Friday, 19 October 2012

Research: EBV and CD8 cells

"This is a complex paper and will not be easy to understand unless you have a degree in immunology. In essence it shows that the immune system of MSers responds with greater vigour and differently to EBV when compared to healthy controls. What does this mean for the EBV viral hypothesis? I am not sure and will need to sleep on it. That is the problem with EBV and MS; I have been sleeping on it for too long. It is time to do some anti-viral trials." 


Epub: Jørgensen et al. Epstein-Barr virus Peptide Presented by HLA-E is Predominantly Recognized by CD8(bright) Cells inmultiple Sclerosis Patients. PLoS One. 2012;7(9):e46120. 

Background: MS is associated with Epstein-Barr virus (EBV) infection, but impaired immune suppression may be part of the disease pathogenesis. CD8(+) T cells that are restricted by HLA-E exert an important immunoregulatory mechanism. 


HLA or human leukocyte antigens are important for telling lymphocytes that there is an infection going on. 

Methods & Results: To explore how EBV might interfere with immune regulation, these investigators examined the expression of HLA-E and the frequency of CD8(+) cells recognizing HLA-E, presenting either an EBV peptide from the BZLF1 protein or a signal sequence peptide from HLA-A2, in RRMSers, PPMSers and healthy controls (HC). Treatment with IFN-α or EBV increased HLA-E expression on CD4(+) cells. However, only PPMSers increased expression of HLA-E on resting CD4(+) cells when compared with HC (p<0.005). CD8(+) cells were divided into CD8(bright) and CD8(dim) cells by flow cytometry analyses

This is a lab method for looking at the messages or markers they have on their surface. These messages can be counted or even used to sort specific cell types.

RRMSers had significantly fewer CD8(dim) cells than HC (p<0.003). Flow cytometry analyses were performed with HLA-E tetramers folded in the presence of the EBV or HLA-A2 peptide to identify HLA-E-interacting cells. 

RRMSers had increased frequency of CD8(bright) cells recognizing HLA-E/A2 (p = 0.006) and HLA-E/BZLF1 (p = 0.016). Conversely, RRMSers had fewer CD8(dim) cells that recognized HLA-E/BZLF1 (p = 0.001), but this could be attributed to the overall lower number of CD8(dim) cells in RRMS. Whereas HLA-E/A2 was predominantly recognized by CD8(dim) cells, HLA-E/BZLF1 was predominantly recognized by CD8(bright) cells in RRMSers and PPMSers, but not in HC. As expected, HLA-E/A2 was also recognized by CD8-negative cells in a CD94-dependent manner, whereas HLA-E/BZLF1 was poorly recognized in all groups by CD8-negative cells. 

Conclusions: These data demonstrate that RRMSers have expanded their CD8(bright) cells recognizing HLA-E/BZLF1. Moreover, HLA-E/BZLF1 appears to be recognized by the immune system in a different manner than HLA-E/A2.

                                                    HLA-E
HLA class I histocompatibility antigen, alpha chain E (HLA-E) also known as MHC class I antigen E is a protein that in humans is encoded by the HLA-E gene.The human HLA-E is a non-classical MHC class I molecule that is characterized by a limited variability (polymorphism). HLA-E has a very specialized role in cell recognition by natural killer cells (NK cells) this study reports that it stimulated CD8 T cells, which are the most abundant T cell type in MS lesions. 

HLA-E binds a restricted subset of peptides derived from signal peptides of classical MHC class I molecules, namely HLA-A, B, C, G. These peptides are released from the membrane of the endoplasmic reticulum (ER) by the signal peptide peptidase and trimmed by the cytosolic proteasome. Upon transport into the ER lumen by the transporter associated with antigen processing (TAP), these peptides bind to a peptide binding groove on the HLA-E molecule. This allows HLA-E to assemble correctly and to be expressed on the cell surface.

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