Tuesday, 12 May 2015

Inside out or outside in? The HERV theory

Int Immunol. 2015 May 8. pii: dxv025. [Epub ahead of print]

Inflammatory response of endothelial cells to a human endogenous retrovirus associated withmultiple sclerosis is mediated by TLR4.

Duperray A, Barbe D, Raguenez G, Weksler BB, Romero IA, Couraud PO, Perron H, Marche PN.

Abstract



The MSRV (Multiple Sclerosis Associated Retro Virus) belongs to the human endogenous retrovirus HERV-W family. The envelope protein originating from the MSRV has been found in most patients with multiple sclerosis (MS). This protein (Env-ms) has pro-inflammatory properties for several types of immune cells and could therefore play a role in MS pathogenesis by promoting the leukocyte diapedesis observed in the central nervous system of patients. Our study aims to analyze the effects of Env-ms on the blood-brain barrier (BBB) at a molecular and functional level. We demonstrate that the recombinant MSRV envelope is able to stimulate several inflammatory parameters in a human BBB in vitro model, the HCMEC/D3 brain endothelial cell line. Indeed, Env-ms induces overexpression of ICAM-1, a major mediator of leukocyte adhesion to endothelial cells, in a dose-dependent manner as well as a strong dose-dependent production of the pro-inflammatory cytokines IL-6 and IL-8. Furthermore, using a silencing approach with siRNAs, we show that Env-ms is recognized via the TLR4 receptor, a pattern recognition receptor of innate immunity present on endothelial cells. We also show using functional assays, that treatment of brain endothelial cells with Env-ms significantly stimulated the adhesion and the transmigration of activated immune cells through a monolayer of endothelial cells. These findings support the hypothesis that MSRV could be involved in the pathogenesis of MS disease or at least in maintenance of inflammatory conditions, thus fueling the auto-immune disorder. MSRV could also play a role in other chronic inflammatory diseases.

The cause of MS has long been debated in the scientific and clinical arena. The popular held hypothesis til now has been that circulating immune cells in the blood cross into the brain via the blood-brain barrier (BBB) setting off a chain of events that results in demyelination, axonal loss etc. 

The discovery of the retroviral element MSRV in the cerebrospinal fluid of an MS patient challenges this view. Several lines of investigation (outlined in the abstract above) now indicate that MSRV and its envelope protein (Env-ms) can trigger/activate inflammatory cells across the BBB, i.e. MS is a disease from within the brain.

The recruitment of activated immune cells across the BBB endothelial cells is the critical step in triggering inflammation and the course of MS.

The investigators point out that Env-ms acts as a superantigen and activates the vascular BBB endothelium and the innate immunity (circulating monocytes, microglial, dendritic cells etc.) via the TLR4/CD14 pathway leading to inflammation in the brain (see figure below).

I say let the debate begin...But on a more ergonomic route I'm sure some biotechnologist/pharmacologist can come up with a way of interfering with the Env-ms/TLR4 pathway, say a specific anti-Env-ms neutralizing antibody??!

Schematic representation of the effects of Env-ms: 1) In the blood Env-ms (ENV) can activate circulating monocytes, macrophages and dendritic cells, but also vascular endothelial cells leading to the production of pro-inflammatory cytokines (IL-6, IL-8 etc.), enhancing the adhesion of circulating cells to the endothelium and their migration through the BBB and into the brain; 2) ENV in the brain provokes activation of macrophages, microglial and dendritic cells which orient Th1 response of T cells; 3) in parallel ENV interferes with oligodendrocyte cells in activating their precursors to produce pro-inflammatory cytokines and in reducing their capacity to build myelin sheaths.

15 comments:

  1. If I got this right, TLR4 receptor activation shown to be crucial for MS development.
    Should then be seen MS prevalence in chronic pain patients on opioids and heroin abusers and LDN trials to be positive?

    ReplyDelete
    Replies
    1. This where things get confusing, the role of TLR4 in opioid analgesic tolerance is additional to its main role in activating the innate immune system. By testing how the ENV protein interacts with TLR4 specifically might be the key. Interacting with TLR4 directly may have a number of effects...

      Delete
  2. Interesting...
    Is this the "Protein X" study from Tisch, or something else?
    http://tischms.org/finding-cause-ms

    ReplyDelete
    Replies
    1. TLR4 is also found expressed by inflammatory B cells, but I suspect protein X will remain a mystery until they patent it. Mostly these discoveries are myelin/axonal/channel proteins.

      Delete
  3. Then would therefore failures of DMT's, since the process would be inside out? And where would fit in this case the efficacy of alemtuzumab and HTSC? And would the HERV same activity for both RRMS and for progressive forms?

    ReplyDelete
    Replies
    1. Technically all DMTs which are anti inflammatory are acting downstream of the innate immune system since they act on T cells which is the adaptive system. But this distinction is not foolproof. As I've mentioned in my blurb above, even this theory relies to an extent on the entry of immune cells across the BBB - so natalizumab would work!

      Delete
  4. Nice! Looks like we are getting closer to the cause of MS :D
    And again IL-6.
    So how about a combination of DMT's e.g. anti-MSRV and Anti - IL6 to stop or inhibit the "communication" line between infected B-cells (EBV-infected)?

    ReplyDelete
    Replies
    1. You're probably right, I think even at immunomodulatory level we need to start thinking about combined targeted therapies

      Delete
  5. Is this supporting your charcot theory and treatment with HAART too?

    ReplyDelete
    Replies
    1. HARRT works at different levels as an anti viral. It's possible that it may have an indirect effect on ENV.

      Delete
  6. Intrathacal rituxen being trailed now. Wouldn't this be an answer?

    ReplyDelete
    Replies
    1. No, I was referring to targeted monoclonal antibody to ENV, which I believe has already been developed.

      Delete
    2. What is this? Do you mean the gnbac1 from GeNeuro or is that an ebv specific therapy

      Delete
    3. REVITaLISe trial has been unblinded & is no longer recruiting. I heard that they were hoping for 50% reduction in B-cell count in CSF, but only got 10%. Hopefully, data will be published soon. I was a subject / volunteer.

      Delete
    4. Yes, its GNbAC1 - there's a phase I and II study in MS but the latter has small sample numbers - so not sure of long term efficacy

      Delete

Please note that all comments are moderated and any personal or marketing-related submissions will not be shown.