scholarly journals Naive B cells in neuromyelitis optica spectrum disorders: impact of steroid use and relapses

2020 ◽  
Vol 2 (2) ◽  
Author(s):  
Malou Janssen ◽  
Arlette L Bruijstens ◽  
Jamie van Langelaar ◽  
YuYi Wong ◽  
Annet F Wierenga-Wolf ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neuromyelitis Optica ◽  
Immunoglobulin G ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Healthy Controls ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Toll Like Receptor ◽  
Spectrum Disorders

Abstract Neuromyelitis optica spectrum disorders are a group of rare, but severe autoimmune diseases characterized by inflammation of the optic nerve(s) and/or spinal cord. Although naive B cells are considered key players by escaping central tolerance checkpoints, it remains unclear how their composition and outgrowth differ in patients with neuromyelitis optica spectrum disorders. Under complete treatment-naive circumstances, we found that naive mature/transitional B-cell ratios were reduced in the blood of 10 patients with aquaporin-4 immunoglobulin G-positive disease (neuromyelitis optica spectrum disorders) as compared to 11 both age- and gender-matched healthy controls, eight patients with myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders and 10 patients with multiple sclerosis. This was the result of increased proportions of transitional B cells, which were the highest in patients with neuromyelitis optica spectrum disorders with relapses and strongly diminished in a separate group of nine patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders who received corticosteroid treatment. These findings need to be confirmed in longitudinal studies. For purified naive mature B cells of seven patients with neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein-immunoglobulin G-associated disorders with relapses, Toll-like receptor 9 ligand synergized with interferon-γ to enhance plasmablast formation during germinal centre-like cultures. This was not seen for 11 patients without relapses and nine healthy controls. In the neuromyelitis optica spectrum disorders group, in vitro plasmablast formation corresponded to total and anti-aquaporin-4 immunoglobulin G secretion, of which the latter was found only for relapsing cases. These data indicate that naive B-cell homoeostasis is different and selectively targeted by corticosteroids in patients with neuromyelitis optica spectrum disorders. This also supports further exploration of naive B cells for their use in Toll-like receptor 9-dependent in vitro platforms in order to predict the activity of neuromyelitis optica spectrum disorders.

scholarly journals Pharmacodynamic modeling and exposure-response assessment of inebilizumab in subjects with neuromyelitis optica spectrum disorders

2021 ◽  
Author(s):  
Li Yan ◽  
Bing Wang ◽  
Dewei She ◽  
Ben Mitchel ◽  
Ryan Criste ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Neuromyelitis Optica ◽  
Drug Exposure ◽  
Response Assessment ◽  
Pharmacodynamic Modeling ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Spectrum Disorders ◽  
Disease Attack ◽  
The Impact

AIM: Neuromyelitis optica spectrum disorders (NMOSD) is an autoantibody-mediated, B cell-driven disease. Inebilizumab is a humanized, affinity-optimized, afucosylated IgG1 kappa monoclonal antibody that binds to the B cell specific surface antigen CD19, resulting in rapid, profound, and sustained depletion of circulating peripheral B cells in NMOSD subjects (pivotal study). The objective of this study was to conduct population modeling of B cell response following inebilizumab treatment in adult subjects with NMOSD, and to assess the impact of drug exposure to outcome. METHODS: A hematopoietic transit model was developed to describe the joint effects of reducing influx from pro-B cells and accelerating CD20+ B cell depletion in the blood by inebilizumab. Furthermore, the relationships between inebilizumab pharmacokinetic (PK) exposure and the primary efficacy endpoint and key secondary efficacy endpoints were evaluated. KEY RESULTS: At the 300 mg dose, there was no apparent relationship between efficacy (reduction in disease attack risk, risk of worsening from baseline in Expanded Disability Status Scale, cumulative total active MRI lesions, and the number of NMOSD-related in-patient hospitalizations) and PK exposure. Subjects with low, medium, and high PK exposure had a similar hazard ratio of NMOSD attack vs placebo group. CONCLUSIONS: The pharmacodynamic modeling confirmed effective depletion of B cells is achieved with a 300 mg intravenous dose of inebilizumab administered on Day 1 and Day 15 and every 6 months thereafter. The PK variability between patients had no apparent effect on clinical efficacy.

