Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders
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 mechani...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Sprog: | English |
| Udgivet: |
National Academy of Sciences
2022
|
| _version_ | 1826307850586030080 |
|---|---|
| author | Damato, V Theorell, J Al-Diwani, A Kienzler, A-K Makuch, M Sun, B Handel, A Akdeniz, D Berretta, A Ramanathan, S Fower, A Whittam, D Gibbons, E McGlashan, N Green, E Huda, S Woodhall, M Palace, J Sheerin, F Waters, P Leite, MI Jacob, A Irani, SR |
| author_facet | Damato, V Theorell, J Al-Diwani, A Kienzler, A-K Makuch, M Sun, B Handel, A Akdeniz, D Berretta, A Ramanathan, S Fower, A Whittam, D Gibbons, E McGlashan, N Green, E Huda, S Woodhall, M Palace, J Sheerin, F Waters, P Leite, MI Jacob, A Irani, SR |
| author_sort | Damato, V |
| collection | OXFORD |
| description | 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.
|
| first_indexed | 2024-03-07T07:09:13Z |
| format | Journal article |
| id | oxford-uuid:71079003-6d16-4c80-abc2-da93c9f4e2a8 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:09:13Z |
| publishDate | 2022 |
| publisher | National Academy of Sciences |
| record_format | dspace |
| spelling | oxford-uuid:71079003-6d16-4c80-abc2-da93c9f4e2a82022-06-13T11:17:04ZRituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disordersJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:71079003-6d16-4c80-abc2-da93c9f4e2a8EnglishSymplectic ElementsNational Academy of Sciences2022Damato, VTheorell, JAl-Diwani, AKienzler, A-KMakuch, MSun, BHandel, AAkdeniz, DBerretta, ARamanathan, SFower, AWhittam, DGibbons, EMcGlashan, NGreen, EHuda, SWoodhall, MPalace, JSheerin, FWaters, PLeite, MIJacob, AIrani, SRNeuromyelitis 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. |
| spellingShingle | Damato, V Theorell, J Al-Diwani, A Kienzler, A-K Makuch, M Sun, B Handel, A Akdeniz, D Berretta, A Ramanathan, S Fower, A Whittam, D Gibbons, E McGlashan, N Green, E Huda, S Woodhall, M Palace, J Sheerin, F Waters, P Leite, MI Jacob, A Irani, SR Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders |
| title | Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders |
| title_full | Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders |
| title_fullStr | Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders |
| title_full_unstemmed | Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders |
| title_short | Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders |
| title_sort | rituximab abrogates aquaporin 4 specific germinal center activity in patients with neuromyelitis optica spectrum disorders |
| work_keys_str_mv | AT damatov rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT theorellj rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT aldiwania rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT kienzlerak rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT makuchm rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT sunb rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT handela rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT akdenizd rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT berrettaa rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT ramanathans rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT fowera rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT whittamd rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT gibbonse rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT mcglashann rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT greene rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT hudas rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT woodhallm rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT palacej rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT sheerinf rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT watersp rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT leitemi rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT jacoba rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders AT iranisr rituximababrogatesaquaporin4specificgerminalcenteractivityinpatientswithneuromyelitisopticaspectrumdisorders |