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HLA-B27 and the Genetics of Spondylitis

Medically reviewed by Remi A. Kessler, M.D.
Posted on July 1, 2021

Spondylitis, or spondyloarthritis (SpA), is a spectrum of diseases defined by inflammatory arthritis of the spine. SpA can lead to significant back pain. However, it can also involve other joints in the body, the eyes (e.g., anterior uveitis), skin (e.g., psoriasis), bowels (e.g., inflammatory bowel disease), and tendons. Although the causes of spondylitis are not entirely understood, it is thought that a combination of genetic (hereditary) and environmental factors play a role. Environmental factors include infections (such as those that can cause reactive arthritis), an imbalance of intestinal bacteria (gut dysbiosis), and/or vitamin D deficiency.

What Is HLA-B27?

HLA-B27 is a gene that encodes a protein called human leukocyte antigen B27, which is a protein found on the surface of cells. This protein is involved in immunity. HLA-B27 plays a major role in spondylitis and is one type of the HLA-B gene. The HLA-B gene is present in the majority of people with certain autoimmune and autoinflammatory diseases, and most importantly, all types of spondyloarthritis. The HLA-B gene has many different normal variations. The type of HLA-B genes that you have depends on which individual copies of genes (alleles) you inherited from each of your parents.

In the United States and the United Kingdom, only about 6 percent to 8 percent of the general population is HLA-B27 positive (they have the HLA-B27 gene). But for those living with spondylitis, HLA-B27 positivity is much more common. One small study showed that 88 percent of these individuals are HLA-B27 positive. Numerous HLAB-27 subtypes, known as single nucleotide polymorphisms (SNPs), may be responsible for either mild or severe symptoms in certain people.

The Role of HLA-B27 in the Immune System

HLA-B27, and other HLA genes, are part of the major histocompatibility complex class I (MHC-I) group of genes. This group of genes is found together on human chromosome 6. These genes play a significant role in adaptive immunity. Adaptive immunity is the immune system’s ability to distinguish between self (i.e., your own body) and non-self (i.e., external pathogens). It also mounts an immune response to new threats that the body has not encountered before, such as viruses, bacteria, and cancer. MHC-I genes code for proteins responsible for presenting antigens (portions of foreign proteins) on the surface of cells. In other words, when cells in the body find something inside themselves that does not belong, MHC-I proteins take a portion of it and place it on the outside of the cell for white blood cells to recognize as foreign.

MHC-I proteins attract the attention of CD8+ T lymphocytes, marking the cells for destruction. MHC class II genes code for proteins responsible for presenting antigens on the cell surface to B lymphocytes (B cells), so that they will create antibodies to attach the antigens.

HLA-B27 in Autoimmune and Autoinflammatory Disease

Autoimmune disorders, such as spondyloarthritis, lupus, psoriatic arthritis, rheumatoid arthritis, and some other rheumatic diseases, occur when the body’s immune system mistakenly attacks healthy tissue. Sometimes, a distinction is made between autoimmunity (which involves autoantibodies) and autoinflammation (all other immune responses that attack healthy tissue). Here, the term autoimmune is used to include both antibody-associated autoimmunity and autoinflammation.

The role of HLA-B27 in the autoimmune response is not entirely clear, but there are several theories. The first theory is that HLA-B27 on the cell surface may present parts of proteins to cytotoxic T cells, resulting in an autoimmune response. Second, HLA-B27 proteins can form a linkage to each other in pairs called homodimers, leading to an immune response and inflammation. Third, the HLA-B27 protein may not be folded properly when it is made in the cell, resulting in damage to the cell and an inflammatory response. When proteins are assembled in a cell, they start as a chain of amino acids (small units that make up proteins). These amino acid chains must be folded into the proper three-dimensional shape to function. This configuration is similar to how a paper airplane must be folded properly in order to fly.

It is not clear exactly how HLA-B27 contributes to spondyloarthritis. It may involve one or more of these theories and other mechanisms. Simply having a certain version of a gene, such as HLA-B27, is not enough to cause spondylitis on its own. Combinations of genetic and environmental factors working together are the likely cause of spondyloarthritis.