Mapping white matter damage distribution in neuromyelitis optica spectrum disorders with a multimodal MRI approach

2020 ◽  
pp. 135245852094149
Author(s):  
Laura Cacciaguerra ◽  
Maria A Rocca ◽  
Loredana Storelli ◽  
Marta Radaelli ◽  
Massimo Filippi
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Fractional Anisotropy ◽  
Neuromyelitis Optica ◽  
Mean Diffusivity ◽  
Healthy Controls ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
White Matter Damage ◽  
Axial Diffusivity ◽  
Spectrum Disorders

Background: The pathogenetic mechanisms sustaining neuroinflammatory disorders may originate from the cerebrospinal fluid. Objective: To evaluate white matter damage with diffusion tensor imaging and T1/T2-weighted ratio at progressive distances from the ventricular system in neuromyelitis optica spectrum disorders and multiple sclerosis. Methods: Fractional anisotropy, mean, axial, and radial diffusivity and T1/T2-weighted ratio maps were obtained from patients with seropositive neuromyelitis optica spectrum disorders, multiple sclerosis, and healthy controls ( n = 20 each group). White matter damage was assessed as function of ventricular distance within progressive concentric bands. Results: Compared to healthy controls, neuromyelitis optica spectrum disorders patients had similar fractional anisotropy, radial and axial diffusivity, increased mean diffusivity ( p = 0.009–0.013) and reduced T1/T2-weighted ratio ( p = 0.024–0.037) in all bands. In multiple sclerosis, gradient of percentage lesion volume and intra-lesional mean and axial diffusivity were higher in periventricular bands. Compared to healthy controls, multiple sclerosis patients had reduced fractional anisotropy ( p = 0.001–0.043) in periventricular bands, increased mean ( p < 0.001), radial ( p < 0.001–0.004), and axial diffusivity ( p = 0.002–0.008) and preserved T1/T2-weighted ratio in all bands. Conclusion: White matter damage is higher at periventricular level in multiple sclerosis and diffuse in neuromyelitis optica spectrum disorders. Fractional anisotropy preservation, associated with increased mean diffusivity and reduced T1/T2-weighted ratio may reflect astrocyte damage.

The clinical spectrum associated with myelin oligodendrocyte glycoprotein antibodies (anti-MOG-Ab) in Thai patients

2015 ◽  
Vol 22 (7) ◽  
pp. 964-968 ◽  
Author(s):  
Sasitorn Siritho ◽  
Douglas K Sato ◽  
Kimihiko Kaneko ◽  
Kazuo Fujihara ◽  
Naraporn Prayoonwiwat
Keyword(s):  
Multiple Sclerosis ◽  
Central Nervous System ◽  
Nervous System ◽  
Optic Neuritis ◽  
Neuromyelitis Optica ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Visual Recovery ◽  
Central Nervous System Disorders ◽  
Spectrum Disorders

Background: Myelin oligodendrocyte glycoprotein (anti-MOG) antibody was reported in anti-aquaporin-4 (anti-AQP4) seronegative neuromyelitis optica spectrum disorders (NMOSD) patients. Objectives: To describe clinical phenotypes associated with anti-MOG. Methods: Seventy consecutive Thai patients with inflammatory idiopathic demyelinating central nervous system disorders (IIDCD) who were previously anti-AQP4 seronegative were tested for anti-MOG. Results: Anti-MOG was positive in six patients, representing 20.7% of the IIDCD anti-AQP4 seronegative patients with a non-multiple sclerosis phenotype, and most had relapses. All first presented with optic neuritis with good visual recovery after treatment. Conclusions: Anti-MOG positive patients may have manifestations that mimic NMOSD but differ in their course and prognosis from anti-AQP4 positive NMOSD.

scholarly journals Short segment myelitis as the initial and only manifestation of aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorders

2020 ◽  
Vol 13 ◽  
pp. 175628641989859
Author(s):  
Wei Fang* ◽  
Yang Zheng* ◽  
Fan Yang ◽  
Meng-Ting Cai ◽  
Chun-Hong Shen ◽  
...  
Keyword(s):  
Neuromyelitis Optica ◽  
Immunoglobulin G ◽  
Correct Diagnosis ◽  
Transverse Myelitis ◽  
Aquaporin 4 ◽  
Chinese Patients ◽  
Careful Study ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Short Segment ◽  
Spectrum Disorders

