New Study in CFS-ME Patients: Possible Acquired Immunodeficiency

Messages
56
Likes
241
Good afternoon,

I am Manuel Ruiz, medical student in Spain and I am sick with CFS/ME. Together with my girlfriend Rosario, graduated in Medicine from the Complutense University of Madrid, we contacted one of the best research centers in Spain, CIMA, to carry out the project described below.

Currently I have seen quite a few lymphocyte typages that have provided me with CFS/ME patients. They could be grouped into two main 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

Figure (photo attached): 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 MHC 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.

What would be achieved if this hypothesis were met?

-1. A diagnosis of immunodeficiency. We would no longer be invisible to health care.

-2. Access treatments for this type of immunodeficiency.

-3. Begin to develop new specific treatments that eliminate cells with latent intracellular pathogens (such as the Epstein Barr virus).

After everything described, I contacted the research team of Dr. Bruno Paiva (https://cima.unav.edu/investigacion/plataformas/citometria/equipo/bruno-paiva) of CIMA of the University of Navarra.

This is the link of crowdfunding:https://helpify.es/comunidades/todo-por-la-causa-del-sindrome-de-la-fatiga-cronica/

I hope you will help us with outreach and fundraising.
I will try to solve all the doubts that I can.
Greetings

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
 

Attachments

junkcrap50

Senior Member
Messages
576
Likes
1,059
I urge you to share your theory with more researchers, including Ron Davis and Mark Davis.

Can you explain how what kind of testing is needed to confirm your hypothesis? Is it possible to measure class II histocompatibility molecules in B lymphocytes expression?
 
Messages
56
Likes
241
I urge you to share your theory with more researchers, including Ron Davis and Mark Davis.

Can you explain how what kind of testing is needed to confirm your hypothesis? Is it possible to measure class II histocompatibility molecules in B lymphocytes expression?
Yes, I shared this hypothesis with Dr. Montoya and Dr. Ron Davis. They both found the hypothesis interesting. An immunologist from Dr. Ron Davis's team told me that they would take a long time to analyze the immunological markers that I proposed because they had several lines of research open. That's why I contacted CIMA in Spain to do the study as soon as possible. The problem is that we need funds for the study, since in Spain not much is invested in research.

For this reason, I ask for your help. No matter how small the amount you donate, if we do it together, it is achieved in a short time. And I would appreciate it if you could share it.
 

Hip

Senior Member
Messages
13,040
Likes
24,167
most severe ME patients have no active or reactivated infections! usually only the mild patients often have infections. at least, if you select the patients according to the ICC criteria..
Depends on how you define "active" infections. If we think of active infections as the acute disease we come down with when we have a cold, flu or gastrointestinal illness, where for some days the blood is full of virus, until the immune system brings the infection under control, then no, most ME/CFS patients do not have that type of infection.

But numerous studies have shown ME/CFS patients have ongoing low-level level intracellular infections with enteroviruses. These infections are detected when you test muscle, intestinal or brain tissue for enterovirus RNA, or for enterovirus viral protein.

In mild and moderate patients, the enterovirus infection is in the tissue, but very little virus is found in the blood (ie, PCR blood tests are often negative). But in the more severe bedbound patients with enterovirus ME/CFS, blood PCR will come back positive about 70% of the time, indicating there is a small amount of virus present in the blood too. Ref: here.
 
Last edited:
Messages
61
Likes
107
Depends on how you define "active" infections. If we think of active infections as the acute disease we come down with when we have a cold, flu or gastrointestinal illness, where for some days the blood is full of virus, until the immune system brings the infection under control, then no, most ME/CFS patients do not have that type of infection.

But numerous studies have shown ME/CFS patients have ongoing low-level level intracellular infections with enteroviruses. These infections are detected when you test muscle, intestinal or brain tissue for enterovirus RNA, or for enterovirus viral protein.

