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From Genes to Joints: Linking Ankylosing Spondylitis and HLA-B27 Gene

Updated: Oct 18, 2023

Understanding Ankylosing Spondylitis, its Symptoms, and the HLA-B27 Gene.


What is Ankylosing Spondylitis (AS)?

Ankylosing Spondylitis (AS), also called Axial spondyloarthritis (AxSpA), is an inflammatory disease. Individuals affected with AS may develop "fused vertebrae" in the spine. The fusion of spinal vertebrae reduces flexibility and then a hunched posture. (1)


Axial Spondyloarthritis affects the Axial bones, composed of the Chest, Spine, and Pelvis. AS in the chest region may lead to a rib injury leading to heavy breathing challenges. (1)


As ankylosing spondylitis progresses, the body attempts to fix itself by forming new bones. The new bone gradually fills the spaces between the vertebrae and, in time, binds whole vertebral segments together. Fused vertebrae can flatten the spine's natural curvature, resulting in a rigid, hunched posture. (1)



What Causes Ankylosing Spondylitis/AxSpA?

Although no established etiology exists for ankylosing spondylitis, genetic factors may play a role. The risk is significantly high among persons with the HLA-B27 gene, however, only some carriers of HLA-B27 develop the condition. (1)


What is HLA-B27 and its connection with Ankylosing Spondylitis/AxSpA?

HLAs are proteins found on the surface of body cells and are in effect, unique to individuals. HLAs assist the body's immune system in discriminating between self-cells and external, foreign bodies. (2)


The Human Leukocyte Antigen (HLA) system is like a security alarm system. Cells that carry HLA proteins, different from the individuals' HLA proteins, can trigger the immune system. HLA types are inherited, and some are linked to autoimmune disorders and other diseases. People with certain HLA antigens are more likely to develop certain autoimmune diseases.


Of the known HLA genes, the HLA-B27 gene holds significance in understanding the development of AS/axSpA.


People who are HLA-B27 positive are also more likely to experience early onset AS than HLA-B27 negative individuals.

HLA-B27 tests look for a protein on the surface of white blood cells in patients suspected of AS/axSpA.


Types of the Ankylosing Spondylitis/axSpA

Two kinds of axial spondyloarthritis exist. When detected on an X-ray, the disorder is recognized as ankylosing spondylitis, sometimes referred to as axial spondyloarthritis.


Nonradiographic axial spondyloarthritis is diagnosed when symptoms, blood tests, and other imaging studies reveal the condition. However, it is not visible on an X-ray. (1)


Symptoms of Ankylosing Spondylitis/axSpA

Ankylosing spondylitis can cause lower back pain and stiffness, especially in the morning and after inactivity. Fatigue and neck aches are common symptoms. Symptoms may get better, worsen, or stop altogether sporadically. (1)






The most frequently impacted Parts include:

  1. The lower back vertebrae.

  2. The heel, where tendons and ligaments connect.

  3. The joint connecting the pelvis to the base of the spine.

  4. The areas along bones, primarily in the spine but sometimes along the back of the heel, where tendons and ligaments connect.

  5. The cartilage that lies between the ribs and the breastbone.

  6. The shoulder and hip joints. (1)






Time of onset and risk factors

In most cases, onset mostly begins in late adolescence or early adulthood. The HLA-B27 gene is primarily present in those with ankylosing spondylitis. However, many individuals with this gene do not develop ankylosing spondylitis. (1)

About 90% of patients have HLA-B27 positive, but only 5% of HLA-B27-positive individuals develop AS. (3)


Association of HLA-B27 gene with other diseases

Every HLA gene is assigned a unique number. Of all rheumatic disorders, Spondyloarthropathies are especially linked to the HLA-B27 gene. These include:

  1. Axial Psoriatic Arthritis

  2. Axial Spondyloarthritis

  3. Reactive Arthritis

These disorders cause pain, stiffness, and inflammation in the spine, hips, and entheses, areas where ligaments and tendons connect to bones. Inflammatory bowel disease (IBD) sufferers and those with uveitis, an eye inflammation, frequently carry the HLA-B27 gene. However, the most prominent link is ankylosing spondylitis (AS), axial spondyloarthritis affecting the spine and lower back. (4)


Prevalence around the world

Studies suggest that 90% of white northern Europeans with AS have the HLA-B27 gene, but people of other races do not. However, fewer Black Americans than Whites possess HLA-B27 despite having a more severe illness. Americans of Hispanic and Chinese descent fall somewhere in the middle.

HLA-B27, on the other hand, is essentially nonexistent in Japan. Therefore, medical professionals there rely on other markers to identify and track AS. (4)


Prevalence among the Indian population

The presence of HLA-B27 in people with seronegative spondyloarthritis ranges from 19 to 94%. In comparison, the general Indian population has a presence of HLA-B27 ranging from 1.4 to 8%. (5)

Approximately 1.65 million Indians are currently diagnosed with the condition. (6)

In a study, 51 North Indian patients with ankylosing spondylitis (AS) were documented. It was found that they had a male-to-female ratio of 16:1 and a mean age of onset of 21.2 years. (7)


The Role of HLA-B27 in Inflammatory Diseases

It is still unknown exactly how HLA-B27 impacts AS and other inflammatory illnesses. The most widely accepted idea, and the one with the most scientific support, is that the gene modifies the composition of the gut microbiome, which refers to the trillions of bacteria, viruses, and fungi that live in the digestive system. (4)

