Human leukocyte antigen associations in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and immune modulating treatment, 2021, Lande

Dolphin

Dolphin

Senior Member (Voting Rights)
PhD thesis

https://www.duo.uio.no/bitstream/handle/10852/86195/1/PhD-Lande-2021.pdf
https://www.duo.uio.no/bitstream/handle/10852/86195/PhD-Lande-2021.pdf

Summary

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a serious and complex disease characterized by medically unexplained chronic fatigue, post-exertional malaise and a variety of additional symptoms. The etiology is unknown, and many different disease mechanisms have been proposed. Several immunologic changes have been reported among patients in different studies. A central hypothesis is that autoimmunity is involved in the pathogenesis of ME/CFS.

Autoimmune diseases (AID) are complex diseases with large variation in symptoms and severity. Genetic associations with the immunologically important human leukocyte antigen (HLA) genes are hallmarks of AID, typically manifested by a higher prevalence of specific HLA risk alleles among patients.

The main aim of this thesis was to evaluate the hypothesis that autoimmunity is involved in ME/CFS pathogenesis. First, we wanted to conduct a large and high resolution genetic HLA association study in ME/CFS. Next, we wanted to assess safety and potential effect of the immunosuppressive agent cyclophosphamide in a smaller group of ME/CFS patients. Finally, we wanted to see whether potential HLA risk alleles were associated with questionnaire-based clinical information or therapeutic effect.

We identified two novel HLA associations for adult, Norwegian ME/CFS patients, represented by a significantly higher prevalence of the alleles HLA-C*07:04 and HLA-DQB1*03:03 among 426 patients than among 4511 healthy controls. 22 out of 40 patients reported substantial clinical improvement after receiving cyclophosphamide, but the results must be cautiously interpreted since there was no control group. The HLA risk alleles were further significantly associated with comorbid autoimmunity among patients, and with clinical improvement after cyclophosphamide treatment.

Our results are in favor of immunological involvement in ME/CFS pathogenesis, possibly in a subgroup of patients, but the results need to be reproduced in additional studies before they can be regarded as established.
 
It begins very good:

Preface

During this doctoral degree I have read a lot about ME/CFS, and I would like to emphasize a few points that I have reflected upon. The first is the striking severity of the disease. Stories from patients and relatives have made me understand how much ME/CFS really impairs the quality of life. Especially, meeting housebound and bedridden patients, in some cases unable to speak or move, has made an unforgettable impression. The second is the tense climate that has characterized the debate about ME/CFS, in Norway as well as internationally. Everybody seems to have an opinion about this disease, and despite the lack of knowledge, some voices have seemingly drawn their conclusions nevertheless. There is no scientific consensus on the causes of ME/CFS, nor has effective treatment been established. It is therefore very important that researchers are curious about different hypotheses, and that research investigate this disease widely, from all angles. This certainly includes a thorough biomedical approach, and many of the patients and relatives I have met express their gratitude for such research being conducted. At the same time, it is my experience that patients and their caregivers are fully aware of the complexity of ME/CFS. A complex puzzle can only be understood bit by bit, and I am humbly aware that the papers in this thesis provide only a small contribution to the sum of knowledge that needs to be accumulated. Still, I am proud to participate in research on ME/CFS, a serious disease that affects a large group of patients and urgently needs to be better understood.
 
So having had to google it, FYI cyclophosphamide is apparently a T(reg) suppressor.


The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy
https://pubmed.ncbi.nlm.nih.gov/27646791/
Besides antimitotic and antireplicative effects, cyclophosphamide has immunosuppressive as well as immunomodulatory properties. Cyclophosphamide shows selectivity for T cells and is therefore now frequently used in tumour vaccination protocols and to control post-transplant allo-reactivity in haplo-identical unmanipulated bone marrow after transplantation. The schedule of administration is of special importance for the immunological effect: while cyclophosphamide can be used in high-dose therapy for the complete eradication of haematopoietic cells, lower doses of cyclophosphamide are relatively selective for T cells. Of special interest is the fact that a single administration of low-dose cyclophosphamide is able to selectively suppress regulatory T cells (Tregs). This effect can be used to counteract immunosuppression in cancer.
Click to expand...


PS I guess this will be of interest to Sepúlveda, Carneiro, Lacerda and Nacul.

https://www.s4me.info/threads/me-cf...nfections-2019-nacul-et-al.12025/#post-213196
 
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