In mild and moderate patients, the enterovirus infection is in the tissue, but very little virus is found in the blood (ie, PCR blood tests are often negative). But in the more severe bedbound patients with enterovirus ME/CFS, blood PCR will come back positive about 70% of the time, indicating there is a small amount of virus present in the blood too. Ref: here.
There are tens of different enterovirus species found. And there is no proven causal relationship. pure theory.
 

Hip

Senior Member
Messages
13,040
Likes
24,167
There are tens of different enterovirus species found.
Yes, there are around 80 enteroviruses that infect humans, and most enteroviruses are not capable of forming chronic infections.

It is only the enterovirus B species that can form chronic infections. These chronic enterovirus B infections are linked to a number of diseases, including type 1 diabetes, Parkinson's, ME/CFS and others.



And there is no proven causal relationship. pure theory.
That's true, but you still find these chronic enterovirus infections in ME/CFS patients much more frequently that in healthy controls, so an association exists. Also, many enterovirus ME/CFS patients make dramatic improvements (bedbound to back to work improvements) when given interferon therapy, which is is known to have a potent antiviral effect for enterovirus.
 
Messages
61
Likes
107
That's true, but you still find these chronic enterovirus infections in ME/CFS patients much more frequently that in healthy controls, so an association exists. Also, many enterovirus ME/CFS patients make dramatic improvements (bedbound to back to work improvements) when given interferon therapy, which is is known to have a potent antiviral effect for enterovirus.
Yes interferons are used in many diseases. also autoimmune diseases, cancer etc.
as I said, a causal relationship is not proven. Correlation is not causality.
 

Hip

Senior Member
Messages
13,040
Likes
24,167
Yes interferons are used in many diseases. also autoimmune diseases, cancer etc.
Well interestingly enough, only patients with enterovirus-associated ME/CFS respond to interferon; those with herpesvirus associated ME/CFS do not.

If interferon therapy were addressing some non-viral aspect of ME/CFS, like for example some immune dysfunction, you would expect it to work for ME/CFS irrespective of the virus involved.
 

percyval577

basal and ganglia
Messages
814
Likes
1,091
Location
Ik waak up
If interferon therapy were addressing some non-viral aspect of ME/CFS, like for example some immune dysfunction, you would expect it to work for ME/CFS irrespective of the virus involved.
It could be a consequence of the infection not the infection itself.

This consequence might build up a subgroup of mecfs.
Interferones work on the immunesystem, so this would be the second guess right after the viral aspect.
There might be a third one in such a subgroup.
The viral theory doesn´t seem to hold much water already empirical (review: Rasa et al 2018).

I remain sceptical on a theory of normal infections as causative agents for crucial PEM,
sometimes regularly delayed, wide ranged in symptoms and obviously (as far as I can see) not adressable to one specific agent, and exaggerated that one may not be able to follow one´s doings, see Pacing which hardly can be a possibility for dealing with other illnesses.

I completly agree though that the triggers are important to know in their properties.


I don´t want to disagree with the theory that altered immunesystems are part of the illness.
The problem I see nevertheless (not to mention that it´s difficult enough to conclusive investigate its parts)
that it will not tell us about PEM.
I would agree that the immunesystem can be the first organ that had got an impact,
but this is in terms of etiology by no means necessary.

It would be nice of course if one could read in the immunesystem what might go on,
and how to influence the illness.


If I have understood rightly, there are 517 of the most often SNP´s especially found in mecfs patients,
Perez et al, accepted Mai 3.2019 . I guess it will be difficult to interprete. However, all best luck, @Manuel.
 

Hip

Senior Member
Messages
13,040
Likes
24,167
It could be a consequence of the infection not the infection itself.

This consequence might build up a subgroup of mecfs.
Interferones work on the immunesystem, so this would be the second guess right after the viral aspect.
Logically you are right, it could be that those with enterovirus ME/CFS have a particular immune dysfunction triggered by the virus, and the interferon therapy addresses that dysfunction rather than the virus itself.

But Occam's razor would tend to suggest a simpler explanation: that interferon therapy just directly fights the virus.
 

percyval577

basal and ganglia
Messages
814
Likes
1,091
Location
Ik waak up
But Occam's razor would tend to suggest a simpler explanation: that interferon therapy just directly fights the virus.
Yes, and often the razor is applied soon and succesfully, including in cases where not too much is known.

