Human Leukocyte Antigen alleles associated with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Fluge, Mella et al 2020

[SNT Gatchaman]

my thinking also stems from the idea that being hit "hard enough" by whatever trigger or combination of triggers leads to ME/CFS would fit with having a more severe infection.

I agree with Hutan. I think you can be hit hard pathophysiologically in a way that doesn't mandate initially severe symptoms, but sets up the descent into the ME/CFS phenotype. 4-5 years on I think I was hit pretty damn hard by COVID even if it was asymptomatic. It just took a few months before I even noticed.

This would be similar to HIV -> AIDS where the initial infection/transmission event is symptomatically trivial (even while CD4 Ts are acutely lost) and some years might go by before the ongoing CD4+ T cell depletion leads to the AIDS-defining symptomatic opportunistic infections and malignancies.

 

[Jonathan Edwards]

I agree that there is quite likely to be an HLA genetic association if we simply assume that an immune mechanism is involved. HLA genes skew responses. But I think an HLA association with a particular virus may not be a good guide. We know that HLA affects susceptibility to specific microbes - we think that is why it is polymorphic. But the two may not be related much. (And I had very mild Covid and yet had LC.)

The paradigm here is post-infective arthritis - perhaps the best documented form of post-infective immune disease. It is linked to HLA-B27 across a wide range of organisms so presumably the B27 risk is not due to presenting any particular peptide. Yet B27 is protective against severity for a number of infections - it is the best way not to get AIDS for years. So the risk factor we know actually partitions severity and risk of post-infective illness. In most cases of post-infective arthritis the triggering infection is mild - often an asymptomatic STD with mild urethritis.

 

[rvallee]

I agree with Hutan. I think you can be hit hard pathophysiologically in a way that doesn't mandate initially severe symptoms, but sets up the descent into the ME/CFS phenotype. 4-5 years on I think I was hit pretty damn hard by COVID even if it was asymptomatic. It just took a few months before I even noticed.

This would be similar to HIV -> AIDS where the initial infection/transmission event is symptomatically trivial (even while CD4 Ts are acutely lost) and some years might go by before the ongoing CD4+ T cell depletion leads to the AIDS-defining symptomatic opportunistic infections and malignancies.

Also probably similar in MS. I don't think any good research has been done trying to assess whether the severity of mono is of any relevance, but it appears to be more about an unfortunate sequence of steps where some virions get in the 'right' places where the 'right' conditions allow them to initiate the disease process.

Logically, most likely being locality and proximity to axons. Maybe it's further upstream, about simply getting into some nerve pathways. But it all mostly appears to be chance, unlike AIDS where it's an inevitable final outcome.

 

[DMissa]

Thank you all for your insights, tailoring my ideas accordingly

 

[Hutan]

HLA-C0704 associated with Behçet's disease:
Genetics in Behcet’s Disease: An Update Review
Gao et a1,2022
https://www.frontiersin.org/journals/ophthalmology/articles/10.3389/fopht.2022.916887/full

“Recently, we discovered HLA-C0704 to be associated with BD in a GWAS study involving a Chinese Han population, including eight independent SNPs at the genome-wide level (52).”

“Behcet’s disease (BD) is one of the most vision-threatening entities of uveitis. BD patients account for 16.5% of the total uveitis patients according to a Chinese study (1). BD is an autoinflammatory disorder that affects multiple systems, characterized by intraocular inflammation, arthritis, oral and genital ulcers and skin damages (2). While young adults aged 20-40 years are the commonest age group affected by BD, it still can be seen in children and older patients (3). Young male patients are reported to be affected more frequently and more severely than female patients (4).”

Edit - here's the actual study:
Identification of Novel Risk Loci for Behçet's Disease-Related Uveitis in a Chinese Population in a Genome-Wide Association Study, 2022

We conducted a 2-stage study, consisting of a genome-wide association study (GWAS) stage and a replication stage, in a Chinese population. The GWAS stage included 978 cases with BD-related uveitis and 4,388 controls, and the replication stage included 953 cases with BD-related uveitis and 2,129 controls.

Sounds decent

 

[Hutan]

Another reminder that the Norwegians did a follow up study, reported here:
Fine mapping of the major histocompatibility complex (MHC) in (ME/CFS) suggests involvement of both HLA class I and class II loci, 2021, Hajdarevic

I'm not clear yet on whether they replicated the HLA-C07:04 result.