MS a B cell disease…..Wait a minute on not quite yet, T cells are hanging on

Schuh E, Berer K, Mulazzani M, Feil K, Meinl I, Lahm H, Krane M, Lange R, Pfannes K, Subklewe M, Gürkov R, Bradl M, Hohlfeld R, Kümpfel T, Meinl E, Krumbholz M. Features of Human CD3+CD20+ T Cells. J Immunol. 2016 Jul 13. pii: 1600089. [Epub ahead of print]

Monoclonal Abs against CD20 reduce the number of relapses in multiple sclerosis (MS); commonly this effect is solely attributed to depletion of B cells. Recently, however, a subset of CD3+CD20+ T cells has been described that is also targeted by the anti-CD20 mAb rituximab. Because the existence of cells co-expressing CD3 and CD20 is controversial and features of this subpopulation are poorly understood, we studied this issue in detail. In this study, we confirm that 3-5% of circulating human T cells display CD20 on their surface and transcribe both CD3 and CD20. We report that these CD3+CD20+ T cells pervade thymus, bone marrow, and secondary lymphatic organs. They are found in the cerebrospinal fluid even in the absence of inflammation; in the cerebrospinal fluid of MS patients they occur at a frequency similar to B cells. Phenotypically, these T cells are enriched in CD8+ and CD45RO+ memory cells and in CCR7- cells. Functionally, they show a higher frequency of IL-4-, IL-17-, IFN-γ-, and TNF-α-producing cells compared with T cells lacking CD20. CD20-expressing T cells respond variably to immunomodulatory treatments given to MS patients: they are reduced by fingolimod, alemtuzumab, and dimethyl fumarate, whereas natalizumab disproportionally increases them in the blood. After depletion by rituximab, they show earlier and higher repopulation than CD20+ B cells. Taken together, human CD3+CD20+ T cells pervade lymphatic organs and the cerebrospinal fluid, have a strong ability to produce different cytokines, and respond to MS disease modifying drugs.

As ocrelizumab arrives MS is being described as a B cell disease, but to feed a lifeline to the T cell brigade it has been shown that a small subset of T cells express CD20 and these get depleted. Is this why rituximab/ocrelizumab works? I am not sure. However it seems that B cell depletion can reduce antigen presenting cell function and this is maybe why it works. Maybe it is because it is removing EBV infected B cells

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  • "Maybe it is because it is removing EBV infected B cells"

    Then how would it work for EBV- MS patients?

  • In this study a small population of T-cells express CD3+CD20+ and are depleted by rituximab. It is known that some B-cells express alpha4beta1/7 integrins, the target of natalizumab. As researchers debate the question is MS a B-cell or T-cell disease it seems both lymphocyte populations work in concert in MS pathology making this argument moot. As for EBV, gene therapy advances are making it possible to eliminate EBV infection. Hopefully the question of does EBV drive MS can be answered once and for all. It seems we are beating around the bush with regard to EBV.

  • This says that "natalizumab disproportionally increases (CD20-expressing T-cells) in the blood". Does that mean some PWMS might get worse on natalizumab than they would have been without it? If not, why not?

  • Maybe that's why rebound effect post-Natalizumab, confirming the theory of Prof. G, since a population of cells T increased fast if would direct to the CNS, attacking the "possible target"?

    I don't know why participants of the researchs aren't have serology for EBV verified, as well as the rate of vitamin D, hence to publish the researcher would do the note about it.
    I think spare a lot of time and money, it seems that there is a "fear" around it…

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