CD4+ Cytotoxic T Cells Involved in the Development of EBV-Associated Diseases 2022

[pattismith]

Abstract​

Activated cytotoxic CD4 T cells (HLA-DR+) play an important role in the control of EBV infection, especially in cells with latency I (EBNA-1).

One of the evasion mechanisms of these latency cells is generated by gp42, which, via peripherally binding to the β1 domain of the β chain of MHC class II (HLA-DQ, -DR, and -DP) of the infected B lymphocyte, can block/alter the HLA class II/T-cell receptor (TCR) interaction, and confer an increased level of susceptibility towards the development of EBV-associated autoimmune diseases or cancer in genetically predisposed individuals (HLA-DRB1* and DQB1* alleles).

The main developments predisposing the factors of these diseases are: EBV infection; HLA class II risk alleles; sex; and tissue that is infiltrated with EBV-latent cells, forming ectopic lymphoid structures.

Therefore, there is a need to identify treatments for eliminating cells with EBV latency, because the current treatments (e.g., antivirals and rituximab) are ineffective.

the autoimmune diseases linked to EBV quoted:

SLE
MS
Celiac
Thyroiditis
Autoimmune diabetes
RA
Myasthenia gravis




https://www.mdpi.com/2076-0817/11/8/831

 

[heapsreal]

the autoimmune diseases linked to EBV quoted:

SLE
MS
Celiac
Thyroiditis
Autoimmune diabetes
RA
Myasthenia gravis




https://www.mdpi.com/2076-0817/11/8/831

The link wouldn't open for me, but was it more or less saying that diseases linked to ebv have a functional cd4 defiency?
ie like nk studies in cfs showing low nk function although nk numbers may be fine.

There was a study over 10yrs ago I think by Griffith university in Australia, who do the nk function studies also did a study and found many cfsers had a low cd8 t cell function, which is also important in herpes viruses like ebv. So not surprising to find low cd4 function in people with issues related to ebv.

It would be nice to get a lymphocyte subset function test along with a lymphocyte subset count. The next question is how to increase these different T cell subset functions??

 

[pattismith]

The link wouldn't open for me, but was it more or less saying that diseases linked to ebv have a functional cd4 defiency?
ie like nk studies in cfs showing low nk function although nk numbers may be fine.



There was a study over 10yrs ago I think by Griffith university in Australia, who do the nk function studies also did a study and found many cfsers had a low cd8 t cell function, which is also important in herpes viruses like ebv. So not surprising to find low cd4 function in people with issues related to ebv.

I think you understood it right

here the PDF
file:///C:/Users/vet-l/Downloads/pathogens-11-00831-v2.pdf
by Manuel Ruiz Pablos

Discussion:

Thus, EBNA-1-specific cytotoxic CD4 T lymphocytes appear to have a protective role in vivo, as deduced from their reduction/absence or altered function in the EBV-associated diseases discussed here, and in other diseases, such as post-transplant lymphoproliferative disease (PTLD) [269] and in EBV-related Hodgkin’s and non-Hodgkin’s lymphomas [15,75,270,271,272,273].

It may be that their “exhaustion” is caused by chronic exposure to viral antigens by participating in the immune response against the virus [214,274,275,276,277], or it may be an effect of the evasion mechanisms of B lymphocytes and macrophages that are infected by EBV [214,249,278,279]. In both cases, an immunodeficiency would develop that cannot control viral latency. However, this would not explain why a virus that is present in 90% of the population [280] does not affect all hosts equally, and is even innocuous in most cases. It is here that the possession of one of the “ancestral” HLA-II alleles, to which EBV has generated resistance, could favor the development of these diseases.

Pender posited that the defective control of EBV-latent cells in autoimmune diseases was only the fault of CD8 T cells, this being insufficient to explain the decreased cytotoxicity of T cells, as he also discusses [215]. He further posits that autoreactive B cells are directed to organs containing the target antigen, when these autoreactive B cells could be formed from EBV latency I B cells entering the damaged tissue in response to an inflammatory stimulus, forming ectopic lymphoid structures where antigens from that tissue could be presented as foreign antigens. It could also be due to the increase in non-professional antigen-presenting cells in that tissue via an increase in IFN-γ.

This model (Cytotoxic CD4 insufficiency) could even explain the involvement of EBV in the development of chronic fatigue syndrome or myalgic encephalomyelitis [214,278] and long COVID-19 [287]. Both diseases present similar EBV reactivations and chronic symptoms, which could suggest a common EBV immunopathology [278,287,288,289].

In the case of persistent COVID-19, the inflammation caused by the SARS-CoV2 infection of tissues would recruit B cells with EBV latency, where ectopic lymphoid aggregates could form and give rise to viral reactivations. Likewise, it could also help us to understand why the EBV-associated autoimmune diseases, long COVID-19, and chronic fatigue syndrome/myalgic encephalomyelitis are more common in women [290,291,292,293,294,295]. Estrogens, by increasing B-cell survival [66], would allow for a greater permanence of ectopic lymphoid aggregates with EBV latency in the inflamed tissues of patients with “ancestral” HLA-II alleles, and, therefore, a chronification of symptoms. In the case of autoimmunity, this would also favor humoral and cellular autoimmune responses [47,65,66].
Finally, it should be added that EBV-associated autoimmune diseases involve autoreactive cellular (Th1) and/or humoral (Th2) responses, but Th1 to Th2, or Th2 to Th1 polarization would be futile, as it could exacerbate the autoreactive humoral response or the autoreactive cellular response, respectively [169]. In other words, it would fail to cure the autoimmune disease.

My own comment:

Methotrexate has antiinflammatory and immunomodulatory properties, it is used in many auto-immune diseases and also in some leukemia, but increases some cancer risk.

According to recent studies showing Methotrexate is switching CD4 from cytotoxic CD4 to THelpers, There is something I don't understand in Manuel Ruiz Pablos theory, he should come and explain it to us!


https://forums.phoenixrising.me/thr...come-by-methotrexate-2023.90773/#post-2443364

 

[pattismith]

@Manuel , I understand that you are the author, are you?

Congratulation for publishing!

Maybe you can explain us if recent studies with methotrexate are matching with your theory?

 

[Sarahloudobby]

I’m reading this with interest I have a diagnosis of CFS dating back to 2002 but have a lot of symptoms of myasthenia gravis, and a blood test a few months back showed that I have had EBV but it wasn’t currently active. I have had an ultra sound in my neck as I have a permanently swollen lymph node, thankfully no malignancy but it is enlarged