMO but the reaction is changeable, from reduction of relapse rate to increased relapse rate [
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Fujihara K.
      Brazilian committee for treatment and research in multiple sclerosis. Treatment of neuromyelitis optica: an evidence based review.
      ]. Mitoxantrone combined with methylprednisolone reduced attacks and disability after one year of treatment [
      • Cabre P.
      • Olindo S.
      • Marignier R.
      • Jeannin S.
      • Merle H.
      • Smadja D.
      Aegis of French national observatory of multiple sclerosis. Efficacy of mitoxantrone in neuromyelitis optica spectrum: clinical and neuroradiological study.
      ].
      Rituximab is used as an alternative treatment to other nonspecific immunosuppressive therapy. It is a monoclonal antibody against the CD 20 protein which has the property to deplete B cells in a selective manner [
      • Sato D.K.
      • Lana-Peixoto M.
      • Fujihara K.
      • De Seze J.
      Clinical spectrum and treatment of neuromyelitis optica spectrum disorders: evolution and current status.
      ]. Some NMO patients manifest relapses following initiation of rituximab and it may be explained by the transient increase in anti-AQP4 antibody and B cell activating factor levels observed for two weeks following the first infusion [
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Fujihara K.
      Brazilian committee for treatment and research in multiple sclerosis. Treatment of neuromyelitis optica: an evidence based review.
      ]. Cyclophosphamide is an immunosuppressive drug, which decreases DNA synthesis through preventing cell division by cross-linking DNA strands and should be only used when other immunosuppressive treatment fails or is not available [
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Fujihara K.
      Brazilian committee for treatment and research in multiple sclerosis. Treatment of neuromyelitis optica: an evidence based review.
      ,
      • Trebst C.
      • Jarius S.
      • Berthele A.
      • Paul F.
      • Schippling S.
      • Wildemann B.
      • et al.
      Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS).
      ]. Immunoglobulin therapy is suggested as an alternative treatment for NMO patients who have contraindication to other treatments, especially, children [
      • Trebst C.
      • Jarius S.
      • Berthele A.
      • Paul F.
      • Schippling S.
      • Wildemann B.
      • et al.
      Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS).
      ].
      Currently, azathioprine, mycophenolate mofetil, and rituximab tend to be the most-recommended first-line therapies and methotrexate, mitoxantrone and cyclosporine are the second-line therapies for NMO prophylaxis [
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ]. More safe and effective drugs for NMO treatment are needed, even though a number of immunosuppressive drugs seem to be efficacious in NMO [
      • Sato D.K.
      • Lana-Peixoto M.
      • Fujihara K.
      • De Seze J.
      Clinical spectrum and treatment of neuromyelitis optica spectrum disorders: evolution and current status.
      ].

      7. Prognosis

      NMO is frequently more severe than MS. Relapses usually result in permanent neurologic impairment. Some predictors of a relapsing course are reported, such as longer interattack interval between the first two clinical events, female patient, older age at onset, and less severe motor deficit with the first myelitis event. History of other autoimmune disease, better motor recovery following the first myelitis event and higher relapse frequency during the first two years of disease was associated with mortality due to relapsing NMO. NMO disability results from individual attacks. All patients with NMO should be considered at risk of disabling relapses in order to initiate early therapy and emphasize the importance of relapse prevention treatment [
      • Wingerchuk D.M.
      • Weinshenker B.G.
      Neuromyelitis optica: clinical predictors of a relapsing course and survival.
      ].

