Journal Article

CNS inflammation after natalizumab therapy for multiple sclerosis: A retrospective histopathological and CSF cohort study

Stork, Lidia, Metz, Imke, Brück, Wolfgang, Lassmann, Hans, Ziemssen, Tjalf, Häusler, Darius, Akgün, Katja

2021

Overview

Natalizumab, a recombinant humanized monoclonal antibody directed against the α4 subunit of the integrins α4ß1 and α4ß7, has been approved for the treatment of active relapsing‐remitting MS. Although natalizumab is a highly beneficial drug that effectively reduces the risk of sustained disability progression and the rate of clinical relapses, some patients do not respond to it, and some are at higher risk of developing progressive multifocal leukoencephalopathy (PML). The histopathological effects after natalizumab therapy are still unknown. We, therefore, performed a detailed histological characterization of the CNS inflammatory cell infiltrate of 24 brain specimens from natalizumab treated patients, consisting of 20 biopsies and 4 autopsies and 21 MS controls. To complement the analysis, immune cells in blood and cerebrospinal fluid (CSF) of 30 natalizumab‐treated patients and 42 MS controls were quantified by flow cytometry. Inflammatory infiltrates within lesions were mainly composed of T cells and macrophages, some B cells, plasma cells, and dendritic cells. There was no significant difference in the numbers of T cells or macrophages and microglial cells in lesions of natalizumab‐treated patients as compared to controls. A shift towards cytotoxic T cells of a memory phenotype was observed in the CSF. Plasma cells were significantly increased in active demyelinating lesions of natalizumab‐treated patients, but no correlation to clinical disability was observed. Dendritic cells within lesions were found to be reduced with longer ongoing therapy duration. Our findings suggest that natalizumab does not completely prevent immune cells from entering the CNS and is associated with an accumulation of plasma cells, the pathogenic and clinical significance of which is not known. As B cells are considered to serve as a reservoir of the JC virus, the observed plasma cell accumulation and reduction in dendritic cells in the CNS of natalizumab‐treated patients may potentially play a role in PML development. Häusler et al. characterized the CNS inflammation after natalizumab treatment. They found that despite the treatment, immune cells may enter the CNS and even an accumulation of plasma cells occurs, the pathogenic and clinical significance of which is unknown. The accumulation of plasma cells and an additionally observed reduction in dendritic cells, which are important for viral defense, may play a role in PML development.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Accumulation / Adult / Autopsies / Biopsy / Cerebrospinal fluid / Cohort analysis / Cytotoxicity / Demyelination / Dendritic cells / Dendritic structure / Encephalitis / Female / Flow cytometry / Humans / Immune system / Immunologic Factors - adverse effects / Immunologic Factors - therapeutic use / Immunological memory / Inflammation / Integrins / Lesions / Leukoencephalopathy / Leukoencephalopathy, Progressive Multifocal - chemically induced / Leukoencephalopathy, Progressive Multifocal - pathology / Lymphocytes / Lymphocytes B / Lymphocytes T / Macrophages / Macrophages - pathology / Male / Memory cells / Microglia - pathology / Microglial cells / Middle Aged / Monoclonal antibodies / Multiple sclerosis / Multiple Sclerosis, Relapsing-Remitting - drug therapy / natalizumab / Natalizumab - adverse effects / Natalizumab - therapeutic use / Patients / Phenotypes / Plasma / Plasma cells / Progressive multifocal leukoencephalopathy / progressive multifocal leukoencephalopathy (PML) / Retrospective Studies / T-Lymphocytes - pathology / Therapy / tysabri / Viral infections / Young Adult