Autoimmunity to synovial extracellular matrix proteins in patients with postinfectious Lyme arthritis, 2023, Korawit Kanjana et al

[Mij]

BACKGROUND. Autoimmune diseases often have strong genetic associations with specific HLA-DR alleles. The synovial lesion in chronic inflammatory forms of arthritis shows marked upregulation of HLA-DR molecules, including in postinfectious Lyme arthritis (LA). However, the identity of HLA-DR–presented peptides, and therefore the reasons for these associations, has frequently remained elusive.

METHODS. Using immunopeptidomics to detect HLA-DR–presented peptides from synovial tissue, we identified T cell epitopes from 3 extracellular matrix (ECM) proteins in patients with postinfectious LA, identified potential Borreliella burgdorferi–mimic (Bb-mimic) epitopes, and characterized T and B cell responses to these peptides or proteins.

RESULTS. Of 24 postinfectious LA patients, 58% had CD4+ T cell responses to at least 1 epitope of 3 ECM proteins, fibronectin-1, laminin B2, and/or collagen Vα1, and 17% of 52 such patients had antibody responses to at least 1 of these proteins. Patients with autoreactive T cell responses had significantly increased frequencies of HLA-DRB1*04 or -DRB1*1501 alleles and more prolonged arthritis. When tetramer reagents were loaded with ECM or corresponding Bb-mimic peptides, binding was only with the autoreactive T cells. A high percentage of ECM-autoreactive CD4+ T cells in synovial fluid were T-bet–expressing Th1 cells, a small percentage were RoRγt-expressing Th17 cells, and a minimal percentage were FoxP3-expressing Tregs.

CONCLUSION. Autoreactive, proinflammatory CD4+ T cells and autoantibodies develop to ECM proteins in a subgroup of postinfectious LA patients who have specific HLA-DR alleles. Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity.

https://www.jci.org/articles/view/161170

 

[duncan]

Author lists reads like a Who's Who at the IDSA Lyme school. Makes sense it would since they're revisiting the arthritis white whale.

Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity.

They can propose all they like. Wish they'd move away from the arthritis obsession, though. That it's - by some - felt to be a forced fit perhaps attributed to a single strain, or even a restricted symptom pool, clearly does not seem to matter. How about some neuroborreliosis instead?

 

[Ash]

BACKGROUND. Autoimmune diseases often have strong genetic associations with specific HLA-DR alleles. The synovial lesion in chronic inflammatory forms of arthritis shows marked upregulation of HLA-DR molecules, including in postinfectious Lyme arthritis (LA). However, the identity of HLA-DR–presented peptides, and therefore the reasons for these associations, has frequently remained elusive.

METHODS. Using immunopeptidomics to detect HLA-DR–presented peptides from synovial tissue, we identified T cell epitopes from 3 extracellular matrix (ECM) proteins in patients with postinfectious LA, identified potential Borreliella burgdorferi–mimic (Bb-mimic) epitopes, and characterized T and B cell responses to these peptides or proteins.

RESULTS. Of 24 postinfectious LA patients, 58% had CD4+ T cell responses to at least 1 epitope of 3 ECM proteins, fibronectin-1, laminin B2, and/or collagen Vα1, and 17% of 52 such patients had antibody responses to at least 1 of these proteins. Patients with autoreactive T cell responses had significantly increased frequencies of HLA-DRB1*04 or -DRB1*1501 alleles and more prolonged arthritis. When tetramer reagents were loaded with ECM or corresponding Bb-mimic peptides, binding was only with the autoreactive T cells. A high percentage of ECM-autoreactive CD4+ T cells in synovial fluid were T-bet–expressing Th1 cells, a small percentage were RoRγt-expressing Th17 cells, and a minimal percentage were FoxP3-expressing Tregs.

