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In this post I show you how CFS/ME could be an acquired immunodeficiency. Please share this informat

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After having seen several lymphocyte typages of CFS/ME patients, we have seen that they can be grouped mainly in two groups:

-In the first group they present reduced levels of total t lymphocytes (CD4, CD8, activated t lymphocytes) that indicate the presence of an immunodeficiency of T lymphocytes.

-In the second group the patients have total t lymphocytes (CD4, CD8) and immunoglobulins in normal values. But this does not mean that there cannot be some type of cell immunodeficiency. The analysis of activated CD3+ HLA-DR+ and CD3+ CD4+ HLA-DR+ T lymphocytes is used to see if there is indirectly a decrease in the MHC class II antigenic presentation, since CD4 T lymphocytes are activated through this antigenic presentation made by B lymphocytes (antigen-presenting cells) in the secondary lymphoid organs. Therefore, if there is a decrease in the expression of class II histocompatibility molecules in B lymphocytes, they would not present antigens to CD4 T lymphocytes and these would not be activated. For any T-lymphocyte to be able to perform its functions and become an effector lymphocyte, it is necessary for them to be activated. That is to say, the values of the activated CD4+ HLA-DR+ T lymphocytes indicate indirectly if there is any problem in the class II MHC antigenic presentation made by the B lymphocytes.

There is a congenital immunodeficiency called class II MHC deficiency in antigen-presenting cells, which is associated with a severe decrease in CD4+ (activated) T lymphocytes. This absence of cooperating T lymphocytes (CD4+) causes a deficiency in humoral response (the low number of CD4+ T lymphocytes causes a defect in collaboration between T and B lymphocytes) and cellular response (due to the intrinsic defect in the number of CD4+ T lymphocytes). Patients suffer repeated infections, particularly of the digestive tract. The genetic defect of this severe immunodeficiency is found in several proteins regulating the transcription of HLA class II genes.1

Imagen 1.png

Figure: Regulation of class II HLA genes in normal individuals (above) and in patients with class II HLA deficiency (below).1

The following are the ESID (European Society for Immunodeficiencies) diagnostic criteria for this congenital immunodeficiency:2

A. Definitive diagnosis: if both criteria are met:
· Deficit expression (<5%) of MHC-II molecules in B lymphocytes or monocytes.
· Mutation in one of the genes: CIITA, RFX-B, RFX-5 or RFX-AP.

B. Probable diagnosis: if all four criteria are met:
· Deficit expression (<5%) of MHC-II molecules in B lymphocytes or monocytes.
· Failure to thrive, opportunistic infections or persistent viral infections.
· Normal number of T and B cells.
· Normal proliferative responses to mitogens.

C. Possible diagnosis: the first of the criteria plus at least one of the following:
· Deficit expression (<5%) of MHC-II molecules in B lymphocytes or monocytes.
· Hypogammaglobulinemia.
· Normal mitogen responses but absent T cell proliferation to antigens.
· Normal number of T and B cells.
· Reduced number of CD4+ cells.
· Failure of mononuclear cells to stimulate a mixed lymphocyte culture.

The four genetic disorders that give rise to this congenital immunodeficiency are clinically indistinguishable. In most cases, there is no Class II expression. However, in others, the intensity of expression of MHC-II molecules may be as high as 5% of normal. Patients with higher expression tend to have a milder course of disease. These patients may survive beyond early childhood.3

We believe that the difference between this congenital immunodeficiency and that found in the second group of CFS/ME is in the number of antigen-presenting cells that have class II HCM deficiency. In the CFS/ME group it would only occur in those cells infected (mostly B lymphocytes) with an intracellular pathogen and in congenital immunodeficiency is in all antigen-presenting cells.

There are several intracellular pathogens that reduce the MHC class II antigenic presentation as an evasion mechanism of the immune system. The best known is the Epstein Barr virus, where it has been demonstrated that the latent protein LMP2A mediated the reduction of CIITA levels by decreasing the expression of PU.1 and E47 in B cells.4 Others such as human cytomegalovirus, human parainfluenza virus type 3, and varicella zoster virus suppress the IFN-γ-induced expression of class II MHC through inhibition of JAK-STAT activation and the transcription route activator, resulting in a reduction of CIITA expression.4 This may confirm the infectious origin of SFC/ME.

