Blogging my homework – how AxSpa biologics work – Part 1 of n
Original post:I’m trying to learn everything I can about my condition. It’s time to read scientific papers and look up the long words.
This is likely to be a long one with diagrams, and links, and subsections, and… I’m tagging it AxSpa on MBFA, which has Open Mention style open topics for a range of health subjects. This is getting federated, but I have no idea how easy to read it will be. If in doubt, click back to my blog to read it.
First things first – WTF is AxSpa?
Here’s the TL;DR: AxSpa (Axial Spondylosis) is when a bunch of related things go wrong, mostly with your immune system; it affects your back in very bad ways. Symptoms can sometimes get much worse for no reason – that’s called a flare or flare-up. I covered flares here.
AxSpA is a chronic, immune-mediated disease predominantly affecting the axial skeleton (sacroiliac joints and spine). The immune system does damage; the spine grows back in an unusual way. Spinal fusion can happen. It’s nasty.
Axial spondyloarthritis (axSpA), previously known as ankylosing spondylitis, is a type of arthritis that mainly affects the back, by causing inflammation in the spine. This can make your back, rib cage and neck stiff and painful.
In response to inflammation, the body produces extra calcium around the bones of the spine. This can make extra bits of bone grow and cause your back and neck to be more stiff.
This is sometimes referred to as ankylosing spondylitis.
Arithritis UK, Axial spondyloarthritis
Last year I spent two weeks on a physio course. It helped. More here.
What’s all this about biologics?
One way to arrest the progress of AxSpa is to interrupt the immune process that makes it happen. The most common tool for this is biologics – a range of drugs that block your immune system from harming you.
Biologics are pretty great. They have helped me a lot. (Aside from those administrative errors that interrupt the supply).
In the rest of this post, I am going to write down what I have learned about how biologics work.
Starting at the beginning.
I had not got the faintest clue where to start, so I asked ChatGPT to help me find some sources. It offered to draw me a diagram. I let it.
This is that diagram. By the end of this process, maybe I can tell you if it is any good.
IL-17 in the immunopathogenesis of spondyloarthritis
Deep breath now.
Spondyloarthritis (SpA) is a term that refers to a group of inflammatory diseases that includes psoriatic arthritis, axial SpA and nonradiographic axial SpA, reactive arthritis, enteropathic arthritis and undifferentiated SpA. The disease subtypes share clinical and immunological features, including joint inflammation (peripheral and axial skeleton); skin, gut and eye manifestations; and the absence of diagnostic autoantibodies (seronegative). The diseases also share genetic factors. The aetiology of SpA is still the subject of research by many groups worldwide. Evidence from genetic, experimental and clinical studies has accumulated to indicate a clear role for the IL-17 pathway in the pathogenesis of SpA. The IL-17 family consists of IL-17A, IL-17B, IL-17C, IL-17D, IL-17E and IL-17F, of which IL-17A is the best studied. IL-17A is a pro-inflammatory cytokine that also has the capacity to promote angiogenesis and osteoclastogenesis. Of the six family members, IL-17A has the strongest homology with IL-17F. In this Review, we discuss how IL-17A and IL-17F and their cellular sources might contribute to the immunopathology of SpA.
Taams, L.S., Steel, K.J.A., Srenathan, U. et al. IL-17 in the immunopathogenesis of spondyloarthritis. Nat Rev Rheumatol 14, 453–466 (2018). https://doi.org/10.1038/s41584-018-0044-2 [LINK]
Yeah, that’s kind of a lot. Let’s break it down into manageable chunks.
AxSpa is bad. The immune system is involved. There’s a bunch of nasty symptoms and a few things to look for while diagnosing it. Also, there’s a genetic factor.
Then I hit the bit that went “The aetiology of SpA is still the subject of research…” I reached for a dictionary. Aetiology, it turns out, is the study of the causes of a disease. So, I guess they are saying that we are still figuring out how AxSpa works. I’m not sure if I don’t quite understand the word or if the authors used it badly. I’ll assume it’s me and move on.
Pathogenesis is the process by which a disease or disorder develops. Which means that the next bit means that this IL-17 is quite likely to be the bit we want to be having words with on account of it being key in the nasty stuff happening.
IL-17A is a pro-inflammatory cytokine…
I’m going to have to do some more reading before I can even begin to tell you what that means.
I found an outfit called Thermo Fisher Scientific that had a few things to say about cytokines understandable by mortal men.
Cytokine is a general term used for small secreted proteins that are key modulators of inflammation. They are produced in response to invading pathogens to stimulate, recruit, and proliferate immune cells. Cytokines include interleukins (IL), chemokines, interferons, and tumor necrosis factors (TNF). These proteins are subdivided based on the nature of the immune response and the source of their production. There are two main subtypes of cytokines: pro-inflammatory cytokines, which promote inflammation, and anti-inflammatory cytokines, which help to reduce inflammation and support healing by opposing the actions of pro-inflammatory cytokines. Together, the balance between pro-inflammatory and anti-inflammatory cytokines is crucial for a regulated immune response and overall immune system function.
