Stage-dependent immunity orchestrates AQP4 antibody-guided NMOSD pathology: a role for netting neutrophils with resident memory T cells in situ.

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the CNS characterized by the production of disease-specific autoantibodies against aquaporin-4 (AQP4) water channels. Animal model studies suggest that anti-AQP4 antibodies cause a loss of AQP4-expressing astrocytes, primarily via complement-dependent cytotoxicity. Nonetheless, several aspects of the disease remain unclear, including: how anti-AQP4 antibodies cross the blood-brain barrier from the periphery to the CNS; how NMOSD expands into longitudinally extensive transverse myelitis or optic neuritis; how multiphasic courses occur; and how to prevent attacks without depleting circulating anti-AQP4 antibodies, especially when employing B-cell-depleting therapies. To address these knowledge gaps, we conducted a comprehensive 'stage-dependent' investigation of immune cell elements in situ in human NMOSD lesions, based on neuropathological techniques for autopsied/biopsied CNS materials. The present study provided three major findings. First, activated or netting neutrophils and melanoma cell adhesion molecule-positive (MCAM+) helper T (TH) 17/cytotoxic T (TC) 17 cells are prominent, and the numbers of these correlate with the size of NMOSD lesions in the initial or early-active stages. Second, forkhead box P3-positive (FOXP3+) regulatory T (Treg) cells are recruited to NMOSD lesions during the initial, early-active or late-active stages, suggesting rapid suppression of proinflammatory autoimmune events in the active stages of NMOSD. Third, compartmentalized resident memory immune cells, including CD103+ tissue-resident memory T (TRM) cells with long-lasting inflammatory potential, are detected under "standby" conditions in all stages. Furthermore, CD103+ TRM cells express high levels of granzyme B/perforin-1 in the initial or early-active stages of NMOSD in situ. We infer that stage-dependent compartmentalized immune traits orchestrate the pathology of anti-AQP4 antibody-guided NMOSD in situ. Our work further suggests that targeting activated/netting neutrophils, MCAM+ TH17/TC17 cells, and CD103+ TRM cells, as well as promoting the expansion of FOXP3+ Treg cells, may be effective in treating and preventing relapses of NMOSD.

Clinicopathological features in anterior visual pathway in neuromyelitis optica.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOsd) is an autoimmune disorder of the central nervous system characterized by aquaporin-4 (AQP4) autoantibodies. The aim of this study was to elucidate the characteristics of involvement of the anterior visual pathway (AVP) and neurodegeneration via glia-neuron interaction in NMOsd. METHODS: Thirty Japanese patients with serologically verified NMOsd were assessed with a neuro-ophthalmological study. Using 27 tissue blocks from 13 other cases of NMOsd, we performed neuropathological analysis of glial and neuroaxonal involvement in the AVP. RESULTS: The AVP involvement in NMOsd was characterized by the following, compared to multiple sclerosis: (1) longitudinally extensive optic neuritis (ON); (2) more severe visual impairment and worse prognosis for ON; (3) unique AQP4 dynamics, including loss of AQP4 immunoreactivity on astrocytes with complement activation in ON lesions, loss of AQP4 immunoreactivity on Müller cells with no deposition of complement in the retinas, and densely packed AQP4 immunoreactivity on astrocytes in gliosis of secondary anterograde/retrograde degeneration in the optic nerves and retinal nerve fiber layer (RNFL); and (4) more severe neurodegeneration, including axonal accumulation of degenerative mitochondria and transient receptor potential melastatin 4 channel with complement-dependent astrocyte pathology in ON lesions, mild loss of horizontal cells, and RNFL thinning and loss of ganglion cells with abundance of AQP4(+) astrocytes, indicating secondary retrograde degeneration after ON. INTERPRETATION: Severe and widespread neuroaxonal damage and unique dynamics of astrocytes/Müller cells with alterations of AQP4 were prominent in the AVP and may be associated with poor visual function and prognosis in NMOsd.

