Rituximab can help patients with NMOSD, but its mechanism is not fully understood. This article explores one possible hypothesis.
Neuromyelitis optica spectrum disorders (NMOSD) are autoimmune conditions caused by immunoglobulin G (IgG) autoantibodies directed against the water channel aquaporin-4. Among patients with NMOSD, clinical relapses tend to lead to disability. Relapses can be prevented by the anti-CD20 therapeutic treatment rituximab, although its mechanism of action remains poorly understood. This study, published in the Proceedings of the National Academy of Sciences of the United States of America, focuses on discovering this mechanism of action.
The authors hypothesized that aquaporin-4 IgG production in germinal centers is a core feature of NMOSD, and that its termination by rituximab is the mechanism by which it functions. For this study, deep cervical lymph node aspirates and blood were studied for 63 patients with NMOSD. Aquaporin-4 IgG generation or shifts in subclass were associated with clinical relapses.
The focus of the study was on lymph nodes that drain the central nervous system (CNS) in patients that have CNS autoimmunity. This focus allowed for an explanation for why rituximab is highly efficacious in autoantibody-mediated diseases, even when there is no accompanying reduction in serum autoantibody levels.
After rituximab administration, the authors found that fewer clinical relapses were accompanied by marked reductions in both aquaporin-4 IgG and intranodal B cells from 11 deep cervical lymph node aspirates. These findings support the idea that germinal center activity is a rituximab-sensitive driver of aquaporin-4 antibody production, which may explain its clinical efficacy, in part. Although this finding needs to be corroborated by further studies, it does highlight the potential value of direct germinal center treatments across various autoimmune conditions, beyond NMOSD.
Damato, V., Theorell, J., Al-Diwani, A., Kienzler, A. K., Makuch, M., Sun, B., . . . Irani, S. R. (2022). Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders. Proc Natl Acad Sci U S A, 119(24), e2121804119. doi:10.1073/pnas.2121804119