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  • Martin Laurence

HLA-B27 + CARD9 + ASCA = fungi cause back pain (AS-type)

Updated: Apr 27

Genetics of spondyloarthropathies

Immune system genes play an extremely important role in spondyloarthropathies. Epidemiologists knew this well before we could sequence DNA and detect genes directly, because spondyloarthropathy-associated symptoms run in families. Having a parent or sibling with Crohn’s disease, psoriasis, ulcerative colitis, spondylitis, sacroiliitis, seronegative arthritis, acute anterior uveitis, chronic prostatitis (men), non-specific urethritis (men) or chronic cervicitis (women) substantially increases your own risk of having any of these diseases. And if your identical twin has one of these diseases, your risk goes through the roof!


The clamp gene (HLA-B27)

The most studied spondyloarthropathy gene is called HLA-B27. This gene’s role is to detect intracellular infections, and then to alert lymphocytes (specifically CD8+ T cells) which go on to kill infected human cells. HLA-B27 increases the risk of all symptoms listed in the previous paragraph. In individuals of European descent, this gene increases the risk of severe chronic back pain more than 60-fold! It also increases the risk of acute anterior uveitis and reactive arthritis more than 10-fold.


HLA-B27 is a “clamp” which grabs onto any protein within human cells. Excess parts of the grabbed protein which do not fit into the clamp are cut-off by ”scissors” called ERAP1. When this process completes, the clamp is placed on the surface of the human cell, and part of the grabbed protein is presented to CD8+ T cells. These T cells patrol the body looking for suspicious-looking proteins. Non-human proteins indicate that a virus or microbe is hiding within the human cell. When a CD8+ T cells find a non-human protein in an HLA-B27 clamp, it kills the human cell from which this protein originated (to protect the body from infection).


The scissor gene (ERAP1)

The link between HLA-B27 and spondyloarthropathies has been known since the 1970s, but the exact mechanism continues to elude researchers. While detection of an intracellular infection was by far the simplest and most likely mechanism, all sorts of less plausible hypotheses have been proposed in the interim.


In 2011, it was discovered that ERAP1 alleles interact with HLA-B27 to affect spondyloarthropathy risk (Evans et al 2011). ERAP1 helps HLA-B27 detect intracellular infections by clipping excess parts of clamped proteins (eg. parts of the protein which are protruding outside the clamp). Different ERAP1 variants exist in the population, and some variants leave more protrusions than others. This changes the efficiency with which CD8+ T cells detect suspicious looking proteins.


Because ERAP1 variants change spondyloarthropathy risk, we can conclude that intracellular protein presentation to CD8+ T cells is the main mechanism which leads to disease. This finding excludes many less plausible hypotheses of disease causation, leaving only two:

  1. T cells are recognizing an intracellular viral/microbial protein in each affected organ.

  2. T cells are accidentally recognizing a human protein in each affected organ.


The fungal infection hotline gene (CARD9)

While many immunity gene variants change spondyloarthropathy risk, they do not tell us much more than “it’s an inflammatory disease”. But we know this already! Wouldn’t it be great if some of these variants gave us a clue as to which intracellular proteins are being detected by HLA-B27? Is it a viral protein? Is it a bacterial protein? Is it a fungal protein? Is it a human protein? CARD9 is the only gene which answers this question unambiguously.


Individuals whose parents each gave them a defective variant of CARD9 are very unlucky: they suffer from chronic fungal infections (Glocker et al 2009). The CARD9 gene is needed to call-up T cells to fight fungal infections. This means CARD9 variants affecting spondyloarthropathy risk are likely changing the probability of calling-up T cells to fight a fungus. IL12 and IL23R variants also suggest a fungal infection might be present (Smeekens et al 2011), but these cytokines are involved in many processes, so their association with fungi is less specific.


ASCA

A chronic intracellular fungal infection being attacked by T cells is the simplest explanation for HLA-B27, ERAP1 and CARD9 variants associated with spondyloarthropathies. Another observation strongly suggests that an immune response against a fungus is occurring: antibodies against fungi (ASCA) are elevated patients as compared to controls (Maillet et al 2016). While other explanations for these observations are possible, they are much more complex. By principle of parsimony, the chronic fungal infection hypothesis is most plausible and should be investigated ASAP.


NB: This post is based on Laurence et al 2018 (simplified for clarity). While many cases of back pain are the results of spondyloarthropathies, others are due to physical trauma, spinal disc herniation, etc.


Animated back pain (AS-type) video (intro): https://youtu.be/S-VhDiqwBnk

Animated back pain (AS-type) video (full): https://youtu.be/e2vpMqmLYQo


Example of a CD8+ T cell recognizing Malassezia within a human cell. This example shows a cell wall protein being recognized through HLA-B*27; it is also plausible that a secreted Malassezia metabolite protein (eg. lipase) is recognized through HLA-B*27.

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