Cognitive impairment and cortical degeneration in neuromyelitis optica.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOsd) is an inflammatory and demyelinating syndrome characterized by optic neuritis and myelitis. Several magnetization transfer magnetic resonance imaging (MRI) studies have revealed abnormalities in normal-appearing gray matter in NMOsd. The aim of this study is to elucidate the characteristics and pathogenesis of cognitive impairment and neurodegeneration in NMOsd brains. METHODS: Fourteen Japanese patients with serologically verified NMOsd, 17 patients with multiple sclerosis (MS), and 37 healthy controls were assessed with the Rao's Brief Repeatable Battery of Neuropsychological Tests (BRBN). Using 128 tissue blocks from 6 other cases of NMOsd, 3 cases of MS, and 4 controls without central nervous system involvement, we performed quantitative analysis of cortical neuronal loss and layer-specific changes in NMOsd. RESULTS: In BRBN assessments, 57% of NMOsd patients and 47% of MS patients had impaired performance on at least 3 cognitive tests. Cognitive impairment in NMOsd was common even in the limited form of disease, indicating that NMOsd may progress insidiously from early stages of disease. Neuropathological assessments showed neuronal loss in cortical layers II, III, and IV, with nonlytic reaction of aquaporin-4 (AQP4)-negative astrocytes in layer I, massive activated microglia in layer II, and meningeal inflammation in NMOsd brains. All NMO cases showed no evidence of cortical demyelination. INTERPRETATION: We demonstrate cognitive impairment and substantial cortical neuronal loss with unique AQP4 dynamics in astrocytes in NMOsd. These data indicate pathological processes consisting not only of inflammatory demyelinating events characterized by pattern-specific loss of AQP4 immunoreactivity but also cortical neurodegeneration in NMOsd brains.

[Clinical features of poor-prognosis patients with adult bacterial meningitis].

We retrospectively investigated prognostic factors of 27 consecutive patients with bacterial meningitis seen at Niigata University Medical and Dental Hospital between 1980 and 2006. Patients were divided into the two categories using the Glasgow outcome scale (GOS) at discharge; the poor outcome group (GOS = 1 to 4; n = 15) and the good outcome group (GOS = 5; n = 12). Poor outcome was significantly associated with the severe consciousness disturbance, and the presence of intracranial (brain swelling, seizure, cerebral hemorrhage) or systemic (pneumonia) complications. The clinical features of patients who died of bacterial meningitis (GOS = 1) were almost identical to those of patients with poor outcome (GOS = 1 to 4); however, the protein and sugar content in the cerebrospinal fluid in the patients who died were significant compared to the patients with good outcome (GOS = 5). Pneumococcal infection was also considered to be a poor prognostic factor. Future prospective studies should be performed on a larger group of patients for establishing the prognostic factors of adult bacterial meningitis.

[Longitudinal analysis of age at onset and initial symptoms in patients with amyotrophic lateral sclerosis].

To investigate the longitudinal changes in age at onset and the initial symptom of patients with sporadic amyotrophic lateral sclerosis (ALS), we performed a single hospital-based retrospective study over the past 38 years. A total of 280 sporadic ALS patients (169 men and 111 women) hospitalized in our department between 1965 and 2003 were investigated in this study. The clinical features including age at onset and the initial symptom of these patients were obtained from medical records. All the patients underwent an intensive diagnostic evaluation including electrophysiological examination, laboratory examinations of blood and cerebrospinal fluid, and neuroimagings of the brain and spinal cord to exclude other conditions similar to ALS. The mean age at onset was 58.3 +/- 11.3 years and age at onset significantly increased at the rate of 0.459 years per year (r = 0.406, p< 0.001). The percentage of patients whose age at onset was > or = 70 years has increased from 3.0% (1980-1984) to 31.1% (2000-2003). To investigate the initial symptom of senile-onset ALS, patients whose age at onset was > or = 70 years were analyzed. The percentages of bulbar palsy-onset patients with onset in terms of age were 62.5% (30/48 patients; > or = 70 years) and 23.3% (54/232 patients; <70 years). The odd ratio for bulbar palsy was 5.40 (95% confidence interval, 2.79-10.44). Taken together, our study demonstrates that the ratio of senile-onset ALS has significantly increased, and that there were more bulbar palsy-onset patients among the patients.