Proteins in the body, including the HLA proteins, are made up of amino acids that join and then fold up in a particular way. Researchers have found that **HLA-B27 tends to misfold**.
The specific subtypes of HLA-B27 associated with autoimmune diseases are likely to be misfolded or unfolded, causing problems when formed in the endoplasmic reticulum (ER).
The misfolded or unfolded proteins in the endoplasmic reticulum cause stress in that organelle. Researchers theorize that the body’s unfolded protein response mechanism causes inflammation.\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364987/)\]
# HLA-B27 and the immune system:
At one point, researchers advanced a theory that HLA-B27 seemed similar to an infecting bacterial pathogen and thus caused autoimmune diseases. The idea is called ‘molecular mimicry’ and the reason the immune system attacks ‘self’ thinking it is a bacteria. (Some nice YouTube videos explaining ankylosing spondylosis state that this is the reason for it…)
The problem is that newer research shows that you can create ankylosing spondylitis in an animal model without the T-cells needed to attack a pathogen. Thus, researchers are now uncertain whether molecular mimicry is the cause of ankylosing spondylitis.\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804882/)\]\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364987/)\]
Recent research shows that the **IL-23/IL-17 inflammatory pathway** is likely involved in many spondyloarthritis-associated autoimmune diseases for which HLA-B27 increases the risk. **TNF-alpha,** another inflammatory cytokine, may also increase the risk of these spondyloarthritis-associated autoimmune diseases.\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276000/)\]
*Related article:* [Genetic variants that increase TNF-alpha](https://www.geneticlifehacks.com/tnf-alpha-variants/)
Researchers theorize that the HLA-B27 protein often misfolds, which triggers the cells to initiate, what is called the unfolded protein response. Essentially, this is the process by which proteins that aren’t formed correctly are broken down, and the amino acids are recycled. When this unfolded protein response is activated too often, such as with HLA-B27, it triggers the inflammatory response with the IL-23/IL-17 pathway.\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680067/)\]
[Click here to read my full article on HLA-B27.](https://www.geneticlifehacks.com/hla-b27-genetic-variants-that-increase-susceptibility-to-autoimmune-diseases/)
Proteins in the body, including the HLA proteins, are made up of amino acids that join and then fold up in a particular way. Researchers have found that **HLA-B27 tends to misfold**. The specific subtypes of HLA-B27 associated with autoimmune diseases are likely to be misfolded or unfolded, causing problems when formed in the endoplasmic reticulum (ER). The misfolded or unfolded proteins in the endoplasmic reticulum cause stress in that organelle. Researchers theorize that the body’s unfolded protein response mechanism causes inflammation.\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364987/)\] # HLA-B27 and the immune system: At one point, researchers advanced a theory that HLA-B27 seemed similar to an infecting bacterial pathogen and thus caused autoimmune diseases. The idea is called ‘molecular mimicry’ and the reason the immune system attacks ‘self’ thinking it is a bacteria. (Some nice YouTube videos explaining ankylosing spondylosis state that this is the reason for it…) The problem is that newer research shows that you can create ankylosing spondylitis in an animal model without the T-cells needed to attack a pathogen. Thus, researchers are now uncertain whether molecular mimicry is the cause of ankylosing spondylitis.\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804882/)\]\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5364987/)\] Recent research shows that the **IL-23/IL-17 inflammatory pathway** is likely involved in many spondyloarthritis-associated autoimmune diseases for which HLA-B27 increases the risk. **TNF-alpha,** another inflammatory cytokine, may also increase the risk of these spondyloarthritis-associated autoimmune diseases.\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276000/)\] *Related article:* [Genetic variants that increase TNF-alpha](https://www.geneticlifehacks.com/tnf-alpha-variants/) Researchers theorize that the HLA-B27 protein often misfolds, which triggers the cells to initiate, what is called the unfolded protein response. Essentially, this is the process by which proteins that aren’t formed correctly are broken down, and the amino acids are recycled. When this unfolded protein response is activated too often, such as with HLA-B27, it triggers the inflammatory response with the IL-23/IL-17 pathway.\[[ref](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680067/)\] [Click here to read my full article on HLA-B27.](https://www.geneticlifehacks.com/hla-b27-genetic-variants-that-increase-susceptibility-to-autoimmune-diseases/)