Review Antigen-driven T cell responses in rheumatic diseases: insights from T cell receptor repertoire studies, 2025, Garrido-Mesa et al.

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tralfamadorian97

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Title: Antigen-driven T cell responses in rheumatic diseases: insights from T cell receptor repertoire studies
Journal: Nature Reviews Rheumatology
Authors: Jose Garrido-Mesa & Matthew A. Brown
Affiliation: Department of Medical and Molecular Genetics, Faculty of Life Sciences and Medicine, King’s College London, London, UK
Link: https://www.nature.com/articles/s41584-025-01218-9

Abstract:

Advances in T cell receptor (TCR) profiling techniques have substantially improved our ability to investigate T cell responses to antigens that are presented on HLA class I and class II molecules and associations between autoimmune T cells and rheumatic diseases. Early-stage studies in axial spondyloarthritis (axSpA) identified disease-associated T cell clonotypes, benefiting from the relative genetic homogeneity of the disease. However, both the genetic and the T cell immunological landscape are more complex in other rheumatic diseases. The diversity or redundancy in the TCR repertoire, epitope spreading over disease duration, genetic heterogeneity of HLA genes or other loci, and the diversity of epitopes contributing to disease pathogenesis and persistent inflammation are all likely to contribute to this complexity. TCR profiling holds promise for identifying key antigenic drivers and phenotypic T cell states that sustain autoimmunity in rheumatic diseases. Here, we review key findings from TCR repertoire studies in axSpA and other chronic inflammatory rheumatic diseases including psoriatic arthritis, rheumatoid arthritis, systemic lupus erythematosus and Sjögren syndrome. We explore how TCR profiling technologies, if applied to better controlled studies focused on early disease stages and genetically homogeneous subsets, can facilitate disease monitoring and the development of therapeutics targeting autoimmune T cells, their cognate antigens, or their underlying biology.
 
My Thoughts:

This paper is not directly relevant to ME/CFS. Nevertheless, it seemed to me to be an interesting methodological discussion of a powerful immunological technique that might eventually become relevant to ME/CFS.

This paper is about a technique called T-cell receptor repertoire profiling. In a nutshell, T-cell repertoire profiling takes a census of a key aspect of a person's immune system. The paper includes a technical survey of this technique.

The following contrast is central to the paper:
- T cell receptor repertoire profiling applied to axial spondyloarthritis has produced fairly clear, replicated findings. These findings suggest insights into the pathobiological process driving the disease. These insights hint at therapeutic approaches. See https://www.s4me.info/threads/targe...losing-spondylitis-2023-chudakov-et-al.37165/ for example.
-T cell repertoire profiling applied to many other rheumatological diseases has produced less clear results. Moreover, these results often fail replication.

One explanation for the above contrast is that many of the other rheumatological diseases considered are driven by B cells, not T cells. The authors acknowledge this, but note that there is still evidence for an important role of T cells in many of these other disease, and so you would still expect to detect some T cell signature of these diseases.


The authors note that T cell receptor repertoire profiling studies of axial spondyloarthritis benefit from the high genetic homogeneity of the disease: the HLA-B27 allele is highly prevalent. Given that HLA alleles strongly shape a person's T-cell repertoire, repertoire studies of rheumatological diseases that are less genetically homogenous than AS need to control for HLA genetics. The authors note that few studies so far have instituted appropriate controls. This could explain the disappointing findings for non-axial spondyloarthritis diseases.

The authors also discuss the phenomenon of epitope spreading, whereby the longer a patient has an auto-immune disease, the more diverse and complex their auto-immunity becomes. Thus, if you want insights into the etiology of a disease, you will get a stronger signal by focusing on patients who have had the disease for a relatively short time

Overall I was interested by this paper's methodological suggestions. I will be interested to see the results if these suggestions are applied to future T cell profiling studies. I also wonder about the potential of applying them to ME/CFS.
 
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tralfamadorian97 said:
One explanation for the above contrast is that many of the other rheumatological diseases considered are driven by B cells, not T cells. The authors acknowledge this, but note that there is still evidence for an important role of T cells in many of these other disease, and so you would still expect to detect some T cell signature of these diseases.
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So they haven't understood what Jo Cambridge and I said in 1999 - which is par for the course.
People have been looking for clones of 'autoreactive T cells' in rheumatic disease since I described the presence of MHC Class II on synovial intimal macrophages in 1980 (misrepresented as evidence of a T cell drive by Janossy and Panayi). Nobody has found them. Better techniques might find them but a much simpler explanation is that they are not there and there is a lot of evidence indicating that they are not (you just invoke bystander help). At least the focus in rheumatology now is on using better anti-B cell therapies.

Finding clonality in ankylosing spondylitis would be much more interesting but I have not heard anything about them being autoreactive clones. It may be difficult to interpret findings though if factors like B27 and cytokine receptor expression skew the whole T cell reading frame. Shifts in clonality may occur across populations that aren't actually involved in the pathology. But it would be nice to see some data. Pity there is nothing in the abstract - which makes me think there is nothing very remarkable out there.
 
tralfamadorian97 said:
Here's an interesting diagram (which I don't fully understand) describing factors purported to influence T cell repertoire in various rheumatological diseases.
Click to expand...
It all looks pretty non-specific stuff we have had around for a long time. Much of it is easily enough explained by general effects as alluded to above or for RA what happens when tissue pathology sets up and clonality inevitably gets altered by localisation.
 
Actually, I realise I know the senior author Matt Brown from twenty five years ago. He is very sharp and he did understand what Jo and I were saying - and I guess they admit that. His great skill was always in the spondarthropathy area. Maybe they have found something crucial and the abstract undersells it badly. I better read the paper. It really is about time someone worked out why B27 is so different.
 
I actually did a TCR repertoire study for Long COVID which won’t get published because we found absolutely nothing of interest. It was a small study, granted, so it was probably underpowered, but there was not even evidence of any differential frequencies of clones regardless of the specific clone between healthy and LC.

I recall some presentations in my old rheumatology division where people had found actually convincing evidence of clonal T cell expansion correlating strongly with outcome in an autoimmune disease or two (maybe it was scleroderma, I can’t really recall). In either case, the diseases where there was any signal at all in clonal expansion data had vastly different clinical characteristics from ME/CFS.
 
jnmaciuch said:
I recall some presentations in my old rheumatology division where people had found actually convincing evidence of clonal T cell expansion correlating strongly with outcome in an autoimmune disease or two (maybe it was scleroderma, I can’t really recall).
Click to expand...

There are certainly some very odd B and T cell dynamics in Sjogren's (sometimes with lymphoma) and in Felty's (large granular lymphocyte pseudoleukaemia) where weird secondary effects occur. The nicest study I remember was of identical twins, one of whom had scerloderma and the other not. No differences in T cell responses could be found. In pretty much all the autoimmune rheumatic diseases searches for altered T cell responses to the B cell antigen are conspicuously negative.
 
I read through some of the paper. I find it disappointing. They are still talking of molecular mimicry like Ebringer did in 1980. There is nothing new to say about why B27 is so different for lots of antigens and maybe for no antigen at all if its trick relates to KIR binding.
 
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