anti-AQP4 Antibody-positive Patients Research Articles

Comparison of clinical, immunological and neuroimaging features between anti-aquaporin-4 antibody-positive and antibody-negative Sjögren’s syndrome patients with central nervous system manifestations

Background and objective: The objective of this study is to clarify clinical, immunological, and neuroimaging features in anti-aquaporin-4 (AQP4) antibody-positive and antibody-negative Sjögren’s syndrome (SS) patients with central nervous system (CNS) involvement. Methods: Medical records and MRI scans were retrospectively analyzed in 22 consecutive SS patients with CNS manifestations. Results: Seven (31.8%) patients were positive for anti-AQP4 antibodies. The frequency of visual impairment was higher in anti-AQP4 antibody-positive patients than in antibody-negative patients (71.4% vs. 0.0%, p = 0.0008). Brain MRI showed that discrete lesions were more commonly found in the cerebrum, brainstem, and optic nerve in anti-AQP4 antibody-positive patients than in antibody-negative patients (p = 0.002, p = 0.006, and p = 0.004, respectively), while spinal cord MRI showed that posterior column lesions in the cervical spinal cord were more frequent in anti-AQP4 antibody-positive patients than in antibody-negative patients (71.4% vs. 14.3%, p = 0.01). SS-A antibody titers were higher in anti-AQP4 antibody-positive patients than in antibody-negative patients (p = 0.012) and were also higher in patients with longitudinally extensive spinal cord lesions (LESCLs) than in those without LESCLs (p = 0.019). Conclusions: In SS, the presence of anti-AQP4 antibodies is associated with involvement of the optic nerve, cerebrum and brainstem, and with cervical posterior column lesions in the spinal cord.

CSF angiotensin II and angiotensin-converting enzyme levels in anti-aquaporin-4 autoimmunity

Background Anti-aquaporin-4 (AQP4) antibody targets perivascular astrocyte foot processes, which contain abundant angiotensinogen, a precursor of angiotensin II, angiotensin-converting enzyme (ACE) and ACE2. Objective To disclose any abnormality in the intrathecal angiotensin II metabolic pathway in Japanese patients with neuromyelitis optica (NMO) or NMO spectrum disorders (NMOs) and positive for anti-AQP4 antibody. Methods We measured CSF angiotensin II, ACE and ACE2 levels in 15 anti-AQP4 antibody-positive patients with NMO or NMOs, 21 anti-AQP4 antibody-negative multiple sclerosis (MS) patients, 32 patients with other neurological diseases (OND) and 24 non-neurologic controls, using established ELISAs. Results CSF angiotensin II levels were lower in patients with NMO/NMOs (2.01 ± 1.82 pg/ml) and those with MS (3.15 ± 1.67 pg/ml) than in the OND (5.41 ± 2.34 pg/ml) and control groups (6.71 ± 2.65 pg/ml) ( P corr < 0.005). The difference in CSF angiotensin II levels between NMO/NMOs and MS patients was nearly significant ( P uncorr = 0.052). In NMO/NMOs and MS patients, angiotensin II levels were negatively correlated with CSF/serum albumin ratio ( P < 0.05). ACE levels in CSF were lower in patients with NMO/NMOs (34.3 ± 5.61 ng/ml) than in MS patients (42.5 ± 8.19 ng/ml, P corr = 0.035) and controls (44.7 ± 4.02 ng/ml, P corr < 0.0003) while ACE2 levels were lower in NMO/NMOs (1.13 ± 0.49 ng/ml) and MS (1.75 ± 0.86 ng/ml) patients than in controls (2.76 ± 0.23 ng/ml, P corr < 0.001 for both). Conclusion CSF angiotensin II, ACE, and ACE2 levels are decreased in NMO/NMOs patients with anti-AQP4 antibody, reflecting severe destruction of perivascular astrocytes.

