Not getting colds a symptom of Lyme

[snowathlete]

We've had topics on some people with ME/CFS not getting colds on here before, but having just been told I probably have Lyme, I have been researching a few things and one thing that comes up is that a significant group of Lyme patients dont get colds either.

Now, just like ME/CFS, not eveyrone is in the same boat. Some people get every cold going, but it's an interesting thing I think that some people with Lyme also don't get them, even. I'd be interesting to hear from people with Lyme (with or without ME/CFS) if they get colds or not.

Moderation question: can we have a Lyme forum for topics like these? (I couldn't see one) Or perhaps a tick-borne infection forum? I know that Phoenix is about ME/CFS but a lot of people with ME/CFS also have Lyme, or other tick-borne co-infections, but would prefer to stay here rather than go find a Lyme forum some place.

 

[Lotus97]

Rich actually thought that not getting colds or flus was common with CFS/ME in general. I don't think I've had a cold or flu in 15 years. Rich said it might be due to elevated interferon responses. This is sort of a long quote, but I thought people might find interesting and he does explain the part of cold and flus at the end
http://forums.phoenixrising.me/inde...lls-perforin-and-glutathione-depletion.17603/
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":

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.

Here's a brief outline of the whole GD-MCB hypothesis, as it currently stands (always subject to modification as we learn more):


1. Genetic predisposition is present (perhaps including SNPs in genes coding for enzymes related to glutathione that cause it to be more easily depleted, as reported in autism by Bowers et al., 2011).

2. Stressors (physical, chemical, biological and/or psychological/emotional, the mix varying from one case to another, based on patient histories) deplete glutathione by various means, some by oxidative stress, some by conjugation, some by lowering its rate of synthesis. The depletion of glutathione is demonstrated by the methylation pathways panel.

3. The state of oxidative stress worsens as a result of the depletion of glutathione, and peroxynitrite rises, due to reaction of rising superoxide with existing nitric oxide.

4. Glutathione depletion lowers the affinity of the CblC complementation group for cobalamin (as reported by Jeong and Kim, 2011), producing a functional B12 deficiency, thus lowering intracellular methylcobalamin and adenosylcobalamin. Anecdotal observations of elevated urine methylmalonate in the presence of normal or elevated serum B12 in ME/CFS patients confirm the presence of a functional B12 deficiency.

5. The lowered methylcobalamin inhibits the methionine synthase reaction, since it is the necessary coenzyme for this reaction.

6. The methyl trap mechanism continues the conversion of other forms of folate into methylfolate, but the lowered rate of the methionine synthase reaction decreases the demand for it.

7. The elevated peroxynitrite catabolizes methylfolate, preventing its rise in the plasma.

8. The above process depletes the intracellular folates in general (as inferred from measurements with the methylation pathways panel).

9. Homocysteine drains into the transsulfuration pathway, since its conversion to methionine is inhibited, and over time, methionine therefore becomes depleted (as found by Bralley and Lord,1994), leading to dysregulation and depletion of the sulfur metabolism in general.

10. The above combination of steps produces a stable vicious circle mechanism, and this is the reason ME/CFS is chronic.
11. Treatment must include a high dosage (relative to the RDA) of a form of vitamin B12 delivered to the bloodstream, such as sublingually or by injection, together with an RDA-level dosage of folate, which can be given orally. The high dosage of B12 is necessary to compensate for the greatly lowered affinity for cobalamin of the CblC complementation group, so as to overcome the functional B12 deficiency, and the oral route is not adequate to supply this necessary high dosage (first reported by Lapp and Cheney, 1993 and 1999). The folate is necessary to compensate for the loss of methylfolate from the cells due to the peroxynitrite catabolism reaction. The B12 is best given as hydroxocobalamin or methylcobalamin. The folate is best given as methylfolate, though folinic acid works for some patients. There are individual differences in genetic polymorphisms that determine the best forms of B12 and folate for individual patients. If there are deficiencies in cofactor vitamins and minerals or in necessary amino acids, these must be supplemented in addition. Replacement of oxidatively damaged essential fatty acids is also needed. If toxic metals levels are high enough to significantly block enzymes in this part of the metabolism, chelation may be necessary before this treatment will be successful.