Background: Short segment myelitis (SSM, < 3 vertebral segments) is an under-recognized initial manifestation of neuromyelitis optica spectrum disorders (NMOSD). Though infrequent, failure to recognize SSM in patients with NMOSD would lead to incorrect diagnosis and treatment. Therefore, delineation of features of NMOSD-associated SSM is of paramount importance. Objective: Our study aimed to determine the demographic, clinical and radiological features of NMOSD-associated SSM, and compare those with NMOSD-associated longitudinally extensive transverse myelitis (LETM) and multiple sclerosis (MS)-associated SSM, respectively. Methods: Chinese patients presenting initially only with acute myelitis and diagnosed with NMOSD ( n = 46) and MS ( n = 11) were included. Clinical, serological, imaging and disability data were collected. Mann–Whitney U test or two-tailed Fisher’s exact tests were used to analyse the data. Results: Of the 46 enrolled NMOSD patients, 34 (74%) collectively had 38 LETM lesions, while 12 (26%) had 14 SSM lesions. When compared with LETM, NMOSD presenting with SSM were more likely to have a delayed diagnosis and a lower level of disability at nadir during the first attack. T1-weighted imaging hypointensity was more prominent in NMOSD-associated LETM lesions than NMOSD-associated SSM lesions. When compared with MS-associated SSM, NMOSD-associated SSM lesions were more likely to be centrally located, grey matter involving and transversally extensive on axial imaging and spanned no less than 2 vertebral segments on sagittal imaging. Conclusion: These findings suggest that SSM does not preclude the possibility of a NMOSD diagnosis. Testing for serum aquaporin-4 immunoglobulin G (AQP4-IgG) and careful study of lesions on spinal cord magnetic resonance imaging could aid in an earlier and correct diagnosis.

Lymphocyte Subsets Are Associated with Disease Status in Neuromyelitis Optica Spectrum Disorders

2021 ◽  
pp. 1-10
Author(s):  
Hong Yang ◽  
Wei Liu ◽  
Yi-Fan Wu ◽  
De-Sheng Zhu ◽  
Xia-Feng Shen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
B Cells ◽  
Neuromyelitis Optica ◽  
Peripheral Blood ◽  
Lymphocyte Subsets ◽  
Disease Status ◽  
Neuromyelitis Optica Spectrum Disorders ◽  
Spinal Cord Lesions ◽  
Cross Sectional ◽  
Spectrum Disorders

<b><i>Objective:</i></b> At present, studies on lymphocytes are mostly conducted on CD19<sup>+</sup> B cells and CD27<sup>+</sup> B cells in neuromyelitis optica spectrum disorders (NMOSDs), but the exact changes in lymphocyte subsets (CD19<sup>+</sup> B cells, CD3<sup>+</sup> T cells, CD4<sup>+</sup> Th cells, CD8<sup>+</sup> Ts cells, the CD4<sup>+</sup>/CD8<sup>+</sup> ratio, and NK [CD56+ CD16] cells) have rarely been studied. This study aimed to assess lymphocyte subset changes in patients with NMOSD. <b><i>Methods:</i></b> We performed a cross-sectional study of consecutive patients with acute NMOSD (<i>n</i> = 41), chronic NMOSD (<i>n</i> = 21), and healthy individuals (<i>n</i> = 44). Peripheral blood samples were obtained upon admission, and lymphocyte subsets were analyzed by flow cytometry. Levels of lymphocyte subsets among 3 groups were compared and its correlation with the length of spinal cord lesions was analyzed. <b><i>Results:</i></b> The levels of peripheral blood CD19<sup>+</sup> B cells were significantly higher in patients with acute and chronic NMOSD than in healthy controls (HCs) (17.91 ± 8.7%, 13.08 ± 7.562%, and 12.48 ± 3.575%, respectively; <i>p</i> &#x3c; 0.001) and were positively correlated with the length of spinal cord lesions in acute NMOSD (<i>r</i> = 0.433, <i>p</i> &#x3c; 0.05). The peripheral blood CD4<sup>+</sup>/CD8<sup>+</sup> ratio was significantly lower in patients with acute NMOSD and chronic NMOSD than in HCs (1.497 ± 0.6387, 1.33 ± 0.5574, and 1.753 ± 0.659, respectively; <i>p</i> &#x3c; 0.05), and the levels of peripheral blood NK (CD56+ CD16) cells were significantly lower in patients with acute and chronic NMOSD than in HCs (13.6 ± 10.13, 11.11 ± 7.057, and 14.7 [interquartile range = 9.28], respectively; <i>p</i> &#x3c; 0.01). <b><i>Conclusions:</i></b> The levels of certain subsets of peripheral blood lymphocytes are associated with disease status in NMOSD.