Reappraisal of brain MRI features in patients with multiple sclerosis and neuromyelitis optica according to anti-aquaporin-4 antibody status

Brain lesions are not uncommon in neuromyelitis optica (NMO) patients with anti-aquaporin-4 (AQP4) antibody; however, the appearance of these lesions is said to be different from that of those in Western patients with multiple sclerosis (MS). To clarify the similarities and dissimilarities of brain lesions in anti-AQP4 antibody-positive and -negative MS and NMO patients, we examined the presence of anti-AQP4 antibody in the sera of 148 consecutive patients fulfilling Poser's criteria for clinically definite MS, of whom 38 also met the revised NMO criteria, using an immunofluorescence method, and analyzed brain lesions by magnetic resonance imaging (MRI). Brain lesions fulfilling the Barkhof criteria were significantly more common in 121 patients without anti-AQP4 antibody than in 27 patients with anti-AQP4 antibody (57.0% vs. 33.3%, P = 0.033), while the frequency of those that met the Paty criteria was not different between the two groups (74.4% vs. 73.5%). Ovoid lesions were detected more commonly in patients without anti-AQP4 antibody than in those with the antibody (72.3% vs. 48.2%, P = 0.022). The anti-AQP4 antibody-positive patients had significantly more atypical brain lesions, such as extensive brain lesions, than the anti-AQP4 antibody-negative ones (18.5% vs. 1.7%, P = 0.0023). Thus, although MS-like brain lesions are more common in anti-AQP4 antibody-negative patients than anti-AQP4 antibody-positive patients, approximately 30 to 50% of patients with anti-AQP4 antibody harbour brain MRI lesions indistinguishable from those present in typical MS patients, such as periventricular ovoid lesions, suggesting the existence of considerable overlap in brain MRI features between anti-AQP4 antibody-positive and -negative Asian patients. In the present study, NMO patients with brain lesions showed a significantly higher annualized relapse rate ( P corr = 0.017) and higher frequency of anti-AQP4 antibody ( P corr < 0.0001) than typical NMO patients without brain lesions, suggesting that development of brain lesions in NMO may reflect high disease activity and thus be a warning sign.

Aquaporin-4 autoimmune syndrome and anti-aquaporin-4 antibody-negative opticospinal multiple sclerosis in Japanese

Background Antibodies to aquaporin-4 (AQP4) are found in a fraction of Japanese opticospinal multiple sclerosis (OSMS) patients. However, it remains unknown whether anti-AQP4 antibody-positive and negative OSMS patients possess an identical disease. Objective The objective of the current study was to clarify immunological differences between the two groups of patients. Methods We studied the serum antibody titers against AQP4 in 191 patients with idiopathic central nervous system demyelinating diseases and clarified their relationships with immunological parameters. Results Anti-AQP4 antibody positivity rate was higher in patients with OSMS (21/58, 36.2%), idiopathic recurrent myelitis (4/17, 23.5%), and recurrent optic neuritis (7/26, 26.9%), than in conventional MS (CMS) patients (6/90, 6.7%) and patients with other diseases (0/87). Anti-AQP4 antibody titer was significantly higher in patients with SS-A/B antibodies than in those without them. Anti-AQP4 antibody-negative OSMS patients showed significantly higher CD4+IFN-γ+IL-4−T cell percentages and intracellular IFN-γ/IL-4 ratios than anti-AQP4 antibody-positive patients, anti-AQP4 antibody-negative CMS patients, and healthy controls, and CD4+IFN-γ+IL-4−T cell percentages were negatively correlated with anti-AQP4 antibody titers. Conclusion Anti-AQP4 antibody-positive patients are immunologically distinct from anti-AQP4 antibody-negative OSMS patients owing to a Th2 shift in the former group in comparison to a Th1 shift in the latter.

