How does HLA-B27 lead to ankylosing spondylitis?

HLA-B27 gene is closely related to Ankylosing spondylitis. It is found in almost 70-90% of patients with Ankylosing spondylitis.

HLA B27 stands for Human Leukocyte Antigen 27. The HLAB 27 gene produces the HLA B27 molecule, which belongs to the family of MHC class I molecules. The function of this family of molecules is to present antigenic peptides to the T cells.

Let us understand this process of antigen presentation further. Whenever a pathogen (bacterium/ virus) enters the body, body’s immunity recognizes these as foreign. The next step is to inform the other immune cells about these pathogens & provide them with sufficient information about the pathogens. With this information, immune cells then launch an attack against these pathogens. This information about the pathogens consists of parts of the pathogen (called antigens) & is presented by the antigen presenting cells to the T cells. These parts are the signatures of these particular virus/ bacteria. The T cells can trace the location of these pathogens based on the signature antigens they have & launch an attack on them.

Now, let us focus on what happens inside these antigen presenting cells. The signature antigens are given final touches in a structure called proteosomes. The final antigens are carried to another structure called the Endoplasmic reticulum where they are mounted onto the MHC class I molecule. The MHC molecule folds & is then taken to the surface of the cell. This complex is presented to the T cells, which then recognize it & mount an attack on the pathogen. The T cells do not recognize the antigens in absence of the HLA molecule.

A few pathogens have antigens that are similar to proteins in our joints. When such pathogens (eg. Yersinia, Chlamydia) enter the body (generally the gut & cause loose motions), their antigens are picked up by the antigen presenting cells. It is hypothesized that HLA-B27 tends to pick up the particular antigens in the pathogen that are similar to the joint proteins & present them to the T cells. T cells recognize these as foreign & attack any structure with these proteins. The pathogen is definitely taken care of; but as I said, T cells also start considering our joints as foreign & attack them as well. This is precisely what happens in reactive arthritis (ankylosing spondylitis & reactive arthritis belong to the same group of arthritis). In reactive arthritis, one has loose motions followed by joint inflammation. This is called the ‘Arthritogenic peptide hypothesis’

There is an alternative hypothesis to explain the cause of joint inflammation. This is called the HLA-B27 folding hypothesis. The difference between HLA-B27 & the other HLA molecules is that B27 has a slower rate of folding & is prone to misfolding. When this happens on a large scale, the endoplasmic reticulum malfunctions & triggers generation of cytokines (TNF-α, IL-1, IL-6). These cytokines attack the joint & cause inflammation. This sequence of events has been shown in cells of the synovial fluid in patients.

This is how the HLA-B27 positivity; in the presence of infections/ environmental factors translates into inflammation of the joints (spine & other joints) & ultimately manifests as ankylosing spondilytis/ reactive arthritis.

References:
Mear JP, Schreiber KL, Munz C, Zhu X, Stevanovic S, Rammensee HG, et al: Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. J Immunol 163:6665–6670, 1999

Smith JA, Märker-Hermann E, Colbert RA: Pathogenesis of Ankylosing spondylitis: current concepts. Best Pract Res Clin Rheumatol 20:571–591, 2006

Turner MJ, Sowders DP, DeLay ML, Mohapatra R, Bai S, Smith JA, et al: HLA-B27 misfolding in transgenic rats is associated with activation of the unfolded protein response. J Immunol 175: 2438–2448, 2005

Robert A., Monica L., Erin I.: From HLA-B27 to spondyloarthritis: a journey through the ER Immunol Rev. 2010 January ; 233(1): 181–202

Benjamin R, Parham P. Guilt by association: HLA-B27 and ankylosing spondylitis. Immunol Today 1990: 11: 137–42.

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26 Responses to How does HLA-B27 lead to ankylosing spondylitis?

  1. Kavita says:

    Hello Doc,

    This article has definately added a value to my existing knowledge about Ankylosing Spondylitis. But, I am curious to know through which medium does these pathogen enter our body.
    Eagerly awaiting ur reply.

    Regards,
    Kavita

    Like

    • Dear Kavita,

      The pathogens generally enter through the gut or the genitourinary tract. Reactive arthritis would involve loose motions (gut infection) followed by arthritis.

      Like

      • Kavita says:

        Thanks Doc,

        Does it mean that both ankylosing spondylitis & reactive arthritis are caused in same manner i.e. thru pathogens?

        Like

      • Ankylosing spondylitits & reactive arthritis belong to the same group of arthritis i.e. seronegative spondyloarthropathy. Genetic factors (HLA-B27 & other genes) predispose to these arthritis while environmental factors like infections ultimately trigger the arthritis. This is the soil (genetic predisposition) & the seed (infections) hypothesis.

