A Key Genetic Player in Autoimmunity (HLA-B)

The human leukocyte antigen (HLA) system is a group of human genes encoding the major histocompatibility complex (MHC) proteins, or HLAs. This system has three groups or classes; HLA-A, HLA-B, and HLA-C genes belong to class I [R].

HLAs are proteins or antigens on the surface of white blood cells. They help flag and remove external agents that may cause infection. HLA-B antigens bring bacterial or viral proteins from the inside to the cell surface so T-lymphocytes can detect and kill infected or foreign cells [R].

They also have anti-cancer effects and play a role in immune rejection or acceptance of organ transplants [R, R].

HLA genes come in many different forms, and there are millions of their possible combinations. Their diversity ensures that humans are protected against a huge array of disease agents, but it can be a double-edged sword: some types of HLAs are associated with autoimmune disorders [R].

The HLA genes encode proteins that present external components on the surface of white blood cells, enabling your immune system to detect and destroy them.

HLA-B27 Antigen

The HLA-B27 antigen is one of the hundreds of possible forms of HLA-B. It supports the antiviral immune response by “flagging” peptides from viruses—such as influenza, HIV, and Epstein-Barr—and presenting them to T-killer cells. These cells then recognize viral peptides as dangerous and use them as a beacon to find and destroy other viruses [R].

HLA-B27 has over 100 sub-variations. Despite its beneficial roles, HLA-B27 is also strongly associated with a group of autoimmune joint disorders known as spondyloarthritis (SpA) [R, R].

HLA-B27 enables an antiviral immune response, but it's strongly associated with certain autoimmune disorders.

Prevalence

The prevalence of HLA-B27 varies from 50% in some Indian populations to almost zero in Australian Aborigines. About 6% of the US population carries this gene, which is most common among white people [R].

Ankylosing Spondylitis & Other Conditions

HLA-B27 strongly correlates with certain autoimmune diseases, such as [R]:

• Psoriasis
• Ankylosing spondylitis (spine deformation)
• IBD (inflammatory bowel disease), in combination with spondylitis
• Reactive arthritis (Reiter’s syndrome)—inflammation of the joints, urethra, and eyes

These conditions fall under the umbrella of spondyloarthritis, with the most common form being ankylosing spondylitis (AS). In AS, inflammation gradually fuses the vertebrae in the spine, causing back pain and limited movement. It usually affects young men [R, R].

HLA-B27 is associated with autoimmune disorders known as spondyloarthritis. The main one is ankylosing spondylitis, which causes spine inflammation and chronic back pain.

How Strong is This Connection?

The connection between HLA-B27 and ankylosing spondylitis (AS) is extremely strong: 90–95% of all AS patients have this gene. For other autoimmune conditions, the prevalence of HLA-B27 ranges between 50-90% [R].

Does this mean almost everyone with HLA-B27 will get AS or another autoimmune disease? Not at all!

Approximately 1.3% European HLA-B27 carriers have AS, though Caucasian (white) ethnicity and the presence of a family member with AS increase the odds 16-20 times. These statistics suggest that HLA-B27 is just one of several risk factors [R, R].

Similarly, over 50% of people with anterior uveitis (eye inflammation) have this variant, but only 1% of all HLA-B27 carriers develop uveitis [R].

In other words, HLA-B27 correlates with the above disorders, but many more factors contribute and decide which carriers develop autoimmunity. Below you can learn more about these factors and whether you can influence some of them.

HLA-B27 variant strongly correlates with spondyloarthritis and other forms of autoimmunity, but only a fraction of HLA-B27 carriers develop a disease. It depends on many more factors discussed below.

Despite the well-known link, the exact mechanisms of HLA-B27-related autoimmunity are still not clear. According to the main theories, an error probably occurs in one of two processes [R, R, R, R]:

1. The way it presents peptides to T-killer cells: upon activation, T-killer cells are supposed to only flag the foreign peptide and not HLA-B27 itself. However, T-cells may mistakenly flag HLA-B27 fragments or other peptides as foreign and attack them.
2. The biochemical properties (structure) of HLA-B27 itself: the protein may misfold in such a way that causes inflammation within the cell and triggers an immune response. 

Whatever the root cause, one thing is for sure: inflammation lurks behind all autoimmune disorders associated with HLA-B27 [R].

The Microbiome Connection

A solid body of evidence also implicates the role of microbes in autoimmune disorders associated with HLA-B27 [R, R, R].

Microbial infections such as Salmonella, Yersinia, Klebsiella, and Chlamydia can contribute to autoimmune disorders in HLA-B27 carriers because [R, R, R, R, R, R]:

1. They increase the expression of HLA-B27 on the surface of infected cells.
2. Some parts of the HLA-B27 antigen are similar to peptides from these bacteria, so the immune system attacks them.
3. This antigen weakens the anti-bacterial immune response, leading to persistent infections that trigger autoimmunity.

Other Genes

The interaction of the ERAP1 gene with HLA-B27 seems to play an important role, so you may want to check your data for that gene, too.

Specifically, the ‘T’ allele at rs30187 and the ‘A’ allele at rs27434 correlate with ankylosing spondylitis when combined with HLA-B27 [R].

HLA-B27 can partake in an autoimmune response by misfolding, “confusing” T-killers and other immune cells, or weakening the anti-bacterial immune response.

Primary SNPs: 

HLA-B rs4349859 [R, R, R, R]:

• “A” allele correlates with the HLA-B27 variant
• “G” allele doesn’t correlate with the HLA-B27 variant

HLA-B rs13202464

• “G” allele correlates with the HLA-B27 variant
• “A” allele doesn’t correlate with the HLA-B27 variant

rs116488202

• “T” allele correlates with the HLA-B27 variant
• “C” allele doesn’t correlate with the HLA-B27 variant

HLA-B27 is inherited in a dominant model; that is, both one or two copies of the associated allele imply the same correlation with autoimmune diseases [R].

Please note: To confirm the presence of this gene and detect the exact subtype, you may want to do the HLA-B27 blood test in a healthcare institution.