Natural killer cells, perforin and glutathione

[Guest guest]

Hi, all.

As many of you know, the most reliable immune-related marker for ME/CFS is

probably the low cytotoxic (cell-killing) activity of the natural killer cells.

As you may also know, natural killer cells normally kill cells that are

infected with viruses. They do this by secreting a substance called perforin,

which makes a hole in the cell membrane, and then injecting granzymes, which

induce the cell to undergo apoptosis (programmed cell death). The CD8 cytotoxic

T cells operate in the same way in terms of their killing mechanism.

Some years ago, Dr. Maher, who was in Dr. Klimas's group,

reported that the natural killer cells in PWMEs are low in perforin. It was also

found that the CD8 cytoxic T lymphocytes were also low in perforin. This would,

of course, inhibit their cytotoxic activity.

The question then became " Why are the NK and CD8 cells in ME/CFS low in

perforin?

In 2007, when I proposed the Glutathione Depletion-Methylation Cycle Block

(GD-MCB) hypothesis, I noted that the perforin molecule has a large number (20)

of cysteine residues in its protein structure. It is known that in order for a

cell to be able to synthesize a protein that contains cysteine residues, it must

have sufficient glutathione and a high enough ratio of reduced to oxidized

glutathione to keep the cysteine molecules in the cytosol of the cell in their

chemically reduced state as cysteine, and not oxidized as cystine. Otherwise,

the cell cannot assemble the chain of amino acids properly and join the cysteine

residues to their proper partners to form the proper tertiary structure of the

molecule. I therefore proposed then that the perforin deficit in NK cells and

CD8 cells in ME/CFS is due to glutathione depletion in these cells. If this is

true, one would expect that the gene expression of the perforin gene (as

measured by the level of messenger RNA corresponding to the PRF1 gene) would not

be below normal, because the glutathione deficit would impact the protein

synthesis process downstream of gene expression.

Recently, a group at Bond University in Australia (lead author Ekua W.

Brenu) published a paper entitled " Immunological abnormalities as potential

biomarkers in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis " :

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3120691/pdf/1479-5876-9-81.pdf

In this paper, together with a following one:

http://www.translational-medicine.com/content/pdf/1479-5876-10-88.pdf

they reported that the NK cell and CD8 cell cytotoxic activities were

consistently low in ME/CFS patients, but the messenger RNA for the perforin gene

PRF1 was significantly higher in both cell types in the PWMEs than in the normal

control subjects.

I suggest that this new result is consistent with the mechanism I have

proposed for low perforin in ME/CFS. It indicates that the NK cells and CD8

cells are " trying hard " to produce perforin by boosting the transcription of the

PRF1 gene to messenger RNA, but the protein synthesis process is at least

partially blocked and cannot respond. If glutathione is somewhat depleted in the

NK cells and CD8 cells, the protein synthesis process would indeed be partially

blocked.

I continue to propose, as I did in 2007, that other features of the observed

immune dysfunction in ME/CFS can also be explained by the GD-MCB hypothesis.

These include the shift to Th2 immune response, the elevated RNase-L and

formation of the low-molecular-weight RNase-L, the elevated inflammation, the

failure of lymphocytes to proliferate when stimulated with mitogens, the

reactivation of viruses and intracellular bacteria, and the accumulation of

pathogens over time.

Best regards,

Rich