Monday, 30 January 2012

Research: Virus Causing autoimmunity

Libbey JE, Cusick MF, Tsunoda I, Fujinami RS. Antiviral CD8(+) T cells cause an experimental autoimmune encephalomyelitis-like disease in naive mice. J Neurovirol. 2012 Jan 27. [Epub ahead of print]

Major histocompatibility complex class I-restricted CD8(+) cytotoxic T lymphocytes are involved in the pathogenesis of multiple sclerosis (MS) and both autoimmune, experimental autoimmune encephalomyelitis, and viral, Theiler's murine encephalomyelitis virus (TMEV) infection, animal models of MS.

Following TMEV infection, certain T cell hybridomas, generated from cloned (single identical cells) TMEV-induced CD8(+) T cells, were able to produce clinical signs of disease (flaccid hind limb paralysis) upon adoptive transfer into naive mice. Dual T cell receptors (TCR) are present on the surface of these cells as both Vβ3 and Vβ6 were detected by polymerase chain reaction (PCR) screening and flow cytometry and multiple Vα mRNAs were detected by PCR screening.

This is the first demonstration of antiviral CD8(+) T cells having more than one TCR initiating an autoimmune disease in the natural host of the virus. We hypothesize that this is a potential mechanism for virus-induced autoimmune disease initiated by CD8(+) T cells.

Theiler's murine encephalomyelitis virus is a natural pathogen of mice, which sometimes gets into the brain and causes a demyelinating disease, that may generate the development of autoimmunity by a number of different mechanisms such as molecular mimicry (sequence similarities between foreign(virus) and self-peptides are sufficient to result in the cross-activation of autoreactive T or B cells by pathogen derive peptides. So viral directed immune responses are mis-directed to attack the nervous tissue) or deteriminant spread (where damage generated in response to the immune attack of virus, triggers the development of a immune responses to the damaged protiens and thus trigger autoimmune attack. This study suggests another mechanism.

The T cell receptor is the stucture that allows the T cell to see its target. This is anchored in the cell membrane and consists of two halves, which form a pair of protein chains. The halves are called the alpha (α) and beta (β) fragments (in γ/δ T cells, the halves are gamma (γ) and delta (δ) fragments). Each fragment is divided in turn into a constant (C) and variable (V) region. These are constructed by the action of joining the gene products of a variable number of constant, joining, diversity and variable T cell receptor gene. There are about 50 variable genes for the beta chain and over 70 for the alpha.

So in this cell there were two variants (3 and 6) of the beta chain variable reion and many different alpha genes. Normally only one alpha and beta are present and can recognise one target if there is an extra beta then it could recognise a different target. T cells that reacted with the virus were cloned (so all the cells are identifical) and so the T cell receptor would react with the virus. So that they have a source of immortal cells to do reach with they fused the T cell clone with a tumor that lacks T cell receptor. They found that the T cell clone must have contained many different T cell receptor and when they put one of these tumours in mice it caused neurological problems suggesting that some of the T cell receptors were reacting with a nerve component. So by having more than one set of T cell receptors viral specific cells could also react with nerve proteins and trigger autoimmunity.

This concept whereby cells have dual (two) T cell receptors has been demonstrated many years ago, particularly with cells containing extra alpha chains in the context of of other viral infection or autoimmune conditions. This is yet another way that autoimmunity could develop following viral infection.

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