BACKGROUND:Natalizumab for multiple sclerosis (MS) increases the risk of progressive multifocal leukoencephalopathy (PML).
OBJECTIVE:We aimed to assess the effect of natalizumab on cellular composition and functional B cell parameters including patients with natalizumab-associated PML (n=37).
METHODS: Cellular composition by flow cytometry, levels of immunoglobulin (Ig)G/IgM by immunonephelometry, and oligoclonal bands by isoelectric focusing were studied in blood and cerebrospinal fluid.
RESULTS:In MS patients treated with natalizumab without PML (n=59) the proportion of CD19+ B cells was higher in blood, but lower in cerebrospinal fluid compared with MS patients not treated with natalizumab (n=17). The CD4/CD8-ratio in cerebrospinal fluid was lower, and IgG and IgM levels as well as the IgG index dropped in longitudinal samples during natalizumab therapy. Oligoclonal bands persisted, but the total amount of the intrathecally produced IgG fraction, and the polyclonal intrathecal IgG reactivity to measles, rubella, and zoster declined. At the time of diagnosis of PML patients with natalizumab-associated PML had low total IgG levels in blood and cerebrospinal fluid.
CONCLUSIONS:Natalizumab impacts B and T cell distribution and exerts an inhibitory effect on surrogates of B cell function in periphery and in cerebrospinal fluid, potentially contributing to the increased risk of developing PML.
EAE has given us the T cell as he target for MS, however one may argue that T cell -immunotherapy has yet to inhibit relapsing MS and most immunotherapeutics that affect MS inhibit B cell function. This study looks at B cell function. Natalizumab blocks white cell migration into the CNS and in people taking the drugs that B cell seems to get stuck in the blood and there were fewer B cells in the CNS and the amounts of antibody, including anti-viral drugs dropped in the CSF. So could suggest that B cells are not necessarily generated within the CNS, from B cell follicles but come from the blood. Another possibility could be that T cells coming from the blood are blocked and so the growth factors used by B cells for making antibodies are blocked.
ProfG may argue that the reason these drugs work is because they block B cells that carry the virus that drives MS. However, do T cells play no role in susceptibility to MS. The genetics say that MHC class II is the major susceptibility function in MS, so why did depletion of T cells not impact in MS? Either Tcells are not important or most likely the trials were fundementally flawed and the level of depletion was not enough.