Damato, Valentina;
Theorell, Jakob;
Al-Diwani, Adam;
Kienzler, Anne-Kathrin;
Makuch, Mateusz;
Sun, Bo;
Handel, Adam;
... Irani, Sarosh R; + view all
(2022)
Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders.
Proceedings of the National Academy of Sciences (PNAS)
, 119
(24)
, Article e2121804119. 10.1073/pnas.2121804119.
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Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders.pdf - Other Download (3MB) | Preview |
Abstract
Neuromyelitis optica spectrum disorders (NMOSDs) are caused by immunoglobulin G (IgG) autoantibodies directed against the water channel aquaporin-4 (AQP4). In NMOSDs, discrete clinical relapses lead to disability and are robustly prevented by the anti-CD20 therapeutic rituximab; however, its mechanism of action in autoantibody-mediated disorders remains poorly understood. We hypothesized that AQP4-IgG production in germinal centers (GCs) was a core feature of NMOSDs and could be terminated by rituximab. To investigate this directly, deep cervical lymph node (dCLN) aspirates (n = 36) and blood (n = 406) were studied in a total of 63 NMOSD patients. Clinical relapses were associated with AQP4-IgM generation or shifts in AQP4-IgG subclasses (odds ratio = 6.0; range of 3.3 to 10.8; P < 0.0001), features consistent with GC activity. From seven dCLN aspirates of patients not administered rituximab, AQP4-IgGs were detected alongside specific intranodal synthesis of AQP4-IgG. AQP4-reactive B cells were isolated from unmutated naive and mutated memory populations in both blood and dCLNs. After rituximab administration, fewer clinical relapses (annual relapse rate of 0.79 to 0; P < 0.001) were accompanied by marked reductions in both AQP4-IgG (fourfold; P = 0.004) and intranodal B cells (430-fold; P < 0.0001) from 11 dCLNs. Our findings implicate ongoing GC activity as a rituximab-sensitive driver of AQP4 antibody production. They may explain rituximab’s clinical efficacy in several autoantibody-mediated diseases and highlight the potential value of direct GC measurements across autoimmune conditions.
| Type: | Article |
|---|---|
| Title: | Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1073/pnas.2121804119 |
| Publisher version: | https://doi.org/10.1073/pnas.2121804119 |
| Language: | English |
| Additional information: | Copyright © 2022 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY). |
| Keywords: | Aquaporin, autoimmunity, cervical lymph nodes, neuromyelitis optica, rituximab, Aquaporin 4, Autoantibodies, Germinal Center, Humans, Immunologic Factors, Lymph Nodes, Neuromyelitis Optica, Rituximab |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Institute of Prion Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10166088 |
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