Damato, Valentina; Theorell, Jakob; Al-Diwani, Adam; Kienzler, Anne-Kathrin; Makuch, Mateusz; Sun, Bo; Handel, Adam; ... Irani, Sarosh R; + view all Damato, Valentina; Theorell, Jakob; Al-Diwani, Adam; Kienzler, Anne-Kathrin; Makuch, Mateusz; Sun, Bo; Handel, Adam; Akdeniz, Deniz; Berretta, Antonio; Ramanathan, Sudarshini; Fower, Andrew; Whittam, Daniel; Gibbons, Emily; McGlashan, Nicholas; Green, Edward; Huda, Saif; Woodhall, Mark; Palace, Jacqueline; Sheerin, Fintan; Waters, Patrick; Leite, Maria I; Jacob, Anu; Irani, Sarosh R; - view fewer (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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Text 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.

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