12. This treatment is directed at the core of the pathophysiology. However, it does not directly treat the etiologies ("stressors" in step #2 above) that brought about this pathophysiology, nor does it directly treat pathogens and toxins that may have accumulated since the onset of ME/CFS, while the body's immune and detoxication systems have been dysfunctional as a result of the dysfunction of the sulfur metabolism. Additional treatments are needed in most cases to deal with them directly, to work toward achieving full recovery, because even though the immune system and the detoxification system may be largely restored, they are often not able to overcome these etiologies and accumulated factors on their own. Some of the etiologies and accumulated factors in various cases are Lyme disease and its coinfections, biotoxin illness, entrenched viral infections (and perhaps retroviral infections), and high body burdens of toxins.

I don't know how many of the cysteines are involved in sulfide bridges, but I suspect that quite a few, and maybe all of them, are. And yes, glutathione depletion will likely cause misfolding of the protein structure. I should note that there is a quality control system built into the endoplasmic reticulum of cells, so that many of the misfolded proteins are detected and recycled via disassembly of the amino acids in the proteasomes, but some are probably released, and yes, they might have low activity.

Incidentally, I have invoked this same mechanism to explain why some other secretory proteins, such as some of the peptide hormones, are deficient in ME/CFS. I think that vasopressin and oxytocin are in this category, and I think that ACTH is, also. All of these have cysteine residues that have to form particular disulfide bonds to produce the proper tertiary structure of their molecules. Any secretory protein that normally has disulfide bonds and is formed in a cell that is depleted in glutathione will have this problem. I think the hypothalamus and pituitary are depleted in glutathione. On the other hand, it's likely that the pancreas is not, so insulin is properly formed in ME/CFS. The reason the pancreas is not likely to be depleted in glutathione is that it is one of the few vital organs that have a complete transsulfuration pathway, and thus are able to make cysteine from methionine, so that they can maintain glutathione synthesis when the body as a whole is having problems maintaining its glutathione inventory.

I also think it's possible that some of the autoimmune activity in ME/CFS may result from the immune system trying to clean up these misshapen proteins. To go a step further, that may be why Rituximab helped some people. By knocking out the B lymphocytes, the antibodies will be decreased over time, and that should lower the autoimmune reactions and the accompanying inflammation with its oxidative stress. Maybe that allows glutathione to come back up and restore things.

To try to respond to your questions, I think I should first summarize how the immune system normally responds to viral infections, then discuss what I think the dysfunction in ME/CFS involves, and then comment on your questions:

So first, how does the immune system normally respond to viral infections? There are basically four types of responses, listed here in roughly the chronological order in which they normally occur:

1. Type I interferon (interferons alpha and beta) responses
2. Natural killer cell response
3. Virus-specific cytotoxic T lymphocyte (CD-8 "killer" T cell) response.
4. Antibody response

Type I interferons are secreted by infected cells, to alert nearby cells, and hopefully prevent them from becoming infected. The Interferon responses include the PKR, the 2,5-OAS RNase-L, and the Mx responses, among others. The PKR response inhibits the synthesis of viral proteins inside host cells. The 2,5-OAS RNase-L response degrades viral RNA inside host cells. The Mx response inhibits viral gene expression and assembly of the virions inside host cells.

The natural killer cells recognize virally infected cells in which the viruses are attempting to hide from the immune system by shutting off the Class I HLA mechanism that the CD-8 cells use to recognize virally infected cells. If the Class I HLA molecules are not displayed on the cell surface, the NK cell kills the cell.

The CD-8 killer T cells kill cells that are displaying viral antigens by means of the Class I HLA molecules.

Antibodies against viral antigens are made by B lymphocytes and plasma cells, and they bind to viruses that are outside the host cells, as when an infection is beginning or when viruses are spreading from one host cell to another.
This neutralizes the viruses, so that they cannot enter new host cells, and it can also "mark" them for attack by other cells of the immune system, such as macrophages.

O.K., now what happens to these responses in ME/CFS?

