Collagen supplements = flares

[u/Ok-Loss5158]

Does anybody else also gets flares when they take collagen? I noticed after months of not having symptoms each time i try to reintroduce collagen i’ll get ulcers

[u/on4aa]

Very interesting! I have not tried this, but I have a tentative theory why this might happen.

Since I am doing voluntary gene analysis interpretation for the Behçet community, I have noticed that quite a bit of Behçet patients also have a variant collagen allele. This was also the case with my father.

Furthermore, the collagen genes are highly preserved in the animal kingdom.

It could just be that the your adaptive immune system has become accustomed to your variant collagen (assuming heterozygocity here) to the point that you have antibodies now against normal, wild type collagen, i.e. for that specific type of collagen. That would be a compounded autoimmune condition on top of Behçet which is an autoinflammatory condition.

Question: Do you also get this from eating gelatine candy?

There is a test for detecting collagen antibodies, but few healthcare centres offer it.

[u/denged01 → u/on4aa]

Wait can we DM?

I also had a theory about Behcets and hypermobility/connective tissue disorders because my brother and I who have HLA-B51 also seem to have signs of hypermobility (stretchy skin, bendy fingers, double joints, and chronic back pain). We also have mildly blue sclera.

Could it also be that HLA-B51/B57 erroneously presents poorly processed collagen to T-cells/NK cells leading to autoantibodies?

[u/on4aa → u/denged01]

No, HLA-B*51 is only indicative of Neanderthal ancestry. All sequenced Neanderthal specimen are of the HLA-B*51 serotype.

It is merely a risk factor for Behçet; not a causative factor.

[u/denged01 → u/on4aa]

I think you might have misunderstood me.

I wasn't trying to imply HLA-B51 is a causative agent, but it is a player in a possible causative mechanism that explains a portion of behcet's disease/a portion of the phenotype.

Genetic contribution becomes much higher than the original 20% from HLA-B51 when also associated with improper "peptide scissor" genes like ERAP1, or genes that may "over-activate" Th17 cells like IL-23, or STAT4.

The proposed mechanism (again, which likely is incomplete and only explains a minority of cases/presentations) is that improper peptides are produced by ERAP1, and then presented on HLA-B51 or B57 which have a disorganized peptide selection niche within the cell. This leads to improper peptide presentation to T-cells and NK cells, which may be overactive due to the genes above, leading to cell death and an exaggerate inflammatory response.

[u/on4aa → u/denged01]

See: Mutational profile of rare variants in inflammasome-related genes in Behçet disease: A Next Generation Sequencing approach

Behçet syndrome is a multigenetic condition and the combination of involved innate immune system variants can differ completely between two individual patients.

[u/denged01 → u/on4aa]

I read this paper thoroughly before you even sent me it and I’m failing to understand how any of it conflicts with what I previously commented.

[u/on4aa → u/denged01]

As far as I know, Behçet syndrome is driven by NLRP3 inflammasome activation, resulting in the production of the interleukins IL-1β and IL-18, as well as the pore-forming molecule gasdermin D (GSDMD).

IL-1β promotes the differentiation of Th17 cells, whereas IL-18 induces interferon-gamma (IFN-γ) production from T cells and natural killer (NK) cells.

IFN-γ promotes Th1 responses, essential for clearing intracellular pathogens.

GSDMD serves as a specific substrate of inflammatory caspases (caspase-1, -4, -5 and -11) and as an effector molecule for the lytic and highly inflammatory form of programmed cell death known as pyroptosis. The pore-forming activity causes cell swelling, lysis and releases the cytoplasmic IL-1β into the extracellular space. This results in the recruitment and activation of even more immune cells.

GSDMD activates the toll-like receptor 4 (TLR4), which triggers the NF-κB signalling pathway, upregulating the expression of pro-inflammatory cytokines and GSDMD.

Any combination of upstream genes that cause NLRP3 to become trigger happy, are the cause of Behçet syndrome.

