TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis, 2018, Conrad et al.

[jnmaciuch]

TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis​

Although anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2–5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity.

Link (open access)

 

[jnmaciuch]

I hope others don't mind me posting papers as a way to collect things that caught my interest and potentially spark discussion on them. I've recently been interested in the capability of type I interferons to induce symptoms without the involvement of T cells.

Psoriasis might be relevant given potential genetic associations with HLA-C from Zhang et al. HLA-C is one of the most frequent sites of mutation in psoriasis, though interestingly I don't think I've ever heard mention of skin issues in ME/CFS.

 

[jnmaciuch]

Explain like I'm brain foggy:

Skin pathology in psoriasis is commonly associated with T-cell infiltration and T-cell mediated tissue damage. This paper explores cases of psoriasis induced by a TNF blocker (such as humira/adalimumab used for treatment of many immune diseases, including psoriasis itself).

Since TNF blockers induce cell death in T cells (among others), this is a case of "paradoxical" psoriasis where damage must be mediated by another cell type. The findings show that type I interferon production by plasmacytoid dendritic cells, an innate immune cell type, are sufficient to create psoriasis-like pathology in certain individuals.

 

[Jonathan Edwards]

It is highly relevant. Keep the papers coming. I agree that this sort of 'paradoxical' signal effect could well be a clue to the MECFS situation.

I had patients with minimal psoriasis plus arthritis who got gross palmar keratosis on Humira. I hate the old 'cytokine balance' idea but these paradoxical kick backs are very real and may be telling us something crucial

 

[hotblack]

I and I’m sure others really appreciate the ELIABFs too!

 

[V.R.T.]

interestingly I don't think I've ever heard mention of skin issues in ME/CFS.

I don't have psoriasis but my Dad and sister both do!

 

[jnmaciuch]

I and I’m sure others really appreciate the ELIABFs too!

I’m glad I’ll keep them coming when I remember to do it. Feel free to prompt me if you see me on other threads—my program administrators told us that we ought to be Practicing Effective Science Communication™ every chance we get.

 

[jnmaciuch]

I don't have psoriasis but my Dad and sister both do!

That’s interesting! Have any of you ever done a genetic screen?

 

[Jonathan Edwards]

Psoriasis might be relevant given potential genetic associations with HLA-C from Zhang et al. HLA-C is one of the most frequent sites of mutation in psoriasis, though interestingly I don't think I've ever heard mention of skin issues in ME/CFS.

I suspect that HLA-C is taking us on a merry dance. But there is method in this madness.

 

[V.R.T.]

That’s interesting! Have any of you ever done a genetic screen?

Not that I'm aware! Do you mean a general one or one specific to psoriasis?

 

[jnmaciuch]

Do you mean a general one or one specific to psoriasis?

Either! I’m not sure how limited a psoriasis-specific screen might be, though I think there is room for many of the most commonly mutated pathways in psoriasis to also be relevant in ME/CFS (besides HLA-C).

Just figured I’d ask on the off chance someone in your family had already had it done for one reason or another. It’s not always informative but can sometimes be an interesting tidbit.

 

[V.R.T.]

Either! I’m not sure how limited a psoriasis-specific screen might be, though I think there is room for many of the most commonly mutated pathways in psoriasis to also be relevant in ME/CFS (besides HLA-C).

Just figured I’d ask on the off chance someone in your family had already had it done for one reason or another. It’s not always informative but can sometimes be an interesting tidbit.

I can certainly ask my Dad whether he's done one tomorrow.

 

[jnmaciuch]

I can certainly ask my Dad whether he's done one tomorrow.

Only if you’re so inclined, certainly not important! I’m just always interested by cases of families where a high proportion seem to end up afflicted with some chronic debilitating issue, but the specifics differ person to person (especially if there happens to be some specific information about triggers for the various individuals)

 

[Kitty]

We have the HLA profile – or whatever it is that mediates susceptibility to psoriasis – but only one person in each generation seems to get it.

My mam and I were the, erm, lucky ones and I got the arthritis too (disabling because it wrecks your hands), but no one else.

So I suspect that either other triggers are required, or that penetrance is low. We also have genetic haemochromatosis, but even with two mutated copies of the gene people don't necessarily develop that.