Other Genes That Interact With HLA-B27

ERAP1 and ERAP2

ERAP1 and ERAP2 are proteins found inside cells that are involved in the functioning of MHC-I proteins, including HLA-B27. Specific subtypes of ERAP1 have been identified in people with spondyloarthritis. ERAP1 and 2 may also contribute to the autoimmune response by failing to remove certain portions of proteins before sending them to the cell surface.

Genes Associated With Spondylitis

As many as 60 other genes in the human genome have been identified that are associated with spondylitis. These genes, either on their own or in combination with other genes, may help cause spondyloarthritis in unknown ways. Neither genetic factors nor environmental factors alone cause spondylitis, and no single combination of hereditary and environmental risk factors explains how spondylitis develops. It is unlikely that there is a single cause of spondyloarthritis, but rather several different ways that genes and the environment can interact that lead to an increased risk of the disease.

Research into spondyloarthropathies and other autoimmune and autoinflammatory conditions is constantly leading to discoveries as to how these diseases develop. As research advances, so does our understanding of how to better diagnose and treat spondylitis.

Talk With Others Who Understand

MySpondylitisTeam is the social network for people with spondylitis and their loved ones. On MySpondylitisTeam, more than 66,000 members come together to ask questions, give advice, and share their stories with others who understand life with spondylitis.

Are you or someone you care for living with spondylitis? Share your experience in the comments below, or start a conversation by posting on your Activities page.

References
  1. Microbes, the Gut and Ankylosing Spondylitis — Arthritis Research & Therapy
  2. Does the Microbiome Cause B27-Related Acute Anterior Uveitis — Ocular Immunology and Inflammation
  3. Dysbiosis of the Gut Microbiota in Disease — Microbial Ecology in Health and Disease
  4. Vitamin D, Autoimmune Disease and Rheumatoid Arthritis — Calcified Tissue International
  5. The Role of Vitamin D in Disease Activity in Axial Spondyloarthritis — EMJ Rheumatology
  6. HLA-B27 Antigen — Icahn School of Medicine at Mount Sinai
  7. Ankylosing Spondylitis — U.S. National Library of Medicine
  8. The Prevalence of HLA-B27 in the US: Data From the US National Health and Nutrition Examination Survey, 2009 — Arthritis & Rheumatology
  9. Ankylosing Spondylitis Causes — National Health Service
  10. High Association of HL-A Antigen, W27, With Ankylosing Spondylitis — New England Journal of Medicine
  11. Polymorphism of HLAB-27: 105 Subtypes Currently Known — Current Rheumatology Reports
  12. An Update of the HLA Genomic Region, Locus Information and Disease Associations: 2004 — Tissue Antigens
  13. Introduction to Immunology (Tutorial) — The Biology Project of the University of Arizona
  14. Major Histocompatibility Complex (MHC) Class I and MHC Class II Proteins: Conformational Plasticity in Antigen Presentation — Frontiers in Immunology
  15. CD8+ T Cells — British Society for Immunology
  16. Antigen Processing and Presentation — British Society for Immunology
  17. Autoinflammation and HLA-B27: More Than an Antigen — Ocular Immunology and Inflammation
  18. ERAP1 Gene — U. S. National Library of Medicine
  19. The Impact of the ‘Mis-Peptidome’ on HLA Class I-Mediated Diseases: Contribution of ERAP1 and ERAP2 and Effects on the Immune Response — International Journal of Molecular Sciences
  20. The Role of Polymorphic ERAP1 in Autoinflammatory Disease — Bioscience Reports
  21. ERAP1 Enzyme-Mediated Trimming and Structural Analyses of MHC I-Bound Precursor Peptides Yield Novel Insights Into Antigen Processing and Presentation — Journal of Biological Chemistry
  22. Overview of Ankylosing Spondylitis — Spondylitis Association of America
Posted on July 1, 2021
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Remi A. Kessler, M.D. is affiliated with the Medical University of South Carolina and Cleveland Clinic. Learn more about her here
Kristopher Bunting, M.D. studied chemistry and life sciences at the U.S. Military Academy, West Point, and received his doctor of medicine degree from Tulane University. Learn more about him here

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