Rebound after natalizumab show memory cells are the major cell type(s) to target in MS

Larochelle C et al. Immunological and pathological characterization of fatal rebound MS activity following natalizumab withdrawal MSJ 2017 Jan;23(1):72-81

We have talked about this before

Our results underline the differences in immune cell populations between the CSF and the CNS parenchyma, and suggest that aggressive immunosuppressive therapy targeting both T and B lymphocytes is warranted to control the overwhelming CNS


In this study the person was on for natalizumab for 2 years and switched to copaxone 1 month before discountinuation of natalizumab (NTZ), 4 months later the patient was hospitalised with a relapse. 

In the brain autopsy was performed within 1 hour of death and histologically there was demyelinating lesions, plasma cells and more T cells. The final pathological interpretation was severe MS rebound inflammatory demyelinating activity after NTZ withdrawal, with presence of numerous active demyelinating lesions.

CD4+ and CD8+ T lymphocytes in peripheral blood were mostly effector memory T lymphocytes (CD45RA neg, CD45RO+, and CCR7neg. As expected, CD19+ and CD20+ B lymphocytes as well as CD14+ monocytes/macrophages were less abundant than T lymphocytes in the peripheral blood compartment

CD4+ and CD8+ T lymphocytes in CSF were mostly effector memory T lymphocytes (CD45RAneg, CD45RO+, and CCR7neg, data not shown)

 A ratio of 1:2 was observed for CD4:CD8, concordant with pathological findings, but inverse to the blood and the CSF ratio. Most CD4+ (86%) and CD8+ (70%) cells were CD45RO+ and CD45RAneg, and were also CCR7neg. There were B cells in the CNS and they were mainly plasma cells

Therefore the dominant T cell response was of the memory effector type

This is consistent with animal studies the T cell accumulating in the CNS exhibit characteristics of a memory cell (CD45RO+. In animals CD45RBhigh) in particular an effector memory cell (CCR7-).

Its not always T cells. 

Massive exacerbation of multiple sclerosis after withdrawal and early restart of treatment with natalizumabLA Beume, R Dersch, H Fuhrer, O Stich, S Rauer 2015

They present a 46-year-old woman with a relapse of multiple sclerosis (MS) that began 3 months after withdrawal from long-term treatment with natalizumab. Shortly after restart of a single dose of natalizumab she developed a fulminant MS rebound with stupor and tetraparesis. Cerebral MRI showed massive progression in the number of lesions and tumefactive lesions with ring gadolinium-enhancement. Stereotactic brain biopsy evealed acute demyelination and B-cell dominated inflammation

In this case there were B cells in lesions in the biopsy, in the above case the disease had been going for some months plenty of time for B cells to turn into plasma (B) antibody-producing cells