Both groups of CFS/ME have a type of immunodeficiency and it appears that those with a total T lymphocyte immunodeficiency (not just activated) are in a more advanced stage of the disease, and those with only decreased activated t lymphocytes are in an early stage. Both justify the recurrent infections that these patients present and the chronic fatigue that they present.

For all these reasons, we ask that the analyses of all patients diagnosed with CFS/ME be reviewed to confirm this decrease in activated T lymphocytes and to verify the deficit in the expression of MHC-II molecules in B lymphocytes. Given the complexity of the disease, we believe that these patients should be carried by clinical Immunologists.

Please share this information with as many CFS/ME patients, associations, researchers...as you can. This could serve as an analytical marker of CFS/ME and thus be able to seek a treatment for this type of immunodeficiency.

The analysis of activated T lymphocytes can be done in the following laboratories:

· In the United States, it can be done in this laboratory: Mayo Medical Laboratories. https://asantelab.testcatalog.org/s...M37d-WeXbA_9V7GcIwG3lDfojWrGvB9GteQrs_VooXdGs
· In Spain it can be done in Megalab, analizA, Cerba, Echevarne.

If you want to know more about how the Epstein Barr virus can do this type of immunodeficiency I recommend this thread, where you can download the paper I did.

Bibliography.

1. Regueiro González J.R., López Larrea C., González Rodriguez S. y Martínez Naves E. Inmunología: Biología y patología del sistema inmunitario. 4ª edición. Editorial Médica Panamerica, 2010.

2. Serrano Martín MªM. , et all. Déficit de expresión de moléculas de clase II del complejo mayor de histocompatibilidad. Anales de pediatría. Marzo 2007. Vol: 66, nº3 pag:227-339. Available in:http://www.analesdepediatria.org/es-deficit-expresion-moleculas-clase-ii-articulo-13099694

3. MHC class II deficiency diagnostic criteria. European Society for Inmunodeficiencies. Available in:https://esid.org/Working-Parties/Clinical-Working-Party/Resources/Diagnostic-criteria-for-PID2#Q10

4. Jiun-Han Lin, Ju-Yin Lin, Ya-Ching Chou, Mei-Ru Chen, Te-Huei Yeh, Chung-Wu Lin, Sue-Jane Lin and Ching-Hwa Tsai. Epstein-Barr virus LMP2A suppresses MHC class II expression by regulating the B-cell transcription factors E47 and PU.1. American Society of Hematology. April 2, 2015. Col. 125 no. 14 2228-2238. Available in: http://www.bloodjournal.org/content/125/14/2228/tab-figures-only?sso-checked=true
 
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I have only met one person with losw CD4 ( can be way more). What they found mostly in Cfs is low CD57 on the Cfs group ( or 56, sorry the NK one) w mostly normal cd4 and cd8.
Me particularly had high cd8 normal cd4. Why the regular tests find us “ok” becuase they run most commonly the cd4, cd8 ration.
 
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I have only met one person with losw CD4 ( can be way more). What they found mostly in Cfs is low CD57 on the Cfs group ( or 56, sorry the NK one) w mostly normal cd4 and cd8.
Me particularly had high cd8 normal cd4. Why the regular tests find us “ok” becuase they run most commonly the cd4, cd8 ration.
The decrease of the CD4 occurs in the first group that I have put. In the second group these values are normal and only the activated T lymphocytes have decreased.
Have you ever had an analysis of the activated T lymphocytes?:
  • CD3+ HLA-DR+
  • CD4+ HLA-DR+
  • CD8+ HLA-DR+

If you are from the United States you can do it here: https://asantelab.testcatalog.org/s...M37d-WeXbA_9V7GcIwG3lDfojWrGvB9GteQrs_VooXdGs

This serves to indirectly see if there is a decrease in the MHC class II antigenic presentation. If this decrease exists, a clinical immunologist could analyze you if there is a decrease in the expression of class II MHC molecules in B lymphocytes (some intracellular pathogens do this to avoid the immune response) that would justify this decrease in activated t lymphocytes. With this you could already have demonstrated an immunodeficiency due to MHC class II deficiency.
 
