Tuesday, 10 November 2015

Linking genes to the envoironment and B cells

Hammer C, Begemann M, McLaren PJ, Bartha I, Michel A, Klose B, Schmitt C, Waterboer T, Pawlita M, Schulz TF, Ehrenreich H, Fellay J. Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses.Am J Hum Genet. 2015 Oct pii: S0002-9297(15)00372-9. 

The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation. We observed an overlap between variants affecting the humoral response to influenza A and EBV and variants previously associated with autoimmune diseases related to these viruses. The results of this study emphasize the central and pathogen-specific role of HLA class II variation in the modulation of humoral immune response to viral antigens in humans.

HLA-DRbeta 1 harbours the major MS  susceptibility genes and when they looked for the genes associated with B cell immune responses to viral targets EBV they pulled out HLA-DRB1. 

We have been teaching that CD8 responses are associated with anti-viral responses due to loading of viral peptides in the golgi apparatus and so if you see a CD8 T cell mediated response think . Virus. Likewise CD4 responses are restricted by MHC class II such as HLA-DR and the MHC is loaded in endosomes (CLICK HERE).

However it is not so clear cut and virus peptides can be loaded into MHC class II
Endogenous antigen processing drives the primary CD4(+) T cell response to influenza. Miller MA, Ganesan AP, Luckashenak N, Mendonca M, Eisenlohr LC. Nat Med. 2015;21(10):1216-22.By convention, CD4(+) T lymphocytes recognize foreign and self peptides derived from internalized antigens in combination with major histocompatibility complex class II molecules. Alternative pathways of epitope production have been identified, but their contributions to host defense have not been established. We show here in a mouse infection model that the CD4(+) T cell response to influenza, critical for durable protection from the virus, is driven principally by unconventional processing of antigen synthesized within the infected antigen-presenting cell, not by classical processing of endocytosed virions or material from infected cells. Investigation of the cellular components involved, including the H2-M molecular chaperone, the proteasome and γ-interferon-inducible lysosomal thiol reductase revealed considerable heterogeneity in the generation of individual epitopes, an arrangement that ensures peptide diversity and broad CD4(+) T cell engagement. 

4 comments:

  1. Very interesting, thank you for posting and explaining!

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  2. Oh MD Thank you! When I read this article in the journal Cell I thought the link between EBV, viruses, autoimmunity, and an aberrant genetic response ... the time came to mind as ripple effects of some viruses in those who are genetically susceptible to autoimmunity ... I even thought it might be a link between the fact that many of us have outbreaks MSers terms to any viruses such as flu ...

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  3. Dear MD,

    This is exciting; it feels like we're closer than ever before to being able to say:

    X + Y + Z = MS

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  4. I think tests to check the level of vitamin D, and for those who have symptoms similar to infectious mononucleosis that are also made diagnosis need it, as well as tests for anti-EBV antibodies ...

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