Well, the Type I interferon responses continue to work, and even though they are intended to be short term responses to hold back the viral infection until the "cavalry" in the form of the CD-8 killer cells arrives, and the CD-8 cells, together with the NK cells, knock out the viral infection, in ME/CFS the interferon responses continue to work overtime (and even become dysregulated in the case of the RNase-L) because the CD-8 killer cells are not able to take over. Sadly, the "cavalry" never arrives, leaving the "civilians" to battle the "Indians" in an ongoing guerrilla war.
What causes the formation of the dysregulated low-molecular-weight RNase-L molecules? I propose that glutathione depletion is responsible. It activates calpain, and calpain cleaves the normal RNase-L molecules. The cleaved parts join together, forming the unregulated LMW RNase-L.

Both the NK cells and the CD-8 killer T cells are rendered impotent by their inability to make perforin and granzymes in normal amounts. Furthermore, the CD-8 killer T cells are not able to multiply to outnumber the "bad guys" as they should. Why does this happen? I propose that it is a result of glutathione depletion and depletion of folates, respectively, which are part of the GD-MCB vicious circle mechanism that I believe is at the basis of the pathogenesis of ME/CFS.

Antibody production continues, and in fact may be increased, because of the shift toward the Th2 immune response in ME/CFS, which favors humoral immunity, i.e. the production of antibodies by B lymphocytes and plasma cells. What causes this shift? Again, I have proposed that glutathione depletion is responsible, in this case in the "naive" T cells.

So what we have are heightened interferon and antibody responses, but failure of the main "kill" mechanisms. The result is that latent viruses in the body (such as EBV, CMV and HHV6) are able to reactivate, and the immune system continues to fight with the weapons it has left, confining the viruses and keeping the host alive, but not winning the war against the viruses by completely knocking them out or putting them back into latency.

Now, what about your questions?

Would interferon treatment work? Well, to some degree, but without the other dysfunctional immune responses to help them, they cannot completely knock out the viruses.

Why don't PWMEs get colds and flus? I think it's because of the constantly elevated interferon responses. This produces what has been called the "antiviral state." With this going on, it's difficult for a newly introduced virus to get a foothold.

Does this have anything to do with the elevated cytokines in ME/CFS? Yes. The immune system is well aware that there are enemies inside the perimeter, and it is sounding the alarm, trying to organize the defense. The cells of the immune system are sending chemical messages back and forth to each other in the form of cytokines. However, because the NK cells and the CD-8 cells are impotent, even though the trumpet sounds, they don't respond, because they are not able to, so the messages just keep flying back and forth, unheeded.

Beyond that, because viruses that are well-entrenched have various ways of foiling the immune system, even though the immune system is restored, other measures will likely also be needed. One interesting one is GcMAF, which overcomes one of the strategies used by viruses to foil the immune system, i.e. nagalase. Antivirals are another possibility, especially in view of some success using them, as in Dr. Lerner's experience.

So what's the solution to this problem? How do we win the war? Well, I'm still working on that, but I think that a big part of it will be to restore glutathione, folates and methylation, and that will probably require a methylation protocol.

Best regards,

Rich

 

[NilaJones]

Lotus, thank you so much for posting that! I hadn't seen it, and it's an excellent summary for a newbie like me.

When I get exposed to a cold or flu virus, sometimes I get the cold or flu, but more often my ordinary symptoms get worse for a few weeks. I'm concerned about this, so I take steps to avoid those viruses -- I get a flu shot, and avoid contact with sick people, and wear a mask in germy places.

 

[Lotus97]

Lotus, thank you so much for posting that! I hadn't seen it, and it's an excellent summary for a newbie like me.

When I get exposed to a cold or flu virus, sometimes I get the cold or flu, but more often my ordinary symptoms get worse for a few weeks. I'm concerned about this, so I take steps to avoid those viruses -- I get a flu shot, and avoid contact with sick people, and wear a mask in germy places.

So do you think your ordinary symptoms get worse due to an overactive immune response? Such as inflammatory cytokines.

 

[NilaJones]

Well, I have very high levels of antibodies to HH6, which IIUC implies active viral infection. (Is this controversial? Or pretty much for sure?)