      8. Future perspectives

      Improved understanding of the mechanisms of NMO pathogenesis has led to discovery of novel therapeutic targets. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19, initially developed for other conditions, are under clinical evaluation for repurposing for NMO [
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ].
      There is a strong association with eosinophils in the pathogenesis of the acute phase of NMO. The approved but usually non-prescribed drugs cetirizine and ketotifen, which are antihistamines, have eosinophils stabilizing effect and decreased the severity of NMO lesions in a mouse model, reducing eosinophil-dependent NMO pathology [
      • Zhang H.
      • Verkman A.S.
      Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica.
      ,
      • Akaishi T.
      • Nakashima I.
      The treatment of neuromyelitis optica: present and future perspective.
      ].
      Intravenous immunoglobulin therapy has been suggested to be effective and an alternative in the NMO acute phase of patients’ refractory to treatment with intravenous corticosteroids. It has been also suggested in the remission period, monthly or bimonthly, in order to prevent relapses [
      • Akaishi T.
      • Nakashima I.
      The treatment of neuromyelitis optica: present and future perspective.
      ,
      • Wingerchuk D.M.
      Neuromyelitis optica: potential roles for intravenous immunoglobulin.
      ]. However, the data supporting the clinical benefits of intravenous immunoglobulin in NMO are limited [
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ]. It could also become an effective preventive treatment in the future [
      • Akaishi T.
      • Nakashima I.
      The treatment of neuromyelitis optica: present and future perspective.
      ].
      Numerous neutrophils are also known to appear in NMO lesions and may exacerbate them. It was reported that Sivelestat, a neutrophil elastase inhibitor, reduced the expression of cytokines IL-17, IL-5, and IL-2 in Th17-induced EAE, which is thought to be analogous to NMO [
      • Zhang H.
      • Verkman A.S.
      Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica.
      ,
      • Herges K.
      • De Jong B.A.
      • Kolkowitz I.
      • Dunn C.
      • Mandelbaum G.
      • Ko R.M.
      • et al.
      Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein.
      ].
      Glatiramer acetate, which is already a MS preventive therapy, has been described as a hypothetical therapeutic agent and may be an effective treatment in preventing relapses of NMO in the future [
      • Wang K.C.
      • Lee C.L.
      • Chen S.Y.
      • Lin K.H.
      • Tsai C.P.
      Glatiramer acetate could be a hypothetical therapeutic agent for neuromyelitis optica.
      ].
      Complement activation is thought to be a major determinant of CNS inflammation and astrocytic injury in NMO. Eculizumab is a humanized monoclonal IgG antibody and a complement C5 inhibitor, which binds to complement protein C5 and inhibits its cleavage by the C5 convertase, preventing cleavage into C5a and C5b. It reduces relapses frequency and may improve neurological disability in patients with NMO [
      • Zhang H.
      • Verkman A.S.
      Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica.
      ,
      • Sato D.
      • Callegaro D.
      • Lana-Peixoto M.
      • Fujihara K.
      Brazilian committee for treatment and research in multiple sclerosis. Treatment of neuromyelitis optica: an evidence based review.
      ,
      • Pittock S.J.
      • Lennon V.A.
      • Mckeon A.
      • Mandrekar J.
      • Weinshenker B.G.
      • Lucchinetti C.F.
      • et al.
      Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study.
      ] who were refractory to other treatments [
      • Pittock S.J.
      • Lennon V.A.
      • Mckeon A.
      • Mandrekar J.
      • Weinshenker B.G.
      • Lucchinetti C.F.
      • et al.
      Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study.
      ].
      Some reports suggested that interleukin-6 (IL-6) contributes to the NMO attacks and showed a favorable effect of the IL-6 receptor-blocking antibody tocilizumab, in cases of failure with other therapies [
      • Sato D.K.
      • Lana-Peixoto M.
      • Fujihara K.
      • De Seze J.
      Clinical spectrum and treatment of neuromyelitis optica spectrum disorders: evolution and current status.
      ,
      • Trebst C.
      • Jarius S.
      • Berthele A.
      • Paul F.
      • Schippling S.
      • Wildemann B.
      • et al.
      Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS).
      ].
      Several therapeutic approaches have been developed to block the binding of AQP4-IgG to AQP4, thereby reducing ADCC, CDC, and downstream pathogenicity [
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ]. Recombinant monoclonal anti-AQP4 antibody, which prevents pathogenic anti-AQP4 antibodies to bind AQP4 on astrocytes has been suggested as a future possibility. NMO is an ideal disease for monoclonal antibody blocker because of the sole target of the pathogenic autoantibodies [
      • Tradtrantip L.
      • Zhang H.
      • Saadoun S.
      • Phuan P.W.
      • Lam C.
      • Papadopoulos M.C.
      • et al.
      Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica.
      ]. Some experimental studies demonstrated beneficial effects in animal models of aquaporumab, a non-pathogenic AQP4 specific antibody [
      • Wingerchuk D.M.
      Neuromyelitis optica: potential roles for intravenous immunoglobulin.
      ]. Blocking antibodies could become a new therapy in the future [
      • Akaishi T.
      • Nakashima I.
      The treatment of neuromyelitis optica: present and future perspective.
      ].
      Antibody inactivation is considered as a potential therapeutic alternative for autoimmune disorders caused by pathogenic antibodies. Several bacterial enzymes selectively target IgG-class antibodies, and some of these enzymes interfere with the binding site for complement component C1q on the antibody, thereby neutralizing the Fc effector functions, which are involved in CDC, whereas others target the Fcγ receptor binding motif that is involved in ADCC [