Thermo Fisher Scientific, Pro-Inflammatory Cytokines Overview, What are cytokines?
Right, that makes sense. So cytokines are little bits your body makes for controlling inflammation in response to stuff getting inside you that has no business being there, like viruses and bacteria. Your pro-inflammatory cytokines tell your cells, “more inflammation please, chaps”. On the other hand, pro-inflammatory cytokines are the messenger that says, “Careful now, lads” and “Down with this sort of thing”.
Right then, so this IL-17A is part of the group of cytokines doo-dads that say “more inflammation please”. This IL-17A bastard has the capacity to promote angiogenesis and osteoclastogenesis. Which means… No, wait, I know this one. It means I have to go look stuff up. BRB.
Angiogenesis is, apparently, the physiological process through which new blood vessels form from pre-existing vessels. I’d have to say that angiogenesis sounds dead helpful in the art of staying alive. I might have to take it back about calling IL-17A a bastard.
What’s osteoclastogenesis? No idea. I’ll google it.
Osteoclastogenesis is a multistep process involving cells such as osteoblasts and MSCs; thus, it is related to multiple skeletal diseases such as osteoporosis, rheumatoid arthritis, and periodontitis. Osteoclasts are multinucleated giant bone-resorbing cells belonging to the myeloid lineage, whose maturation requires macrophage colony stimulating factor (M−CSF) and receptor activator of nuclear factor κB ligand (RANKL)/RANK activation [94]. Osteoclastogenesis is orchestrated at different stages and time points, from precursors to mature osteoclasts. For example, the osteoblast-osteoclast interactions play vital roles in bone modeling, bone remodeling, and calcium homeostasis [95]. The therapies that disrupt this balance lead to severe side effects, such as bisphosphonate-induced osteonecrosis. Moreover, the process of differentiation of myeloid cells to osteoclasts inevitably involves osteoimmunology. Based on different disease models or physical conditions, osteoclastogenesis can be divided into two types: site-specific inflammation-related osteoclastogenesis and systemic inflammation-related osteoclastogenesis.
Science Direct, Inflammasome Complexes: Crucial mediators in osteoimmunology and bone diseases, 3.3 Osteoclastogenesis
Oh boy…
So, it turns out that osteoclasts are cells that reabsorb bone that your body is not using anymore (or thinks it can do away with). These wee demolition guys are regulated by cytokines, which include IL-6, which, I am guessing, must be related to IL-17. Which is why my spine is getting damaged and these are the sods who might be to blame.
Right, time for a TL;DR: IL-17 is a family of things your immune system uses to signal other things to do things. The older brother of IL-17A is pro-inflammation, pro-new blood vessels branching off existing ones, and anti bones. That sounds quite a lot like my problem. I’m not sure how new blood pathways factor in, but okay.
IL-17A is the best studied and has the strongest homology with IL-17F. Wait, what? Are we talking about counting and loops in maths? BRB
Right, no, nothing to do with maths. In biology, homology is a word for the similarity in anatomical structures or genes between organisms (even or especially of different taxa) due to shared ancestry, regardless of current functional differences.
So IL-17A and IL-17F are super similar. Why not just say that?
In this essay, the authors will explore how IL-17A and IL-17F and their cellular sources might contribute to the immunopathology of AxSpa.
Some findings
I would keep reading the paper, but of course there’s a paywall in the way. So while I look for a less expensive source, here are some findings that we get for free.
- Genetic and animal model studies indicate that the IL-23–IL-17 axis is involved in the pathogenesis of spondyloarthritis (SpA).
- IL-17A has been identified directly in the blood and synovial fluid of patients with SpA, with T cells representing a key source of this cytokine.
- IL-17A and IL-17F act in synergy with other pro-inflammatory mediators to induce pro-inflammatory responses across a range of cell types.
- IL-23–IL-17-targeted therapies have been shown to be effective in psoriatic arthritis and ankylosing spondylitis.
- Increased understanding of the pathogenic role of the IL-23–IL-17 axis, the cellular sources of these cytokines and their molecular regulation in SpA is essential to develop novel therapeutic strategies that target this pathway.
In short, IL-17A is a wanker, and his family are all sus.
I requested a copy of the paper. While I wait to see if any of the authors want to send me a copy, I’ll do some more reading. BRB
I found this.
IL-17A was identified in 1993, when it was referred to as cytotoxic T lymphocyte antigen 8 (CTLA8). I’m not sure how that helps, but I love a fun fact.
It turns out that the relationship between IL-23 and IL-17 is pretty key and resulted in the idea of the IL-23–IL-17 axis of inflammation.
IL-17A is, as I said earlier, a bit of a bastard. It’s linked to a bunch of nasty stuff that involves inflammation and joint (arthritis) stuff.
