Disease-specific Autoantibodies Research Articles

Glycine receptor antibodies in stiff-person syndrome and other GAD-positive CNS disorders

Stiff-person syndrome (SPS) is characterized by stiffness in trunk and limb muscles, phobic anxiety, and sudden spasms. A disturbance in inhibitory GABAergic pathways, presumably by autoantibodies against GAD (the main GABA-synthesizing enzyme), is considered fundamental for SPS pathogenesis.1 As the precise role of anti-GAD antibodies in SPS remains unclear,2,3 several other candidate disease-specific autoantibodies associated with inhibitory pathways have been explored3,4 or are actively pursued. Recently, McKeon et al.5 described anti-glycine-α1 receptor (GlyR) antibodies in a subset of patients with SPS. Glycine is a neurotransmitter in spinal inhibitory interneurons and GlyR are primarily expressed in the spinal cord, brainstem, and cerebellum. Anti-GlyR antibodies have been associated with progressive encephalomyelitis with rigidity and myoclonus (PERM), a syndrome resembling SPS.6 Our aims were to search for GlyR antibodies in a large number of patients with well-characterized SPS and other CNS autoimmune controls and other GAD-positive disorders; and to correlate anti-GlyR titers with clinical symptomatology using quantitative scales of stiffness and spasms.7 The authors thank Dr. Goran Rakocevic and Beverly McElroy, RN, for helping with the care of patients studied at the NIH under Dr. Dalakas's protocols.

Headache in Systemic Lupus Erythematosus: Results From a Prospective, International Inception Cohort Study

To examine the frequency and characteristics of headaches and their association with global disease activity and health-related quality of life (HRQOL) in patients with systemic lupus erythematosus (SLE). A disease inception cohort was assessed annually for headache (5 types) and 18 other neuropsychiatric (NP) events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 (SF-36) mental and physical component summary scores were collected. Time to first headache and associations with SF-36 scores were analyzed using Cox proportional hazards and linear regression models with generalized estimating equations. Among the 1,732 SLE patients enrolled, 89.3% were female and 48.3% were white. The mean ± SD age was 34.6 ± 13.4 years, duration of disease was 5.6 ± 5.2 months, and length of followup was 3.8 ± 3.1 years. At enrollment, 17.8% of patients had headache (migraine [60.7%], tension [38.6%], intractable nonspecific [7.1%], cluster [2.6%], and intracranial hypertension [1.0%]). The prevalence of headache increased to 58% after 10 years. Only 1.5% of patients had lupus headache, as identified in the SLEDAI-2K. In addition, headache was associated with other NP events attributed to either SLE or non-SLE causes. There was no association of headache with SLEDAI-2K scores (without the lupus headache variable), SDI scores, use of corticosteroids, use of antimalarials, use of immunosuppressive medications, or specific autoantibodies. SF-36 mental component scores were lower in patients with headache compared with those without headache (mean ± SD 42.5 ± 12.2 versus 47.8 ± 11.3; P < 0.001), and similar differences in physical component scores were seen (38.0 ± 11.0 in those with headache versus 42.6 ± 11.4 in those without headache; P < 0.001). In 56.1% of patients, the headaches resolved over followup. Headache is frequent in SLE, but overall, it is not associated with global disease activity or specific autoantibodies. Although headaches are associated with a lower HRQOL, the majority of headaches resolve over time, independent of lupus-specific therapies.

Primary biliary cirrhosis in an 85-year-old woman

Primary biliary cirrhosis is a chronic cholestatic disease with a progressive course. Its etiology is thought to be due to a combination of genetic predisposition and environmental triggers. The characteristic serological hallmark of this disease is a highly disease-specific autoantibody, antimitochondrial antibody. The diagnosis of primary biliary cirrhosis should be suspected in the setting of chronic cholestasis after exclusion of other causes of liver diseases. The authors present the case of a 85-year-old woman, who was referred to the Internal Medicine Outpatient Department for study of an elevation on the alkaline phosphatase, gamma-glutamyltransferase and a slight elevation of aminotransferases found on two routine laboratory evaluations.

Glycoprotein 2 antibodies in adult and pediatric inflammatory bowel disease: Significance and correlations with phenotype

Background: The zymogen granule membrane glycoprotein (GP2) has been recognised as the major antigenic target of Crohn's disease (CD) specific pancreatic autoantibodies [1]. Recent investigations have shown a reactivity to GP2 ranging from 20% to 30% in adult patients with CD and an association with distinct phenotypes as ileo-colonic location, stricturing behaviour and perianal disease [2].