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ].
      Small-molecule inhibitors of AQP4 antibodies binding, such as antiviral arbidol, flavonoid tamarixetin, and several plant-derived berbamine alkaloids, were also shown to reduce astrocyte cytotoxicity in NMO, and could become future therapies [
      • Tradtrantip L.
      • Zhang H.
      • Anderson M.O.
      • Saadoun S.
      • Phuan P.W.
      • Papadopoulos M.C.
      • et al.
      Small-molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitis optica.
      ].
      Plasma cells in the peripheral tissues could also become possible treatments once antibody-secreting plasma cells were believed to be short-lived and continuously replenished by signals from memory B-cells in autoimmune neurological diseases [
      • Akaishi T.
      • Nakashima I.
      The treatment of neuromyelitis optica: present and future perspective.
      ,
      • Slifka M.K.
      • Antia R.
      • Whitmire J.K.
      • Ahmed R.
      Humoral immunity due to long-lived plasma cells.
      ].
      Many of the drugs currently used for preventing NMO relapses are also used to treat patients with rheumatoid arthritis. Nowadays, anti-tumor necrosis factor (TNF) therapies are central to the treatment of rheumatoid arthritis and could be potentially repurposed for NMO treatment. Anti-TNF therapies might have limits in use in the prevention of NMO exacerbations because serum levels of TNF are not elevated in patients with the disease [
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ,
      • Pentón-Rol G.
      • Cervantes-Llanos M.
      • Martínez-Sánchez G.
      • Cabrera-Gómez J.A.
      • Valenzuela-Silva C.M.
      • Ramírez-Nuñez O.
      • et al.
      TNF-α and IL-10 downregulation and marked oxidative stress in neuromyelitis optica.
      ].
      As exposed above, disruption and dysfunctions in the BBB are involved in the pathogenesis of NMO. Drugs modifying the BBB could help NMO patients as a preventive therapy. CD19, CD38, or CD138 could be also possible target molecules in the future, and monoclonal antibodies against these specific molecules may possibly benefit NMO patients [
      • Akaishi T.
      • Nakashima I.
      The treatment of neuromyelitis optica: present and future perspective.
      ]. Many CD19-targeted therapies are currently under investigation [
      • Hammer O.
      CD19 as an attractive target for antibody-based therapy.
      ] and could also be effective in NMO treatment. Another attractive target in NMO is CD59, the major complement inhibitor protein in astrocytes. CD59 is a glycophosphoinositol-anchored membrane protein that inhibits formation of the terminal C5b–9 membrane attack complex [
      • Davies A.
      • Lachmann P.J.
      Membrane defence against complement lysis: the structure and biological properties of CD59.
      ]. Studies in NMO mouse models created by passive transfer of AQP4-IgG [
      • Asavapanumas N.
      • Ratelade J.
      • Papadopoulos M.C.
      • Bennett J.L.
      • Levin M.H.
      • Verkman A.S.
      Experimental mouse model of optic neuritis with inflammatory demyelination produced by passive transfer of neuromyelitis optica-immunoglobulin G.
      ], CD59 neutralization or deletion greatly increased NMO pathology in the optic nerve, spinal cord and brain and this is of potential therapeutic value in NMO [
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ].
      Antigen-specific tolerance against AQP4 provides an option for suppression of the immune response in NMO. AQP4 tolerance could effectively stop the pathological immune response that drives CNS tissue injury while leaving the remainder of the immune surveillance system intact [
      • Papadopoulos M.C.
      • Bennett J.I.
      • Verkman A.S.
      Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
      ]. An alternative strategy for restoring immune tolerance in NMO is autologous haematopoietic stem cell transplantation, which has shown benefit in the treatment of severe MS [
      • Fagius J.
      • Lundgren J.
      • Oberg G.
      Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation.
      ] and SLE [
      • Illei G.G.
      • Cervera R.
      • Burt R.K.
      • Doria A.
      • Hiepe F.
      • Jayne D.
      • et al.
      Current state and future directions of autologous hematopoietic stem cell transplantation in systemic lupus erythematosus.
      ].
      Several aspects of NMO pathogenesis remain unclear. More advances in the understanding of NMO disease mechanisms are needed in order to develop other effective therapeutic options and more specific therapeutic strategies.

      9. Conclusions

      Although substantial progress has been made recently in understanding the involvement of anti-AQP4 IgG in NMO pathogenesis and the central role of CDC, ADCC and glutamate excitotoxicity, major questions remain. It is not known why NMO lesions are mainly localized in spinal cord and optic nerves rather than in the brain, and why peripheral, AQP4-expressing organs are unaffected. It is not known how anti-AQP4, which has been assumed to be produced peripherally, initially enters the CNS. Moreover, the studies need to show if AQP4-specific Th1, Th17, and Th2 cells are unessential or if they are part of a more complex scheme of NMO pathogenesis. It is critical to determine the role of these specific inflammatory cell types and their cytokines in NMO pathogenesis.
      Continuous advances in the understanding of NMO disease mechanisms are needed to identify more specific biomarkers to NMO diagnosis and to define the role of anti-AQP4, T cell subtypes and their cytokines in the pathogenesis of NMO. The new biomarkers, cell subtypes and their cytokines and chemokines involved in the NMO pathogenesis may have potentially important diagnosis and therapeutic implications.

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