Natural killer cells, perforin, and glutathione depletion

Discussion in 'Fibromyalgia Main Forum' started by richvank, May 26, 2012.

  1. richvank

    richvank New Member

    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. Kevin Maher, who was in Dr. Nancy 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":

    In this paper, together with a following one:

    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,


  2. MicheleK

    MicheleK Member

    Thanks Rich for that information. After having M.E for 20 years and keeping on top of research, it never ceases to amaze me how we keep getting back to the same things we suspected all those years ago.
    Our bodies are such fascinating machines, even when they are sick! It amazes me how much can be going wrong in the body and still the majority of things still are going right! The body is the very definition of the word, complexity.