Sunday, 26 June 2016

How do cells enter the Brain?

Internalization and presentation of myelin antigens by the brain endothelium guides antigen-specific T cell migration. Lopes Pinheiro MA, Kamermans A, Garcia-Vallejo JJ, van Het Hof B, Wierts L, O'Toole T, Boeve D, Verstege M, van der Pol SM, van Kooyk Y, de Vries HE, Unger WW.Elife. 2016;5. pii: e13149. doi: 10.7554/eLife.13149. [Epub ahead of print]

Trafficking of myelin-reactive CD4+ T-cells across the brain endothelium, an essential step in the pathogenesis of multiple sclerosis (MS), is suggested to be an antigen-specific process, yet which cells provide this signal is unknown. Here we provide direct evidence that under inflammatory conditions, brain endothelial cells (BECs) stimulate the migration of myelin-reactive CD4+ T-cells by acting as non-professional antigen presenting cells through the processing and presentation of myelin-derived antigens in MHC-II. Inflamed BECs internalized myelin, which was routed to endo-lysosomal compartment for processing in a time-dependent manner. Moreover, myelin/MHC-II complexes on inflamed BECs stimulated the trans-endothelial migration of myelin-reactive Th1 and Th17 2D2 cells, while control antigen loaded BECs did not stimulate T-cell migration. Furthermore, blocking the interaction between myelin/MHC-II complexes and myelin-reactive T-cells prevented T-cell transmigration. These results demonstrate that endothelial cells derived from the brain are capable of enhancing antigen-specific T cell recruitment.

The function of the blog is to provide up-to-date research news, This paper suggests that endothelium cells in the blood vessel present myelin antigens to T cells and this is why they migrate into the central nervous system.  This would imply that evey cell in the brain recognises something in blood vessels, However, not all cells in the inflammed brain recognise the same thing based on analysis of their T cell receptors (see education),

This contrasts with a view the cells get pulled into inflammed tissues by blood vessels expressing adhesion molecules and chemokines (attractant proteins) so not all of them have to recognise anythin in the brain. If they don't, the cells can leave or die and we can make some new ones.

The other part of the blog is to publise our own work and get a few altmetics, so being ancient one can remember stuff, so have a read.

Thirty years ago it was suggested that if you express MHC class II (see education section) you can present antigen to T cells and this may be a way autoimmunity occurs. Did enothelial cells present antigens to T cells? 

Read

Antigen presentation in brain: brain endothelial cells are poor stimulators of T-cell proliferation. Pryce G, Male D, Sedgwick J. Immunology. 1989;66(2):207-12

D
on't believe..... read a repeat




Endothelial cells no not express the co-stimulatory molecules as found in professional antigen presenting cells and so tend to turn off cells rather than stimulate them

But there are loads of other papers were you give endothelial cells gamma interferon and they express MHC class II antigens..I say give a wellington boot gamma interferon and they express MHC class II antigens?

But do endothelial cells actually  express MHC class II in the disease process. Have a read.

An immunoelectron microscopical study of the expression of class II major histocompatibility complex during chronic relapsing experimental allergic encephalomyelitis in Biozzi AB/H mice.
Butter C, O'Neill JK, Baker D, Gschmeissner SE, Turk JL.
J Neuroimmunol. 1991;33(1):37-42.



Is there anything else on migration




Post-arrest stalling rather than crawling favors CD8+ over CD4+ T-cell migration across the blood-brain barrier under flow in vitro.
Rudolph H, Klopstein A, Gruber I, Blatti C, Lyck R, Engelhardt B.
Eur J Immunol. 2016. doi: 10.1002/eji.201546251. [Epub ahead of print]

Although CD8+ T cells have been implied in the pathogenesis of multiple sclerosis (MS), the molecular mechanisms mediating CD8+ T-cell migration across the blood-brain barrier (BBB) into the central nervous system (CNS) are ill defined. Using in vitro live cell imaging, we directly compared the multi-step extravasation of activated CD4+ and CD8+ T cells across primary mouse brain microvascular endothelial cells (pMBMECs) as a model for the BBB under physiological flow. Significantly higher numbers of CD8+ than CD4+ T cells arrested on pMBMECs under non-inflammatory and inflammatory conditions. While CD4+ T cells crawled prior to their migration across the blood vessel (diapedesis), the majority of CD8+ T cells stalled and readily crossed the pMBMEC monolayer preferentially via a route across cells. Absence of endothelial ICAM-1 and ICAM-2 abolished increased arrest of CD8+ over CD4+ T cells and abrogated T-cell crawling, leading to the efficient reduction of CD4+ , but to a lesser degree of CD8+ , T-cell diapedesis across ICAM-1 & ICAM-2 deficient endothelia. Thus, cellular and molecular mechanisms mediating the multi-step extravasation of activated CD8+ T cells across the BBB are distinguishable from those involved for CD4+ T cells


No myelin in the system so whats the difference

5 comments:

  1. I found this very hard to understand. Is there a beginner's guide to cellular structure of the brain that you could recommend?

    ReplyDelete
    Replies
    1. http://multiple-sclerosis-research.blogspot.com/2012/04/charcot-tapestry.html

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  2. So it would be self immunity result of the true cause of MS? Is self immunity cause of MS by a defect in the lymphocytes? It seems q T cells driving the autoimmune attack and the B cells the drive or not?...
    And if it is a consequence, against whom is this attack, or rather, who are these self heterogeneous antigens? The study cites who are these self antigens?

    ReplyDelete
  3. I loved the Charcot tapestries and feel I understand the structure of the brain much better now. Why weren't they on the shortlist for the Turner Prize in 2012?

    ReplyDelete

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