Celiac Disease-Specific TG2-Targeted Autoantibodies Inhibit Angiogenesis Ex Vivo and In Vivo in Mice by Interfering with Endothelial Cell Dynamics.

A characteristic feature of celiac disease is the presence of circulating autoantibodies targeted against transglutaminase 2 (TG2), reputed to have a function in angiogenesis. In this study we investigated whether TG2-specific autoantibodies derived from celiac patients inhibit angiogenesis in both ex vivo and in vivo models and sought to clarify the mechanism behind this phenomenon. We used the ex vivo murine aorta-ring and the in vivo mouse matrigel-plug assays to address aforementioned issues. We found angiogenesis to be impaired as a result of celiac disease antibody supplementation in both systems. Our results also showed the dynamics of endothelial cells was affected in the presence of celiac antibodies. In the in vivo angiogenesis assays, the vessels formed were able to transport blood despite impairment of functionality after treatment with celiac autoantibodies, as revealed by positron emission tomography. We conclude that celiac autoantibodies inhibit angiogenesis ex vivo and in vivo and impair vascular functionality. Our data suggest that the anti-angiogenic mechanism of the celiac disease-specific autoantibodies involves extracellular TG2 and inhibited endothelial cell mobility.

Establishment of monoclonal antibodies against the extracellular domain that block binding of NMO-IgG to AQP4

Neuromyelitis optica is a demyelinating disease characterized by a disease-specific autoantibody designated as NMO-IgG that specifically recognizes aquaporin-4, and the binding of NMO-IgG to AQP4 causes the progress of the disease. Prevention of the binding of NMO-IgG, therefore, may alleviate the disease. Here we have developed monoclonal antibodies against AQP4 with a baculovirus display system in order to obtain high affinity monoclonal antibodies against the extracellular domains of AQP4. Our monoclonal antibodies can block the binding of NMO-IgG in spite of their heterogeneity. Taken together, we propose that our monoclonal antibodies can be applied in clinical therapy for NMO patients.

FRI0395 Digital ulcers as a “sentinel” sign for early internal organ involvement in very early systemic sclerosis: evidence from a single vedoss/eustar centre.

ObjectivesEvaluation of the presence of digital lesions [1] in patients with diagnosis of very early systemic sclerosis (VEDOSS) [2] and of their correlation with clinical, laboratory and imaging parameters.Methods110 VEDOSS...

SP0116 How to Treat/Manage Myositis

Idiopathic inflammatory myopathies (IIMs) are rare, chronic disorders that may lead to substantial long-term morbidity, reduced quality of life, work disability and mortality. The aetiology of IIMs is largely unknown...

Focus on Cancer Proteomics

Motivated by the ever increasing demands for improved analytical and computational capabilities in support of proteomic research, technology has rocketed forward. As an example, high-end mass spectrometry touts a competitive half-life on par with Moore's law in the computer industry. Every few years we can expect significant technical improvement in the tools applied to this rapidly growing field. Although it is often easy to become enamored by these technological advances, it is critical that these do not distract from the equally important activities related to developing robust applications to maximize the biomedical impact of these developmental cycles. The field of Cancer Proteomics is ultimately dependent upon developing, standardizing and applying novel technologies to difficult, often-elusive, clinical questions. Many of the assumptions used to develop improved technology do not resonate with the realities of experimentation with clinical samples or complex models of disease. The objective of this Focus Issue is to highlight successful efforts in the application of novel technologies for cancer proteomic studies. Included in this issue are four full-length articles and three technical notes that span a variety of technology application. Morrissey et al. describe a robust approach for the application of label-free LC-MS/MS-based quantitation of serum for the discovery of candidate protein biomarkers of prostate cancer. The design is toward a pipeline from discovery within a clinical trial cohort to a testable MRM-based assay. Chao et al., recognizing the important role of the immune response in both disease development and treatment, describe an array-based approach for profiling patient autoimmune responses. They detail an application of this technology to uncover an immunosuppressive effect of hormone therapy in breast cancer patients. Longuespee et al. present a study that employs MALDI MS imaging to uncover molecular events that potentially drive histopathologic etiology of serous ovarian cancer. In an attempt to address the issue of low abundance tumor specific proteins, researchers may be able to resort to the analysis of cell models. In this issue, Marimuthu et al. examine the secretome of gastric tumor cell lines utilizing SILAC-based quantitation. Similarly, Roper et al. employed azido sugar metabolic labeling to assist in the capture and quantitative analysis of the secretome in a prostate cancer stromal cell model. Our series concludes with two articles describing technological improvements in the application of protein arrays. Festa et al. describe the application of 1-Step human-coupled in vitro transcription/translation for the efficient expression of target proteins in a mammalian IVT system. Wang et al., from the same group, describe a novel approach to achieve expression and arraying of denatured proteins specifically targeted at the identification of disease specific autoantibodies. Our sampling of advances in technology application, although somewhat diverse, is focused on overcoming barriers common to the field of clinical proteomics. We thank the authors for their generous commitment of time and energy to make this Focus Issue a success!