        In fact, scientists have shown that genetically predisposed rats when grown in pathogen free environment do not develop this type of arthritis. Later, they do develop arthritis when shifted to the regular environment. (Taurog JD, Richardson JA, Croft JT, Simmons WA, Zhou M,
        Fernández-Sueiro JL, et al: The germfree state prevents development of gut and joint inflammatory disease in HLA-B27 transgenic rats. J Exp Med 180:2359–2364, 1994)

        Like

      • kavita says:

        Hello Doc,

        I have been suffering from this pain on n off for past 6 years now. I have recently found that the pain keeps moving from left hip joint to right in a few days. Is the pain associated with formation of gas in our body. Although, I keep my diet check too.

        Good day!

        Like

      • Gas does not cause this kind of pain. It is probably inflammation in the joints.

        This type of alternating buttock/ hip pain is quite classical of seronegative spondyloarthropathy (Ankylosing spondylitis group of diseases).

        Like

      • Durable says:

        I have had the extreme hip symptom presentation as well. I have found it manageable through diet (avoiding inflammatory triggers like tomatoes, nightshades) and through purging my bowels (using fiber or magnesium citrate). My pain persists until I have eliminated, then it resovles in a matter of hours.

        Like

  2. Sherin says:

    Dear Doc,

    I have ankylosing spondylitis. I am HLAb27 negative.

    In that case, how did I end up getting ankylosing spondylitis?

    Like

    • HLA-B27 is one of the many genetic factors responsible for ankylosing spondylitis. It is the most important one; but not the only one. We are still to unravel the entire maze of ankylosing spondylitis genetics.

      Like

  3. soumyadipta roy says:

    HI DOC,
    Thanks for sharing all the information.i am HLA B27 + , i took remicade sept. 2010 but my pain is still on my hip joints,well i have lesser back stiffness…but hip joints continue..i want to know till what age does this pain stay and is this is a pain i have to live with whole life?or i have to take pain killers to stay good?please guide me with this?

    Like

    • Dear Soumyadipta,

      First of all, one will have to see whether the hip pain is due to inflammation or osteoarthritis (wearing out of hip cartilage) secondary to inflammation.

      If we presume that it is due to inflammation, the DMARD dose should be escalated to control the inflammation. Are you on methotrexate; if yes, what dose of methotrexate?

      Like

  4. Muralagopi says:

    Sir
    i suffer hla.b27 give me solution plz

    Like

  5. soumyadipta roy says:

    No i am not on methorexate….but i take DMARD but do i have to live with the Nucoxia tablets….forever..i want to know till what age does this pain stay and is this is a pain i have to live with whole life?or i have to take pain killers to stay good and are there any side affects to these painkillers which i take?i recently also got a lymph node operated from my neck , which came out to be non Hodgkin lymphoma , after that i got everything tested for Cancer. the doctor says i am okay and there is nothing to worry. is getting a lymph node part of ankylosing spodilytis ?

    Like

    • You need to see a Rheumatologist.

      One has to ascertain the cause of your pain. The treatment would depend on the cause (ankylosing spondylitis itself or osteoarthritis). Nucoxia is an analgesic & not a definitive treatment.

      Lymph node is unlikely to be a part of Ankylosing spondylitis.

      Please see a Rheumatologist asap for a definite diagnosis & further treatment.

      Like

    • Last week I also got a lymph node operated from my neck , which also came out to be non Hodgkin lymphoma. I am HLA-B27

      My understanding is non Hodgkin lymphoma.is cancer.

      Like

  6. ayad obidy says:

    please,i need program of physiotherapy,forAS. thanks

    Like

  7. Hurting says:

    I’d just love my gp and local health authority take me serious and give me testing and a diagnosis. ive had one MRI 4 years ago and i saw a specialist of some sort breifly 20 mins once before he quit the hospital they just tell my gp to keep me medicated.

    my gp thinks i have AS

    but my de-generation of my spine is worsening i have several diseases that are recognised as AS related instead the deterioration of my health in the last 4 years i would presume is irretrievable and all the do is change and increase my medications.

    .

    Like

  8. dr.ayad says:

    plz wt good diet for ankylosing spondylitis

    Like

  9. Sheila Skelhorn says:

    Hi my mother was as without the hlab27 gene I recently diagnosed with the hlab27 have oa of the spine and hips and several joints so I’m now very confused why I have the gene and my mother didn’t

    Like

  10. Sheila Skelhorn says:

    Thank you I also have ibd gerd but that’s under control healthy eating and swimming 5x a week but still my lower back goes into severe spasm every 4-6 weeks I can’t take any ibrufen tramadol diclofenic ect as it agitates my bowels and stomach my back clicks when left leg gets lowered but not sure why this happens thanks for advising

    Like

  11. Sheila Skelhorn says:

    Ps my mother had ankelosing without the gene marker

    Like

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    And i am glad reading your article. But wanna remark
    on few general things, The website style is great, the articles is
    really excellent : D. Good job, cheers

    Like

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