So my explanation, which I completely made up and pulled out of my butt, tho my doc called it 'plausible', is that my immune system considers the cold/flu virus a higher priority and takes resources off keeping the HH6 in check, in order to prevent me getting pneumonia or something.

IOW, I have no idea, but hope to hear other folks' thoughts on the subject .

 

[NilaJones]

My inflammation issues, which are pretty severe, do not get worse with exposure to cold/flu viruses, if that means anything...

 

[snowathlete]

Thanks Lotus97. Rich was a clever man. Indeed my Perforrin expression is high -1398 (250-750) which I realised meant that my NK cells were active but I hadn't considered that there might still be an actual deficit in perforrin, dispute this.

Wish I knew what my interferon levels were.

 

[Lotus97]

My inflammation issues, which are pretty severe, do not get worse with exposure to cold/flu viruses, if that means anything...

I wasn't sure what you meant when you said "ordinary symptoms". So which symptoms do you consider your ordinary symptoms and which symptoms are from inflammation?

 

[NilaJones]

Ah, I can see how what I wrote made no sense

I have connective tissue inflammation problems going back 20 years, but have only felt 'sick' for a few years. So I think of them as seperate health problems, and I was referring to the malaise, low fever, fatigue, sore throat, fuzzy thinking, that sort of stuff. Basically my 'ordinary symptoms' are like the flu except the fever is lower and my nose does not run .

Do some ME/CFS folks have severe tendonitis and sprains that do not heal (decades after original injuries, in my case)? Is that a part of CFS?

 

[Lotus97]

Ah, I can see how what I wrote made no sense

I have connective tissue inflammation problems going back 20 years, but have only felt 'sick' for a few years. So I think of them as seperate health problems, and I was referring to the malaise, low fever, fatigue, sore throat, fuzzy thinking, that sort of stuff. Basically my 'ordinary symptoms' are like the flu except the fever is lower and my nose does not run .

Do some ME/CFS folks have severe tendonitis and sprains that do not heal (decades after original injuries, in my case)? Is that a part of CFS?

What's the connective tissue inflammation from? I don't know much about that other that Lyme or autoimmune diseases can cause that. I'm not sure if any of your other symptoms are from inflammation, but there's a lot more to inflammation than just pain. There's a series of articles about ME/CFS being a neuroinflammatory condition. This is the first article
http://www.cortjohnson.org/blog/201...xplain-chronic-fatigue-syndrome-mecfs-better/
If you want to read more, there's links to the other articles at the bottom of the 4th article:
http://www.cortjohnson.org/blog/201...akes-on-symptoms-of-chronic-fatigue-syndrome/

 

[NilaJones]

Thank you for the links, I will check them out.

No diagnosis for the connective tissue disorder. My sis has it too; she also has had CFS for decades. Our grandmother had the connective tissue problem but not the fatigue.

Doc currently thinks maybe a form of Ehlers-Danlos; I see people here speculate about a connection between that and CFS.

 

[ukxmrv]

A friend with MS said that patients in her support group also say that they don't get colds and flus. It may be something that appears in other diseases as well.

My experience is that I had few colds and flus for the first 15 or so years and then lots of colds and flus since then. Never had a Lyme test because of the problems getting one that was easy, reliable and cheap plus the treatment options were usually things I has tried before.

 

[cigana]

I have been given a Lyme diagnosis and I didn't get a single cold or flu for about an 8 year period (which began prior to my illness), despite people around me getting them. Since I've started treatment for Lyme, this has changed slightly, in that I now notice I am more tired often when others (eg. my flatmate) around me have colds, with some earache too. Don't really know how much this is related to treatment.

I've also often wondered, for those of us that don't get colds, is it (a) because our immune system is on red alert and we therefore kill anything before it gets a chance or (b) because our immune system is suppressed and therefore we do not get symptoms?

My perforin is also raised: 2538 (250-750).

 

[cigana]

Moderators: I would also like to see a Lyme section! The Lyme forums on the net are mainly for people who remember getting bitten and/or the acute infection. I think we really need something for people coming in from a different perspective.