Autoantibodies targeting neurotransmitter biosynthetic enzymes in attention-deficit/hyperactivity disorder (ADHD)

Autoantibodies targeting neurotransmitter biosynthetic enzymes in attention-deficit/hyperactivity disorder (ADHD)

Crohn’s disease-specific pancreatic autoantibodies are specifically present in ruminants with paratuberculosis: Implications for the pathogenesis of the human disease

Mycobacterium avium subspecies paratuberculosis (MAP) induces paratuberculosis (ptb) in ruminants and has clinical and histological features resebling Crohn’s disease (CD). Pancreatic autoantibodies (PAB) targeting glycoprotein 2 (GP2) are specifically found in CD, but it is currently unknown whether these autoantibodies can be found in ruminants with ptb. IgG anti-MAP and anti-GP2 antibodies were tested by ELISA in 286 ruminants (212 sheep and 74 cattle). PAB testing was performed by indirect immunofluorescence (IIF) using anti-sheep or anti-cattle specific antisera. PCR analysis confirmed the presence of MAP in anti-MAP positive samples. Anti-GP2 antibodies were more prevalent in anti-MAP antibody positive (26.9%) than in anti-MAP negative ruminants (8.7%, p < 0.001). Anti-GP2 antibodies were found in 16/70 (22.9%) anti-MAP positive sheep compared to 10/142 (7%, p = 0.001) anti-MAP antibody negative and in anti-MAP positive cattle than in negative counterparts (5/8 versus 8/66, p = 0.003). Absorbance values for anti-GP2 antibodies were higher in cattle than in sheep (mean 21 AU/mL ± 25.4SD versus 12.2 AU/mL ± 23 SD, p < 0.001). There was no correlation between anti-GP2 and anti-MAP antibody concentrations. Anti-GP2 antibodies persisted up to 1/1000 and showed the characteristic IIF pancreatic pattern seen by anti-GP2 antibody positive CD samples. This is the first study to demonstrate the presence of CD-specific GP2-reactive pancreatic autoantibodies in MAP-infected ruminants. Our data suggest that CD and ptb are characterised by an antigen-driven loss of immunological tolerance to GP2, implying commonalities in the immunopathogenesis of the human and ruminant inflammatory bowel disorder.

Paraneoplastic and Other Autoimmune Disorders of the Central Nervous System

As a result of the burgeoning growth of disease-specific neural autoantibody markers available for diagnostic patient evaluation, there has been increasing awareness of autoimmune central nervous system (CNS) disorders in hospital practice. Hospital-based neurologists have also taken great interest in these disorders since many occur in the setting of an occult systemic cancer which can be detected and treated at an early stage, and many affected patients are responsive to immunotherapy. Associated neurological disorders are typically subacute in onset, some are common or classic (eg, limbic encephalitis, cerebellar degeneration), but others have atypical or multifocal presentations. For patients with a suspected paraneoplastic disorder, many and costly oncological evaluations may be required for diagnosis. Comprehensive serological and cerebrospinal fluid (CSF) evaluation for neural autoantibodies may permit a focused cancer evaluation (eg, antineuronal nuclear antibody type 1 [ANNA-1] is associated with small cell lung carcinoma), and in some circumstances may indicate the likelihood of a good response to therapy (eg, voltage-gated potassium channel complex antibody) or poor neurological prognosis (eg, purkinje cell cytoplasmic antibody type 1 [antiYo]). Positron-emission tomography-computed tomography (PET-CT) imaging of trunk may increase the diagnostic yield for certain cancers where other modalities have been negative. For some patients, rapid treatment with immunotherapy may facilitate marked improvement, or full recovery; multiple sequential trials of one or more of steroids, intravenous immunoglobulin or plasma exchange, or combination therapy are often required. For patients with N-methyl-d-aspartate receptor antibody encephalitis, early treatment with immunosuppressants and weeks or months of supportive intensive care may additionally be required. One or more of clinical examination, electroencephalogram (including video telemetry), and imaging provide objective parameters to which posttreatment outcomes can be compared.