Multimodality-evoked potential study of anti-aquaporin-4 antibody-positive and -negative multiple sclerosis patients

Neuromyelitis optica (NMO) is claimed to be a distinct disease entity from multiple sclerosis (MS) because of its strong association with NMO-IgG/anti-AQP4 antibody; however, the in vivo role of the antibody remains unknown. Therefore, we aimed to clarify whether the presence of anti-AQP4 antibody is associated with any abnormalities in multimodality-evoked potentials in 111 patients with relapsing–remitting or relapsing-progressive MS, including the opticospinal form of MS, 18 of whom were seropositive for anti-AQP4 antibody. More patients with anti-AQP4 antibody showed a lack of the P100 component on visual-evoked potentials (VEPs) than those without the antibody (11/17, 64.7% vs. 20/84, 23.8%, p = 0.003), whereas the frequency of delayed P100 latency was significantly higher in the latter group than in the former (1/17, 5.9% vs. 28/84, 33.3%, p = 0.021). The frequencies of non-responses and delayed central sensory conduction times in median and posterior tibial nerve somatosensory-evoked potentials (SEPs) were not significantly different between anti-AQP4 antibody-positive and -negative patients. In terms of upper and lower limb motor-evoked potentials (MEPs), the frequencies of non-responses and delayed central motor conduction times did not differ significantly based on the presence or absence of anti-AQP4 antibody. The frequency of optic nerve lesions on MRI was significantly higher in anti-AQP4 antibody-positive patients than in anti-AQP4 antibody-negative patients ( p = 0.0137). Multiple logistic analyses revealed that anti-AQP4 antibody positivity (OR = 8.406, p = 0.02) and unevoked VEP responses (OR = 35.432, p < 0.001) were significantly related to development of severe visual impairment. Such an association of anti-AQP4 antibody with disability was not found for either severe motor or sensory impairment. These findings suggest a distinctive nature of optic nerve lesions between anti-AQP4 antibody-positive and -negative patients; lesions are supposed to be more necrotic in the former group and more demyelinating in the latter.

Hypercomplementemia at relapse in patients with anti-aquaporin-4 antibody

Objective Because Asian patients with opticospinal multiple sclerosis (OSMS) frequently have anti-aquaporin-4 (AQP4) antibody, complement-mediated disruption of astrocyte foot processes is proposed but not yet proven. We aimed to clarify whether complement consumption occurs at relapse in anti-AQP4 antibody-positive patients. Methods We analyzed serum CH50, C3, C4, and C-reactive protein (CRP) levels and their relation to clinical phases in 118 MS patients with or without anti-AQP4 antibody. Serum CH50 levels were higher in 24 patients with anti-AQP4 antibody than in 39 OSMS and 54 conventional form of MS (CMS) patients without anti-AQP4 antibody at relapse (Pcorr < 0.05) but not in remission. The frequency of hypercomplementemia at relapse was also higher in anti-AQP4 antibody-positive patients than in anti-AQP4 antibody-negative CMS patients (70.4% vs 29.0%, Pcorr < 0.05). C3 and C4 levels did not differ significantly among the three groups at relapse. In patients with anti-AQP4 antibody, the coexistence of hypercomplementemia and high CRP values was more common at relapse than in the remission phase (36.0% vs 10.5%, P < 0.05). In patients with extensive central nervous system lesions, hypercomplementemia was significantly more common in anti-AQP4 antibody-positive patients than anti-AQP4 antibody-negative ones (88.9% vs 16.7%, P < 0.01). We consider that hypercomplementemia in anti-AQP4 antibody-positive patients may reflect a systemic inflammatory reaction at relapse.

Association of the HLA‐DPB1*0501 allele with anti‐aquaporin‐4 antibody positivity in Japanese patients with idiopathic central nervous system demyelinating disorders