IL-17A increases the production and secretion of granulocyte colony-stimulating factor (G-CSF) and granulocyte–macrophage colony-stimulating factor (GM-CSF) in stromal cells, macrophages and T cells, thereby increasing granulopoiesis. IL-17A also regulates production of antimicrobial peptides (defensins and S100 proteins) by IL-17 receptor-bearing target cells.
I’m going to look some stuff up.
Granulocyte colony-stimulating factor (G-CSF or GCSF), also known as colony-stimulating factor 3 (CSF 3), is a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream.
Granulocyte colony-stimulating factor, Wikipedia
In case you were wondering, like me, granulocytes are a bunch of funny-looking blobs that are part of your immune system. They are all kind of important, but the one you might be familiar with is a type of white blood cell. The neutrophils granulocytes are about two-thirds of your white blood cells.
Your common or garden granulocyte–macrophage colony-stimulating factor is released by a bunch of important immunity things. It acts as a cytokine. Which we already established are the things that either demand more or demand less inflammation. GM-CSF is, I think, the way that IL-17A says that.
As far as I can tell, stromal cells are a sort of stem cell, and the other two things are immune system stuff.
Granulopoiesis is how some white blood cells get made. Those are the things that keep your blood from getting invaded by bad stuff from outside the body.
This bit: “antimicrobial peptides (defensins and S100 proteins)” sounds a lot like IL-17A is saying, “holy shit, guys, there’s bacteria in the body, we’re all going to die unless you do something!!!!”
So, when IL-17A is not busy being sus and hurting me, it tells the bones, “be more immune; kill the invaders” and “make more white blood cells, we’re under attack.” Or, in other words, IL-17A has a distinct lack of chill, which is causing me pain.
IL-17A needs to be put in a time-out. Which I assume is what biologics do?
IL-17A has an actual job to do too
I’m ragging on old IL-17A a lot here, but it must have some sort of benefit? Well, yes. IL-17A grants special super protection against some specific pathogens (I’d love to know which ones, but fungas attacking lungs might be indicated).
I guess that if The Last of Us turns out to be prophetic, I might be okay.
Apparently, whatever the invader is, IL-17A causes the body to make stuff that melts very specific proteins, which kills off whatever nasty thing it was that IL-17A is so hype to murder.
While it is getting all merder-hobo about whatever bug it has a hate boner for, IL-17A is also causing production of osteoblasts that are more than happy to melt bones.
When IL-17A gets too buzzed about baddies in the blood – excessive activation, as the smart folks call it – it can slide into its villain arc.
IL-17A also makes sure that maximum blood flow to the joints happens, which is probably why it gets so mean about my spine and joints. That explains the whole make new blood pathways thing comes in, I assume. You see, I was paying attention.
IL-17A and IL-17F are similar, but IL-17F is a bit more well rounded where as IL-17A has zero chill and a murder boner. Something like that, but in more scientific words.
So, in short, one of my ancestors developed the mutant power to be strong against something like Piachoo fighting Squirtle. Squirtle uses Water Pulse. Pekachoo suffers from confusion. It Hurt Itself in Its Confusion!
It’s IL-17A all the way down
It turns out a bunch of cells can make IL-17A. Like loads of them. The various body defenders release their panic at invaders system with it in. But also, tissue-resident memory T cells can make it. These T cells are found in barrier tissues such as the lung, gut, skin, liver and genital tract.
That could mean that my lungs, skin, liver, and balls are killing me. At least, my lungs might be – remember we saw that IL-17A was great at killing certain things such as fungi in the lungs.
Cordyceps 0, my immune system 1.
Sadly, however, my lungs might very well be shouting panic long after the bastard irritant has been melted with immunity acid.
It could be all sorts of other things, but I liked The Last of Us reference the most. Also, mucosal-associated invariant T cells show up in studies where AxSpa victims have psoriasis (flakey, annoying skin). Guess where these are found – the lungs. I rest my case – AxSpa is caused by Cordyceps immunity (prove me wrong).
IL-17+ MAIT cells have also been identified at higher frequencies within the peripheral blood of patients with AS than in the peripheral blood of healthy controls. So say the smart people.
Invariant natural killer T cells can make IL-17A, but there is little evidence that this is the source of the murder-hobo reaction. So that’s a thing you know now.
Conclusion time
After reading one paper, I know that IL-17A is not the sole contributor to the problem, but it is a huge sodding factor and needs to chill the hell out, please. Therapies that target IL-17A are super effective.
More studies are needed (always).
Right, what did we learn, class? I feel like I have a clue about how IL-17A biologics work – they all target IL-17A – but that’s about it. That and some pop culture references and the least scientific-sounding summary of a paper ever.
I’ve a load more papers to read. I am still learning.
PS – was ChatGPT right?
Erm… I don’t know. It was not especially helpful. I’ll get back to you when I understand more.
#ankylosingSpondylitis #AS #AxSpA #biologics #FatherTed #Health #IL17A #immuneSystem #looooooooooongWords #PokemonScience #ProbnablySkipAskingChatGPTForDiagrams #readingPapersAndTryingToUnderstandThem #TheLastOfUs