But here the first guess doesn´t seem to prevail.
Otherwise - assuming that doctors and science are not as stupid as they are sometimes indeed -
a therapy for such a simple subgroup would have already been established.
I admit that I don´t know anything about these improvements, but it doesn´t look to me more than a try.
Why should a virus be eleminated by one helped immunesystem but not by the other helped one?

Why then would the virus cause - or trigger - not in all cases mecfs?
Why then are there other subgroups with still the same collection of symptoms?


If the first guess doesn´t prevail, and the question doesn´t look to be able to get answered
by the first approach, it might be the second one.
Now the question is not about the virus, but about the different immunesystems.
Why could the one enterovirus triggered immunesystem be influenced,
and the other influenced one not?

And then there are other immunesystems with other illnesses
which obviously can be influenced also, sometimes.
Plausibility may be a question of statstic, if you so want,
but this may be true even for true perceptions vs dreamed perceptions. However,
open questions don´t ask for getting cut off by Occam´s razor.


... if even this second guess would turn out to lead to inconclusive answeres or outcomes resp.,
a third guess would be needed.
 
Last edited:

Hip

Senior Member
Messages
13,040
Likes
24,167
Otherwise - assuming that doctors and science are not as stupid as they are sometimes indeed -
a therapy for such a simple subgroup would have already been established.
Although ME/CFS can put patients into near remission for several months, ME/CFS eventually returns. So in order to keep in remission, you would have to keep taking interferon. But interferon therapy cannot be given long-term, because after a some time the body develops autoantibodies to the recombinant interferon, disabling this drug.

There is a workaround though: if you take interferon by suppository, then it does not cause autoantibodies, so interferon suppositories may be able to place some enterovirus ME/CFS patients into long-term near remission. But no ME/CFS doctor has tried interferon suppositories to my knowledge. I know one forum member with coxsackievirus B who is currently trying interferon suppositories.

You can read about interferon therapy for ME/CFS here.



Why then would the virus cause - or trigger - not in all cases mecfs?
Why does coxsackievirus B only cause myocarditis in a small percentage of people who catch this virus?

Why does poliovirus only cause poliomyelitis in about 1% of people who catch it?

Because that's how viruses often behave: it's quite normal for a virus to cause a disease in one person, but no disease (or a different disease) in the next person.


In the case of ME/CFS, there is some evidence that having a weak immune system at the time of catching the virus may facilitate the triggering of ME/CFS.
 

percyval577

basal and ganglia
Messages
814
Likes
1,091
Location
Ik waak up
Why does coxsackievirus B only cause myocarditis in a small percentage of people who catch this virus?
Why does poliovirus only cause poliomyelitis in about 1% of people who catch it?
Because that's how viruses often behave: it's quite normal for a virus to cause a disease in one person, but no disease (or a different disease) in the next person.
Yes, right, I buy it. Thanks for telling it.
But often EBV eg is not active anymore, it´s completly normal. So, right, the question will be restricted to the trigger event, but here all stays unanswered, and then it´s not all too convincing that the non-triggering cases (ongoing infections) set the standard for mecfs, especially when also chemicals appear to be triggers.
Furthermore, even if some virusses contribute in an ongoing manner to the disease, the appearance of pem does look too autonomous, at least to me, it´s too selfdeterminating, to try a description.

In the case of ME/CFS, there is some evidence that having a weak immune system at the time of catching the virus may facilitate the triggering of ME/CFS.
Might well be true, despite genetical predisposition, nevertheless it doesn´t say that a virus now would act as a notorious infection instead of a trigger, so this amount of evidence doesn´t change anything.
E.g. my second trigger made me ill for one year, and only when the titers became normal, my ongoing symptoms appeared, one after another.

(I had a first trigger 25 years earlier, here I too don´t think that this ever has been important enough as a normal combated infection, too slow in dividing, and much too less bacteria, very few and single ones, (borrelia).)