Parthasarathy, R., Santiago, F., McCluskey, P., Kaakoush, N. O., Tedla, N., & Wakefield, D. (2022, September 01). The microbiome in HLA-B27-associated disease: implications for acute anterior uveitis and recommendations for future studies. Trends in Microbiology, 31(2), P142-158.
Parthasarathy, R., Santiago, F., McCluskey, P., Kaakoush, N. O., Tedla, N., & Wakefield, D. (2022, September 01). The microbiome in HLA-B27-associated disease: implications for acute anterior uveitis and recommendations for future studies. Trends in Microbiology, 31(2), P142-158. https://doi.org/10.1016/j.tim.2022.08.008

HLA-B27 may interfere with the extensive colonies of microorganisms that regulate the immune system. People with AS have a less varied microbiome, more harmful bacteria than good bacteria, and a weak gut barrier. This can let toxins and germs enter the body through the stomach.


As proof, AS patients occasionally have microbes in their joints that belong solely to the stomach. (4)


How does HLA-B27 cause ankylosing spondylitis?

HLA-B27 homodimers have been shown to bind to immunoreceptors on natural killer (NK) cells, myelomonocytic cells, and lymphocytes [killer cell immunoglobulin-like receptors (KIR), and leucocyte immunoglobulin-like receptors (LILR)], suggesting a role in the pathogenesis of autoimmune diseases. (8)


An earlier study found that NK and CD4+ T cells are more prevalent in SpA patients. These cells express the killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR3DL2) receptor, which recognizes HLA-B27 homodimers on the cell surface. (8)

Genetics of Ankylosing Spondylitis.
Brown, M., Kenna, T. & Wordsworth, B. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat Rev Rheumatol 12, 81–91 (2016). https://doi.org/10.1038/nrrheum.2015.133

Interestingly, LILRB2 and KIR3DL2 have been shown to increase the survival and differentiation of inflammatory leukocytes in SpA by binding to HLA-B27 dimers with a greater affinity than HLA-B27 and other common HLA-class I heterotrimers. (8)


Zhu, W., He, X., Cheng, K. et al. Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res 7, 22 (2019). https://doi.org/10.1038/s41413-019-0057-8
Zhu, W., He, X., Cheng, K. et al. Ankylosing spondylitis: etiology, pathogenesis, and treatments. Bone Res 7, 22 (2019). https://doi.org/10.1038/s41413-019-0057-8

After being stimulated by antigen-presenting cells that express HLA-B27 homodimers, KIR3DL2+ CD4+ T cells in AS patients proliferated and survived more, and their production of the interleukin-17 (IL-17) increased. (8)


Complications

In advanced cases of ankylosing spondylitis, the body tries to heal by generating new bone. This newly formed bone slowly occupies the gap between the vertebrae, ultimately fusing the entire vertebrae. This results in the spine becoming rigid and losing its flexibility. The fusion process can also reinforce the rib cage, which can restrict lung function and capacity. (1)


Other complications might include:

  • Uveitis refers to an eye inflammation. Uveitis, a common complication of ankylosing spondylitis, can lead to abrupt eye discomfort, sensitivity to light, and compromised vision. (1)

  • Compression fractures: In the early phases of ankylosing spondylitis, some individuals may undergo bone weakening. A weakening Vertebral column may collapse, leading to a stooped posture. Furthermore, collapse of the vertebral column may compress the spinal cord and the nerves in proximity to the spine, leading to further injuries. (1)

  • Cardiac issues: There's an increased risk to the heart for individuals with Ankylosing Spondylitis. The largest arteries in the human body, the aorta, may become inflamed due to AS. Aortic inflammation leading to distortion of the aortic valve will impact how the aorta functions, raising susceptibility to heart diseases in cases with AS. (1)


Understanding Ankylosing Spondylitis (AS), its symptoms, and the role of the HLA-B27 gene is paramount in improving early diagnosis and implementing preventive measures.


AS/axSpA, a form of inflammatory disease, severely impacts the spine, chest, and pelvis, causing fused vertebrae, reduced flexibility, and a hunched posture.


The awareness of the disease and the importance of genetic testing, particularly for the HLA-B27 gene, cannot be overstated.

With advancements in technologies such as RT-PCR, screening for the presence of this gene has become more accessible, allowing individuals at risk to take proactive measures. Early detection empowers healthcare providers and patients to take timely interventions, slowing down the disease progression, and enhancing the overall quality of life.


Encouraging individuals to undergo testing and promoting awareness about AS can significantly contribute to early intervention, thereby making a difference in the lives of people living with Ankylosing Spondylitis/axSpA.



References:
  1. Ankylosing spondylitis - Symptoms & causes. (n.d.). Mayo Clinic. Retrieved October 10, 2023, from https://www.mayoclinic.org/diseases-conditions/ankylosing-spondylitis/symptoms-causes/syc-20354808

  2. HLA-B27 antigen Information. (n.d.). Mount Sinai. Retrieved October 10, 2023, from https://www.mountsinai.org/health-library/tests/hla-b27-antigen

  3. Ankylosing spondylitis: an update. (n.d.). RACGP. Retrieved October 10, 2023, from https://www.racgp.org.au/afp/2013/november/ankylosing-spondylitis

  4. Rath, L. (n.d.). HLA-B27 Gene and Arthritis. Arthritis Foundation. Retrieved October 10, 2023, from https://www.arthritis.org/diseases/more-about/hla-b27-gene-and-arthritis