There are two subtypes of multiple sclerosis (MS) in Asians: the opticospinal (OSMS) form that shows a selective involvement of the optic nerve and the spinal cord and the conventional (CMS) form that has disseminated lesions in the central nervous system including the cerebrum, cerebellum and brainstem. Both show distinct human leukocyte antigen (HLA) class II associations. OSMS has similar features to the relapsing form of neuromyelitis optica (NMO) in Western populations. Recently, it was shown that antibodies to aquaporin-4 (AQP4) are specifically detected in NMO patients and in some Japanese patients with OSMS or recurrent optic neuritis or myelitis. To clarify the immunogenetic background of anti-AQP4 antibody production, we studied HLA-DRB1 and -DPB1 gene polymorphisms in anti-AQP4 antibody-positive and -negative patients with idiopathic demyelinating diseases, such as MS, recurrent optic neuritis and recurrent myelitis. The phenotypic frequency of the HLA-DPB1*0501 allele was significantly increased in anti-AQP4 antibody-positive patients (89.5%, odds ratio = 4.8; 95% confidence interval = 1.6-14.3, n = 38, P(corr) = 0.032) compared with controls (64.0%, n = 125) but not in either anti-AQP4 antibody-negative OSMS (75.0%, n = 32) or CMS (69.2%, n = 52) patients. There was no significant correlation between any HLA-DRB1 allele and the existence of anti-AQP4 antibody. These findings suggest that the emergence of anti-AQP4 antibody is reinforced by the presence of the HLA-DPB1*0501 allele in Japanese.

Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese

Opticospinal multiple sclerosis (OSMS) in Asians has similar features to the relapsing-remitting form of neuromyelitis optica (NMO) seen in Westerners. OSMS is suggested to be NMO based on the frequent detection of specific IgG targeting aquaporin-4 (AQP4), designated NMO-IgG. The present study sought to clarify the significance of anti-AQP4 autoimmunity in the whole spectrum of MS. Sera from 113 consecutive Japanese patients with clinically definite MS, based on the Poser criteria, were assayed for anti-AQP4 antibodies by immunofluorescence using GFP-AQP4 fusion protein-transfected HEK-293T cells. Sensitivity and specificity of the anti-AQP4 antibody assay, 83.3 and 100%, respectively, were calculated using serum samples with NMO-IgG status predetermined at the Mayo Clinic. The anti-AQP4 antibody positivity rate was significantly higher in OSMS patients (13/48, 27.1%) than those with CMS (3/54, 5.6%), other neurological diseases (0/52) or healthy controls (0/35). None of the 11 patients tested with a brainstem-spinal form of MS were positive. Among OSMS patients, the antibody positivity rate was highest in OSMS patients with longitudinally extensive spinal cord lesions (LESCLs) extending over three vertebral segments and brain lesions that fulfilled the Barkhof criteria (5/9, 55.6%). Multiple logistic analyses revealed that emergence of the anti-AQP4 antibody was positively associated only with a higher relapse rate, but not with optic-spinal presentation or LESCLs. Compared with anti-AQP4 antibody-negative CMS patients, anti-AQP4 antibody-positive MS patients showed significantly higher frequencies of severe optic neuritis, acute transverse myelitis and LESCLs while most conditions were also common to anti-AQP4 antibody-negative OSMS patients. The LESCLs in anti-AQP4 antibody-positive patients were located at the upper-to-middle thoracic cord, while those in anti-AQP4 antibody-negative OSMS patients appeared throughout the cervical-to-thoracic cord. On axial planes, the former most frequently showed central grey matter involvement, while holocord involvement was predominant in the latter. In contrast, LESCLs in anti-AQP4 antibody-negative CMS patients preferentially involved the mid-cervical cord presenting a peripheral white matter-predominant pattern, as seen in the short lesions. Anti-AQP4 antibody-positive MS patients fulfilling definite NMO criteria showed female preponderance, higher relapse rate, greater frequency of brain lesions and less frequent responses to interferon beta-1b than anti-AQP4 antibody-negative OSMS patients with LESCLs. These findings suggested that LESCLs are distinct in anti-AQP4 antibody positivity and clinical phenotypes. There were cases of anti-AQP4 antibody-positive MS/NMO distinct from CMS, and anti-AQP4 antibody-negative OSMS with LESCLs in Japanese. This indicated that the mechanisms producing LESCLs are also heterogeneous in cases with optic-spinal presentation, namely AQP4 autoimmunity-related and -unrelated.