Saturday, 19 January 2013

Research: JC virus T cell responses

#MSBlog: Any immunology geeks interested in the immune response to JCV, the virus that causes PML?

Epub: Jelcic et al. T Cell Epitope Mapping of JC Polyoma Virus-Encoded Proteome Reveals Reduced T Cell Responses in HLA-DRB1*04:01+ Donors. J Virol. 2013 Jan.

Background: JC polyoma virus (JCV) infection is highly prevalent and usually kept in a persistent state without clinical signs and symptoms. Only during immunocompromise and especially impaired CD4(+) T cell function in the brain, as seen in AIDS patients or natalizumab-treated MSers, JCV may cause progressive multifocal leukoencephalopathy (PML), an often life-threatening brain disease. Since CD4(+) T cells are likely play an important role in controlling JCV infection, we here describe the T cell response against JCV in a group of predominantly HLA-DR-heterozygotic healthy donors (HD) by using a series of overlapping 15-mer peptides spanning all JCV-encoded open reading frames. 

JC polyoma virus = JC Virus or the John Cunningham virus; please note that JC does not refer to Jesus Christ.

HLA-DR are the molecules that antigen-presenting cells use to post protein signals on their surfaces so that immune cells can see them. If the messages in these HLA molecules are foreign then the T-cells become activated and cause inflammation.

The HLA molecules display small proteins or peptides in their groove for the T cells to sample. The following cartoon shows how the HLA with its peptide stimulates the T-cell via its receptor




Please note there are two main families of T-cells; CD4(+) and CD8(+). They respond to different types of antigens or proteins and each interact with different families of HLA molecules. The HLA system is very complex; the uninitiated reader may find the complexity overwhelming.

Results: These investigators identified immunodominant epitopes and compared T cell responses with anti-JCV VP1 antibody production and with the presence of urinary viral shedding. They observed positive JCV-specific T cell responses in 28.6-77.6%, humoral or antibody immune response in 42.6-89.4% and urinary viral shedding in 36.4-45.5% of HD depending on the threshold. Four immunodominant peptides were mapped, and at least one immunogenic peptide per HLA-DRB1 allele was detected in DRB1*01(+), DRB1*07(+), DRB1*11(+), DRB1*13(+), DRB1*15(+), and DRB1*03(+) individuals.

Conclusions: These investigators show for the first time, that JCV-specific T cell responses may be directed not only against JCV VP1 and Large T antigen, but also against all other JCV-encoded proteins. Heterozygotic DRB1*04:01(+) individuals showed very low T cell responses to JCV together with normal anti-VP1 antibody levels and no urinary viral shedding, indicating a dominant-negative effect of this allele on global JCV-directed T cell responses. Our data are potentially relevant for the development of vaccines against JCV.

"I am not sure if this study's findings are correct. We know from the HIV-AIDS literature that survival and the development of IRIS (immune reconstitution inflammatory syndrome) is dependent on CD8(+) cytotoxic T cells; the cells that are capable of killing virally infected T cells. Why didn't this group then not study CD8(+) cells? I am not sure, but CD8(+) cells are harder to work. Despite this this study is trying to say that some of us may be more prone to develop PML when we are immunocompromised as our immune cells may no be as efficient as other in recognising and eliminating JCV. If we can identify these people we can observe them more closely or not use drugs that are associated with the development of PML."

"This type of research is important and may lead to natalizumab being safer."

1 comment:

  1. "JC polyoma virus = JC Virus or the John Cunningham virus; please note that JC does not refer to Jesus Christ."

    This is why I love this blog! :D

    Thanks!

    ReplyDelete

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