Presence of disease specific autoantibodies against liver sinusoidal cells in primary biliary cirrhosis

To investigate the presence of autoantibodies directed against liver sinusoidal cells in primary biliary cirrhosis (PBC). Liver biopsies from 21 PBC patients were studied and compared with 12 liver biopsies from disease controls [3 patients with hepatitis B (HBV) virus, 3 patients with hepatitis C virus (HCV), 3 patients with non-alcoholic steatohepatitis and 3 patients with acute alcoholic hepatitis (AAH)]. As healthy controls, we used tissue specimens adjacent to metastatic liver adenocarcinoma. Normal serum was taken from staff members of the unit. The determination of the cell type targeted by autoantibodies present in the patients sera was performed by indirect immunofluorescence (IIF) analysis using paraffin-embedded liver sections as a substrate. Sera from homologous or heterologous PBC patients or sera from the disease control group were used as primary antibodies. The presence of autoantibodies was identified using confocal microscopy. In total, 18/21 (85.7%) PBC patients exhibited positive staining in the sinusoidal cells, 10/21 (47.6%) in lymphocytes, 8/21 (38%) in cholangiocytes and 7/21 (33.3%) in hepatocytes, when homologous serum and fluorescein isothiocyanate-conjugated immunoglobulin type G (IgG) secondary antibody were used. PBC sections incubated with heterologous PBC serum showed reduced staining (20% for sinusoidal cells, 20% for lymphocytes, 20% for cholangiocytes and 13.3% for hepatocytes). When IgM immunoglobulin, instead of IgG, was used as secondary antibody, positive staining was observed in 75% of lymphocytes, 62.5% of cholangiocytes, 37.5% of hepatocytes and 50% of the sinusoidal cells with a much stronger staining intensity. No staining was observed when either normal or PBC sera were used as a primary antibody on liver sections from the disease control group. When PBC sera were incubated with healthy control sections, weak positive staining of cholangiocytes was observed in 3/21 (14.3%) PBC serum samples. Steatohepatitis serum on PBC sections gave a positive staining of some hepatocytes and lymphocytes but no staining on viral hepatitis sections. Incubation with HBV sera stained some hepatocytes, cholangiocytes and intra-sinusoidal or portal lymphocytes of PBC, HBV and AAH patients but not HCV patients. In this study, for the first time in diseased liver tissue, we have demonstrated that a large proportion of PBC patients have disease specific autoantibodies against liver sinusoidal cells.

Clinical and Radiographic Heterogeneity of Interstitial Lung Disease in Systemic Sclerosis Based on Disease-Specific Autoantibodies

Patients with SSc have the presence of several autoantibodies, some of which are SSc-specific antibodies associated with the clinical features of SSc (9-13). The presence of anti-topoisomerase I (topo-I) antibody is associated with the development of skin fibrosis and progressive ILD in SSc. Anti-centromere antibody (ACA) is seen in patients with limited skin disease and is a minor risk factor for the development of ILD. However, it remains unclear whether SSc-specific antibodies are associated with pulmonary function and radiological findings of HRCT. We divided SSc patients into 5 clusters on the basis of SSc-specific autoantibodies present and retrospectively evaluated the clinical and radiological features of ILD among these 5 SSc patient clusters. Abstract Background: Patients with systemic sclerosis have the presence of several autoantibodies, some of which are systemic sclerosis-specific autoantibodies that are related to the clinical features of this disease. We retrospectively evaluated the clinical and radiological features of systemic sclerosis in patients with interstitial lung disease on the basis of these autoantibodies. Method: This study comprised 226 patients with systemic sclerosis. We divided patients with systemic sclerosis into 5 clusters based on the systemic sclerosis-specific autoantibodies present and compared the clinical and radiological features of interstitial lung disease among these 5 systemic sclerosis clusters. Results: Of 226 patients, interstitial lung disease was present in 73 (32.3%) patients. Clustering by Ward cluster analysis subsequently identified 5 major clusters of patients. Clusters of patients with anti-topoisomerase I antibody and without systemic sclerosis-specific autoantibodies had a higher incidence of interstitial lung disease compared to the other clusters (75.0% and 51.9%, respectively). Patients in these two clusters had higher percentages of cough and dyspnea, higher incidence of traction bronchiectasis and honeycomb-like cysts in computed tomography, and a decrease in percentage predicted of vital capacity. In contrast, patients with anti-centromere antibody had few clinical and laboratory findings and the lowest incidence of interstitial lung disease (16.8%). Patients with anti- ribonucleic antibody or nucleolar pattern in anti-nuclear antibody had moderate findings among the 5 clusters. Conclusion: The results showed that there were differences in clinical and radiological findings among patients with systemic sclerosis-specific autoantibodies.