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Have you ever had an analysis of the activated T lymphocytes?:
Yes the old school guys ( Klimas, Peterson...) they do lymphocytes Soubsets. Why Klimas says on videos that Cfs is a form of aquiered inmune def. But all this years that has not help the issue on guiding treatment except the antiviral route and inmune mods. They help tremendously after a lot of years but not cure. I still struggle w low NKs
 
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Yes the old school guys ( Klimas, Peterson...) they do lymphocytes Soubsets. Why Klimas says on videos that Cfs is a form of aquiered inmune def. But all this years that has not help the issue on guiding treatment except the antiviral route and inmune mods. They help tremendously after a lot of years but not cure. I still struggle w low NKs
I'm sorry I don't speak English very well, I didn't quite understand your question. NKs are reduced, for example in chronic infection with Epstein Barr virus, one of the pathogens I am referring to.

With what I'm showing, we could end the belief that there are no markers in the SFC/ME. Since this could demonstrate the presence of an immunodeficiency acquired by infection with an intracellular pathogen, especially in B lymphocytes. It would help that in some countries CFS/ME is no longer a psychosomatic disease.
 
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With what I'm showing, we could end the belief that there are no markers in the SFC/ME. Since this could demonstrate the presence of an immunodeficiency acquired by infection with an intracellular pathogen, especially in B lymphocytes. It would help that in some countries CFS/ME is no longer a psychosomatic disease.
I understand, we have known this for a while about the immune system abnomalies. Is not that the proof is not there. The psyco is going on becuase it is cheaper to pay 2 years for disability ( if Cfs/ me ) is psychological vs physical ( paid indefinite disability).

If you are following the Cochrane review and today the NICE issue you see the problem is corruption not lack of proof.

So they do not accept on the NICE guideline people with this knowledge so we can debunk this bio social crap.

Is not for lack of studies showing / proving that there are abnomalies. Is being able to bring those to the guidelines the problems!!!

I really think we need to go to court in U.K. to stop this corruption.
 
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I understand, we have known this for a while about the immune system abnomalies. Is not that the proof is not there. The psyco is going on becuase it is cheaper to pay 2 years for disability ( if Cfs/ me ) is psychological vs physical ( paid indefinite disability).

If you are following the Cochrane review and today the NICE issue you see the problem is corruption not lack of proof.

So they do not accept on the NICE guideline people with this knowledge so we can debunk this bio social crap.

Is not for lack of studies showing / proving that there are abnomalies. Is being able to bring those to the guidelines the problems!!!

I really think we need to go to court in U.K. to stop this corruption.
I totally agree with what you say.
But what he was saying is that for now he hadn't found any studies showing that CFS/ME was an acquired immunodeficiency due to class II MHC deficiency. And this is what I wanted to show.

That is to say, it is something similar to AIDS. The difference is that in AIDS the total number of CD4 lymphocytes (including activated t cells) decreases because HIV infects and destroys this type of CD4 cells, but in CFS/ME even though you have the total number of normal CD4 cells they don't work properly because there are few activated ones. Some intracellular pathogens infect mainly B cells, preventing them from expressing class II MHC molecules and these B cells from activating T cells. However, it seems that some people who have been with CFS/ME for quite some time start to have decreases in CD4 T lymphocytes (the first group).

All this justifies the recurrent infections of latent pathogens (such as herpesvirus), fungi...
 

Wishful

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Would your theory explain why I had a type IV food sensitivity during the first 2.5 years of my ME? I'm convinced that my t-cells were involved in those first years, but I managed to stop the type IV reaction, but still retained the symptoms. Also, I don't suffer from repeated infections. I haven't had a viral infection in over 5 years. No noticeable bacterial infections either.

I do believe that IFN-g is involved in my physically-induced PEM, resulting from the immune system cleaning up damaged muscle cells. Does that fit your theory?
 

JES

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Setting aside the medical hypothesis, I think it's a bit of a generalization to say ME/CFS patients experience recurrent infections. There are certainly some of us who seem to catch every cold or bacterial infection on the planet, but there are also many of us who almost never get colds anymore and used to get sick much more often before ME/CFS hit them.

I used to have a cold or flu at least once ever year, but ever since my ME/CFS symptoms worsened, I have only experienced two colds in the last five years. Both times I experienced a massive, but sadly temporary remission of all ME/CFS related symptoms. I'm not sure how any of this can be related to an immunodeficiency. It's hard for me to understand how an acute infection would improve an already existing immunodeficiency, but it does for many of us. Surely AIDS patients aren't experiencing these type of improvements in their disease when catching an infection.
 