CONCLUSION. Autoreactive, proinflammatory CD4+ T cells and autoantibodies develop to ECM proteins in a subgroup of postinfectious LA patients who have specific HLA-DR alleles. Rather than the traditional molecular mimicry model, we propose that epitope spreading provides the best explanation for this example of infection-induced autoimmunity.

https://www.jci.org/articles/view/161170

I am looking forward to when someone has the free time and energy, to contextualise and explaining this in the simplest of terms down here.

@duncan does Lyme not cause arthritis then?

 

[duncan]

@Ash , yes it can and has.

But that's a loaded topic on many levels. One of those is that Bb has been sometimes, albeit rarely, found in synovial fluid after treatment (rarely cultured even without treatment). Even when it's not cultured, many suspect Bb persisters are behind treatment-resistant arthritis.

Steere and Co have for years been trying to explain intractable Lyme arthritis while insisting no viable Bb spirochetes are at play.

That doesn't even touch on how common Lyme arthritis is relative to other disabling sequelae, which is another matter altogether. One thing to be said about arthritis, though, is that's it's overt; it cannot be so easily dismissed as subjective.

Perhaps assigning an EIS infectious disease person instead of a rheumatologst 60 or so years back would have yielded a different focus?

ETA: er, 50 years, not 60.

 

[Ash]

@Ash , yes it can and has.

But that's a loaded topic on many levels. One of those is that Bb has been sometimes, albeit rarely, found in synovial fluid after treatment (rarely cultured even without treatment). Even when it's not cultured, many suspect Bb persisters are behind treatment-resistant arthritis.

Steere and Co have for years been trying to explain intractable Lyme arthritis while insisting no viable Bb spirochetes are at play.

That doesn't even touch on how common Lyme arthritis is relative to other disabling sequelae, which is another matter altogether. But the thing about arthritis is that's it's overt.

Perhaps assigning an EIS infectious disease person instead of a rheumatologst 60 or so years back would have yielded a different focus?

Oh thanks @duncan!
You shook me. I thought you were saying the opposite.

I’m particularly invested in this because I may have it, and as discussed elsewhere on Lyme&Co my chances of getting this investigated or confirmed are close to nil.

 

[duncan]

I’m particularly invested in this because I may have it, and as discussed elsewhere on Lyme&Co my chances of getting this investigated or confirmed are close to nil.

I don't recall what UK is using these days. It used to be the C6. That's arguably worth a shot if you're covered for it.

The US also used to use the C6. It was being positiioned to replace the 2T I think. But that didn't happen. Now there are the MTTT's, of which I think there are 4 different versions, over and beyond the ELISA & Western Blot.

 

[Ash]

I don't recall what UK is using these days. It used to be the C6. That's arguably worth a shot if you're covered for it.

The US also used to use the C6. It was being positiioned to replace the 2T I think. But that didn't happen. Now there are the MTTT's, of which I think there are 4 different versions, over and beyond the ELISA & Western Blot.

Thanks @duncan.
I will try again with this!

 

[Jonathan Edwards]

I am looking forward to when someone has the free time and energy, to contextualise and explaining this in the simplest of terms down here.

It reads like a Chatbot that has skimmed through some memes from the 1980s. As the person who first demonstrated the presence of HLA-DR expression on synovial cells in 1979 I think I can reasonably say that this is almost certainly complete drivel.

It is a bit like recommending cod liver oil for arthritis to assist lubrication - it does not even begin to make sense (cod liver oil is for vitamin D, not door hinges).

 

[Ash]

It reads like a Chatbot that has skimmed through some memes from the 1980s. As the person who first demonstrated the presence of HLA-DR expression on synovial cells in 1979 I think I can reasonably say that this is almost certainly complete drivel.

It is a bit like recommending cod liver oil for arthritis to assist lubrication - it does not even begin to make sense (cod liver oil is for vitamin D, not door hinges).

Oh thank you.

I was feeling truly overwhelmed at how difficult I was finding this to understand. I feel better now.