Serum Autoantibodies: From Identification to Clinical Relevance

Serum Autoantibodies: From Identification to Clinical Relevance

Altered BANK1 expression is not associated with humoral autoimmunity in chronic joint inflammation

The presence of disease-specific autoantibodies in RA but not spondyloarthritis (SpA) suggests that B-cell tolerance is preserved in the latter condition despite chronic joint inflammation. Which factors control B-cell tolerance vs autoimmunity in chronic arthritis remains incompletely understood. As single nucleotide polymorphisms in the B-cell scaffold protein with ankyrin repeats (BANK1) gene have recently been associated with various autoantibody-positive autoimmune diseases including RA, we explored whether altered expression of BANK1 was associated with humoral autoimmunity in arthritis. Peripheral B-cell subsets and inflamed synovial tissue were obtained from active SpA and RA. Quantitative PCR was used to assess the expression of full-length BANK1 and delta2 BANK1, a splice variant lacking exon 2 that counteracts BANK1 function. B-cell subsets, autoantibody titres and clinical disease were monitored upon CIA induction in Bank1 knockout (KO) mice. Whereas full-length BANK1 was not differentially expressed, the BANK1 delta2 splicing variant was decreased in naïve peripheral B cells as well as in synovial tissue of SpA compared with RA. However, no differences were observed in seropositive vs seronegative RA. Performing functional analysis in mice, we found no differences in B-cell subsets and anti-collagen antibodies upon CIA induction between Bank1 KO mice and littermate controls. Accordingly, the incidence and severity of clinical disease were not altered in Bank1 KO mice. This study did not reveal a major role for BANK1 in humoral autoimmunity in chronic arthritis. The decreased levels of BANK1 delta2 in SpA, however, warrant more detailed analysis of the functional consequences of an altered BANK1/BANK1 delta2 balance.

G.O.8 The first inclusion body myositis-specific autoantibody: Anti-MUP44 targets the cytosolic 5′-nucleotidase IA

<h2>Abstract</h2> Sporadic inclusion body myositis (sIBM) is characterized by both degenerative and autoimmune features. In contrast to other inflammatory myopathies, in sIBM disease-specific autoantibodies were believed not to exist. Recently, we identified a 44-kDa skeletal muscle antigen (Mup44) as a specific autoantibody target in sIBM. The Mup44 antigen was detected in skeletal muscle extracts of both humans and mice, but not in extracts from cultured cell lines including in vitro differentiated murine myotubes. To determine the molecular identity of Mup44, the protein was purified from human skeletal muscle extracts using antibodies isolated from anti-Mup44-positive patient sera. Mass spectrometry analyses identified the cytosolic 5′-nucleotidase IA (cN-IA) as the putative target of anti-Mup44 autoantibodies. A cDNA encoding cN-IA was generated using human skeletal muscle mRNA as starting material. Immunoprecipitations with the in vitro translated cN-IA confirmed that anti-Mup44 autoantibodies are directed to cN-IA. Using a microarray of overlapping synthetic peptides covering the complete cN-IA amino acid sequence, three autoepitope regions were mapped, one of which appeared to be recognized by all anti-Mup44 sera analyzed. The sensitivity and specificity of anti-Mup44 was assessed by the recombinant cN-IA immunoprecipitation assay. Anti-Mup44 was detected in approximately 65% of sIBM sera, whereas it was found in less than 20% of dermatomyositis and polymyositis sera. Moreover, the titers in sIBM were generally higher. Also in other (diseased) control groups anti-Mup44 was found with only low frequencies. Our data suggest that these novel sIBM-specific autoantibodies may find applications as biomarker to facilitate the diagnosis of sIBM. The novelty of these data reside in the identification and characterization of the first disease-specific autoantibody and its target protein in sIBM.