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Learner1

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there are also many of us who almost never get acute colds anymore and used to get sick much more often before ME/CFS hit them.

I used to have a cold or flu at least once ever year, but ever since my ME/CFS symptoms worsened, I have only experienced two colds in the last five years. Both times I experienced a massive, but sadly temporary remission of all ME/CFS related symptoms. I'm not sure how any of this can be related to an immunodeficiency.
I hadn't felt "sick" for over 2 years prior to my diagnosis, but my doctors found I had 7 infections smouldering along, including EBV, which didn't show up with the normal titers but did show up on a PCR.

My immunoglobulins were low. IgM and IgG was below range, as were IgG subclasses 1 and 3. The doctor testing and diagnosing me is a top ME/CFS specislist.

So, if one is immunodeficient, the immune system may not be reacting appropriately to threats. You will see in papers where they talk about what happens in immunocompetent patients vs. immunocompromised patients. The immunocompromised patients will react differently.

And, being immunodeficient with chronic infections that eont go away can lead to autoimmune problems, like POTS, etc., compounding our problems.

Finding and treating immunodeficiency, along with any "hidden" infections can be quite helpful. I know I've benefited from Valcyte, IV antibiotics and IVIG, and wish these problems were found earlier by the docs who wanted to help by offering psychotherapy before my problems multiplied and I had autoimmune POTS and MCAS, too....
 

Wishful

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My viral infections, back when I still had them, made my ME symptoms worse, possibly exactly the same as my physically-induced PEM did, which I believed was due to IFN-g from both.
 

Learner1

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How do you know your viruses specifically raised IFN-g?

Can IFN-g not also be a marker of autoimmunity?

And what effect would IFN-g have that would create PEM? Peroxynitrite production?
 

JES

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It could be that an immune system that is underresponding is the reason some of us never gets sick, but it could also be doing the opposite thing for some of us and constantly overrespond to something and therefore a normal cold infection would never get a chance to cause physical symptoms (e.g. the clonal expansion of T cells found in patients by Mark Davis would support this idea).

I just happen to be fascinated by the fact that mini remissions in this illness can be reached from a short-term infectious agent. Ron Davis spoke about this in the OMF seminar as well, where he noticed ME/CFS cells behaved more normally in the nanoneedle if the test was performed following a bacterial infection of the patient. This improvement during acute infection is seen in some other conditions like autism (the fever effect), but I'm not aware of any immunodeficiency condition that would similarly improve during acute infections. IMO the immunodeficiency model in order to be applied to ME/CFS would need to be able to explain the temporary improvements during a cold.
 
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Good night @JES
We must understand that I have spoken of two groups, one with an immunodeficiency of T lymphocytes (lymphopenia) and the other with normal values of T lymphocytes, with only the activated T lymphocytes decreased. The first group being a more advanced stage and the second group an initial stage.
Let me give you an example with hiv. When you are infected with hiv it takes 10 years for AIDS to appear. And during these years you go through different stages. After the acute infection, it is passed to a latent clinical infection, with persistent inflammation of the lymph nodes. Then it passes to the symptomatic stage where reactivations of latent viruses such as herpesvirus, fungal infections, diarrhea, weight loss but not yet AIDS begin to appear. This stage would be like that of CFS/ME patients with low activated T lymphocytes.

The response against extracellular bacteria is usually sufficient with the innate response (phagocytosis). If this is not enough, the adaptive response is set in motion. However, as most of the time these are extracellular bacteria, the adaptive response is independent of the T lymphocytes, with the B lymphocytes directly responsible for the response against these pathogens by secreting neutralising antibodies.

"The activation capacity of globulins is much higher than that achieved by the innate receptors of these same phagocytes, so if we have preformed antibodies against a microbe our immune response will be much more effective".

This is why these immunodeficient people are able to fight extracellular bacteria well, since the collaboration between T and B lymphocytes does not intervene.

The problem is when the pathogen is intracellular, since the innate response only slows the growth of the infection.
So it is the adaptive response that is needed to kill these pathogens. And here it is necessary the collaboration between T and B lymphocytes to kill them. And since there is a decrease in the activated T lymphocytes due to the decrease in the expression of class II MHC molecules in the infected B lymphocytes (in the case of CFS/ME), the adaptive response is not efficient. Hence the latent chronic infection of past viruses and an inefficient response against new viruses or intracellular pathogens. But as with HIV infection, it depends on the degree of immunodeficiency at the time, the fact that some are better symptomatically and others worse. That is to say, in the case of patients with CFS/ME it depends on the number of B lymphocytes that do not express MHC class II molecules.