Delayed Redistribution of CD27, CD40 and CD80 Positive B Cells and the Impaired In Vitro Immunoglobulin G Production in Patients with Non-Hodgkin Lymphoma Treated with Rituximab.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 938-938
Author(s):  
Mitsufumi Nishio ◽  
Katsuya Fujimoto ◽  
Satoshi Yamamoto ◽  
Toshiya Sakai ◽  
Kohki Kumano ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Healthy Controls ◽  
Immunoglobulin Production ◽  
Significant Difference ◽  
Healthy Control ◽  
Delayed Recovery

Abstract Rituximab (RT) has been proven to be very effective in depleting normal and malignant B lymphocytes in vivo and it is widely used for the treatment of B cell malignancies, particularly B cell non-Hodgkin’s lymphoma (NHL). RT alone does not appear to cause severe hypogammaglobulinemia according to initial clinical trials. However, recent studies revealed that patients who received RT as an adjuvant to stem cell transplantation (SCT) demonstrated an increased risk of developing severe hypogammaglobulinemia. We have found such hypogammaglobulinemia to be due to the delayed recovery of CD27 positive memory B cells and an impaired isotype expression. (Nishio et al. Eur J Haematol, 2006). This finding suggests that RT can influence not only the quantity, but also the quality of B-cell redistribution. Nevertheless, to our knowledge, precisely how the B-cell repertoire regenerates after anti-CD20-mediated transient B-cell depletion in patients with NHL remains to be elucidated. To clarify this, we performed a phenotypical analysis of B cells. A total of 22 patients with NHL who received RT combined with autologous SCT (n=17) or CHOP (n=5) were evaluated to identify their immunophenotype. The median period after the last administration of RT was 33.5 months (range from 12 to 56 months). We investigated the expression of various markers, including CD27, CD38, CD40, CD80, CD86 and CD95 on B cells by immunofluorescence staining with a flowcytometry analysis. A statistically significant difference was noted in three of the six surface antigens when the expressions of those antigens were compared with those in the healthy control populations (N=14). The most striking differences we found was the expression levels of CD27. The healthy control group had a much higher expression of CD27 in comparison to those of the patients treated with RT (28.1±14.1% vs 8.2±6.1%, p&lt;0.001). In addition, significant differences in the expression of CD40 and CD80 were also noted. While the positive rates of CD80 and CD40 on B cells from healthy controls were 21.5±10.8% and 80.5±16.7%, those of patients treated with RT were 9.9±6.9% and 49.7±33.5%, respectively (p&lt;0.01 and p&lt;0.05). Since CD40-CD40L and CD80-CD28 pathways between B and T cells are necessary for the development of CD27 positive polyclonal B-cell activation and immunoglobulin production, we hypothesized that the B cells from patients treated with RT thus had a reduced ability to differentiate into plasma cells and immunoglobulin production in vitro. To test this hypothesis, we purified the B cells from ten patients with NHL treated with RT and then cultured them upon the engagement of immunoglobulin receptor and CD40 in the presence of IL-2 and IL-10. After eight days of stimulation, the supernatants of the culture were harvested and the concentrations of immunoglobulin were measured by ELISA. As a result, the IgG production was found to be significantly impaired in patients with NHL in comparison to those from the healthy controls. The observation of a delayed recovery of the memory B cells with an abnormal cell marker expression and function demonstrates that naive B cells may therefore be responsible for their failure to differentiate into plasma cells after RT therapy.

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