Astrocytic autoantibody of neuromyelitis optica (NMO-IgG) binds to aquaporin-4 extracellular loops, monomers, tetramers and high order arrays

The principal central nervous system (CNS) water channel, aquaporin-4 (AQP4), is confined to astrocytic and ependymal membranes and is the target of a pathogenic autoantibody, neuromyelitis optica (NMO)-IgG. This disease-specific autoantibody unifies a spectrum of relapsing CNS autoimmune inflammatory disorders of which NMO exemplifies the classic phenotype. Multiple sclerosis and other immune-mediated demyelinating disorders of the CNS lack a distinctive biomarker. Two AQP4 isoforms, M1 and M23, exist as homotetrameric and heterotetrameric intramembranous particles (IMPs). Orthogonal arrays of predominantly M23 particles (OAPs) are an ultrastructural characteristic of astrocytic membranes. We used high-titered serum from 32 AQP4-IgG-seropositive patients and 85 controls to investigate the nature and molecular location of AQP4 epitopes that bind NMO-IgG, and the influence of supramolecular structure. NMO-IgG bound to denatured AQP4 monomers (68% of cases), to native tetramers and high order arrays (90% of cases), and to AQP4 in live cell membranes (100% of cases). Disease-specific epitopes reside in extracellular loop C more than in loops A or E. IgG binding to intracellular epitopes lacks disease specificity. These observations predict greater disease sensitivity and specificity for tissue-based and cell-based serological assays employing “native” AQP4 than assays employing denatured AQP4 and fragments. NMO-IgG binds most avidly to plasma membrane surface AQP4 epitopes formed by loop interactions within tetramers and by intermolecular interactions within high order structures. The relative abundance and localization of AQP4 high order arrays in distinct CNS regions may explain the variability in clinical phenotype of NMO spectrum disorders.

Pathogenesis of spondyloarthritis

Spondyloarthritis (SpA) is a chronic immune-mediated inflammatory disease of unknown origin. Here we aim to review whether SpA is driven by T-cell and/or B-cell autoreactivity or by abnormal innate immune responses. SpA does not share genetic risk factors, female predominance, presence of disease-specific autoantibodies and response to T-cell or B-cell-targeted therapies with prototypical autoimmune diseases like rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Growing evidence indicates that increased responsiveness of innate immune cells such as macrophages, mast cells and neutrophils drives inflammation in SpA. The altered innate immune response may be related to nonantigen-presenting functions of HLA-B27, including the induction of an unfolded protein response, and can be triggered by bacterial and mechanical stress. Innate immune cells appear to be the main producers of both pro-inflammatory (tumor necrosis factor, IL-1, IL-23, IL-17) and anti-inflammatory (IL-10) cytokines in SpA. The predominance of myeloid above lymphoid alterations suggests an autoinflammatory rather than autoimmune origin of inflammation in SpA. Therefore, targeting innate cells or their inflammatory mediators may be more effective than T-cell or B-cell-directed therapies.

Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan

Neuromyelitis optica and neuromyelitis optica spectrum disorders have been recently associated with the disease-specific autoantibody aquaporin-4, thought to be pathogenic. Identifying this antibody has allowed the clinical phenotype to be broadened. It is clear that some patients with similar clinical features do not have this antibody and may have a different condition with different outcomes and prognosis. Previous clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies have included such patients. We investigated clinical outcomes and prognostic characteristics of 106 aquaporin-4 antibody-seropositive patients from the UK and Japan. We looked at predictors of disability outcomes, namely visual disability (permanent bilateral visual loss with visual acuity of <6/36 in the best eye), motor disability (permanent inability to walk further than 100 m unaided), wheelchair dependence and mortality. Data were collected largely retrospectively through review of case records. After median disease duration of 75 months, 18% had developed permanent bilateral visual disability, 34% permanent motor disability, 23% had become wheelchair dependent and 9% had died. Age at disease onset appeared to be an important predictor of disability type. Young-onset patients in the UK, but not the Japanese cohort, commonly presenting with optic neuritis, had a high risk of visual disability while older patients in both cohorts had a high risk of motor disability, regardless of their onset symptom. Genetic factors also appeared important. The UK cohort seemed to have more severe disease than the Japanese cohort, with more severe onset attacks, a higher relapse frequency and greater disability at follow-up, despite earlier immunosuppression. Moreover, within the UK cohort, there were important differences between ethnic groups, with Afro-Caribbean patients having a younger age at disease onset, more brain and multifocal attacks and higher likelihood of visual disability than Caucasian patients. Thus, age at disease onset and genetic factors are both likely to be important in determining clinical outcomes in aquaporin-4 disease. This has important implications for interpreting clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies, since clinical features and outcomes appear not to be generic across populations and may need to be tailored to individual groups. These factors need to be explored further in future prospective neuromyelitis optica and neuromyelitis optica spectrum disorder studies.