Then we move on to the AIDS stage, which is when CD4 lymphocytes begin to fall below 200 (it takes 10 years from the time you get infected with hiv until you get AIDS). In the case of the first group of CFS, who happen to be patients who have had CFS for many years, CD4s begin to decline. Hence, this group is thought to be a more advanced stage of the disease.
 

Jenny

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Hi Manuel

I wonder if my results are consistent with your theory. About 8 years ago I had the
following result:

Low CD4 + CD45RA+ CD38+(15.9, range 29-69),
normal absolute CD4, and normal CD4 percentage of lymph.

Low percentage of CD19 B cells (8% of lymph, range 12-22).

Mannose binding lectin deficiency.

At that point I had had relapsing/remitting ME for 30 years.
 

JES

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@Manuel I think I understand the hypothesis you presented, I just don't see it connecting that well to actual ME/CFS symptomatology and to we know about the disease. The temporary recovery many of us experience during a cold or bacterial infection speaks against an immunodeficiency. I also think ME/CFS symptoms are too complicated to be explained by an immune deficiency, even if we grant the slow progression and several different stages that could be present in both ME/CFS and HIV.

In HIV or even AIDS stage I'm not aware of patients experiencing post-exertional malaise or the kind of complete energy and metabolic failure that happens in ME/CFS. And on the other hand, if ME/CFS was an immunodeficiency, you would expect people dropping dead from infections after having had ME/CFS for decades. But the fact is that very rarely do people with ME/CFS die. It does happen, but even in the cases reported, it is often ME/CFS itself that causes the death, not a secondary infection. And there is even a group of people that spontaneously recover from ME/CFS after being ill for years. I'm not aware of any spontaneous recoveries from AIDS or primary immunodeficiencies.

I think there is some kind of inflammatory process in ME/CFS creating the dysfunction of the immune system and some form of immune exhaustion, but I think it may be wrong to characterize the disease as an immunodeficiency. It actually looks like ME/CFS is more similar to multiple sclerosis and Lyme disease based on T cell activation patterns observed by Mark Davis (source).
 

Learner1

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if ME/CFS was an immunodeficiency, you would expect people dropping dead from infections
I am fortunate to live in the western US and be treated by one of the top ME/CFS specialists.

He found that I was immunodeficient, as are several of his other patients, I had several chrinic infections, as do many of his other patients and I have autoimmunity, as do many of his other patients. Treating all of these problems has made a huge difference for me.
I think there is some kind of inflammatory process in ME/CFS creating the dysfunction of the immune system and some form of immune exhaustion, but I think it may be wrong to characterize the disease as an immunodeficiency.
My inflammatory markers havent been very high. When I was at my worst, sed rate was 2 and CRP was .18.

My doctor looked at decades of my health history and said it could be I was born with a bad immune system or could be that I acquired it, but that he would call it a dysfunctional immune system. And, the only thing I can point to in acquiring immunodeficiency is that my mitochondria do not function well, which may have caused my immune system to weaken.

I feel lucky to get IVIG, which is helpful for both autoimmunity and immunodeficiency abd wish more patients could benefit from it. But if no one ever tests them for immunodeficiency or autoantibodies, then they can't qualify.

There are several other patients in this sane category. Probably not everyone, but more than a few.
 

xcell

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In HIV or even AIDS stage I'm not aware of patients experiencing post-exertional malaise or the kind of complete energy and metabolic failure that happens in ME/CFS. And on the other hand, if ME/CFS was an immunodeficiency, you would expect people dropping dead from infections after having had ME/CFS for decades..
PENE protects you from death. The body shuts down the whole system, "closes" the cells so that the pathogens can't spread. (Read for example Cell Danger Response: https://forums.phoenixrising.me/ind...-features-of-the-cell-danger-response.30931/; CDR ist not the problem - it's a result of an infection!).
That would explain why some write the blood values get better after vitamins but not the general condition:
https://nicolaschmid.wordpress.com/nicolas-letzte-jahre/
In September Nicola started microimmunotherapy and additionally received several high doses of vitamin C infusions over a period of 3 months. Her blood values improved, but unfortunately her general condition did not.
 
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