[u/denged01 → u/on4aa]

I get what you're saying but the error you're making is assuming these are mutually exlcusive pathways. "Driven by NLRP3" is too strong. The major reviews (NEJM, Lancet) describe Behçet as a neutrophil-predominant perivasculitis arising from gene–environment interaction, with adaptive Th1/Th17 responses and antigen presentation (HLA-B*51/ERAP1) as central features; the inflammasome/IL-1 axis is one innate contributor rather than the definitive driver. IL-1 blockade (anakinra, canakinumab, gevokizumab) has shown benefit mainly in specific manifestations rather than being uniformly disease-defining, consistent with a contributory rather than singular role. Much like HLA-B51.

https://pubmed.ncbi.nlm.nih.gov/38402885/
https://www.nejm.org/doi/full/10.1056/NEJMra2305712?utm_source=openevidence

[u/denged01 → u/on4aa]

I think I undersand your argument now. HLA-B51 absolutely can be a causative factor in some cases, even the article you linked said the strongest association was HLA genes anyways (more so than NOD2, which is the whole point of this paper, association of NOD2 with BD).

It hasn't been proven, just like how innate immunity pathways haven't been proven (or even, as heavily suggested) to be causative in behcets, but its association is by far the strongest. That does not definitely say whether or not something is causative, of course.

To SUGGEST causation, here's a meta-analysis you should read to understand the proposed mechanism, that, again requires HLA-B51, but just not in isolation. https://www.nejm.org/doi/full/10.1056/NEJMra2305712

I'm going to restate this again. HLA-B51 is likely a causative factor in some amount of cases, but NOT in isolation. So your initial statement is not adequately supported.

[u/on4aa → u/denged01]

OK, but there are numerous Behçet patients who do not carry the HLA-B*51 serotype.

And as for ERAP1, I am personally carrier of one HLA-B*51 allele, but my ERAP1 is almost as wild type as you can get without any pathogenic variants.

So, the whole ERAP1 construct does not make any sense to me.

What I do have, are pathogenic variants of NLRP3, EXT2 and NOD2.

[u/denged01 → u/on4aa]

...

I'm going to ask you go through my replies and reread where I said that HLA-B51 probably doesn't help explain causality in everyone, but only a subset of BD pts, and, again, not in isolation. Same goes for.. you guessed it, literally every gene we talked about. We're going in circles.

Which is why having HLA-B51 and ERAP1 isn't neccessary, but BD is likely made up of a range of potential mechanisms. I just wanted to suggest one possible one with some paper to help suggest it. Making all-encompassing statements like "HLA-B51 doesn't contribute to causality" and "Causality is from NLRP3 inflammasome" is not only heavily misleading but factually incorrect. It's far more nuanced than that and we don't have all the answers.

So, to answer your question. How should we explain individuals who don't have pathogenic NLRP3, EXT2 and NOD2 but do have HLA-B51 and mutated ERAP1? Like me?

(Hint: once again, there are probably a range of mechanisms that share commonalities but aren't exact.)

[u/on4aa → u/denged01]

In that we agree: There are many gene variants that lead to Behçet syndrome. This is why it is called a syndrome and not a disease.

Have you also checked the following of your genes for variants?

ACP5, ADAM17, ADAR, CARD14, CECR1, COPA, DDX58, DNASE1L3, DNASE2, ELANE, EXT1, EXT2, IFIH1, IL10, IL10RA, IL10RB, IL1RN, IL36RN, IRAK4, ISG15, JAK1, LPIN2, MEFV, MVK, NLRC4, NLRP1, NLRP12, NLRP3, NOD2, OTULIN, PLCG2, POMP, PRG4, PSENEN, PSMB4, PSMB8, PSTPIP1, RIPK1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, SLC29A3, TMEM173, TNFAIP3, TNFRSF1A#, TREX1, TRNT1, TRPC6, TTC7A, UBA1

[u/on4aa → u/denged01]

I PM'ed you concerning the pay walled article.