How does HLA-B27 lead to ankylosing spondylitis?

April 18, 2011

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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