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.
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.
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.
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.
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.
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.
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