HLA-B27

HLA-B27 stands for "Human Leukocyte Antigen B27". This is a protein molecule found on the surface of most human somatic cells.The human leukocyte antigen (HLA) system, which corresponds to the major histocompatibility complex (MHC) in humans, plays a central role in antigen presentation of intracellular and extracellular peptides and in the regulation of innate and adaptive immune responses.

HLA-B27 belongs to the MHC class I molecules. Its main function is the presentation of intracellular peptides to CD8-positive T lymphocytes. These MHC class I-activatable T cells have a cytotoxic or regulatory function, and their activation leads either to tolerance when:

• the presented peptides are recognized as "self", or
• lead to activation of cell-mediated immunity when"non-self" antigens are presented, or
• induce an erroneous "maladaptive" autoimmune response when the "self" antigen is falsely recognized as false .

The determination of a person's HLA makeup is referred to as HLA typing .

The HLA-B gene is located on chromosome 6p21.33. It has a distinct genotypic and phenotypic polymorphism with at least 132 alleles and 105 subtypes (HLA-B*27:01 to HLA-B*27:106). Non-synonymous nucleotide substitutions affecting the antigen binding cleft may lead to differences in antigen presentation and ultimately disease association.

The preavelnce of HLA-B27 in versch. Ethnic groups:

The prevalence of HLA-B27 shows a marked north-south gradient in the normal population: it is lowest in the equatorial region (~0%) and highest in northern countries (30-40%). This geographical difference could be due to the fact that HLA-B27 carriers are more susceptible to malaria and also have a more severe disease course. This susceptibility may have led to adverse selection of HLA-B27-positive individuals in endemic malaria areas (Mathieu A et al. 2008).

Remarkably, thePapua New Guinea and Eskimo populations appear to have the highest prevalence of HLA-B27 (13-53% and 25-50%, respectively ). Caucasians have a prevalence of 6-10%, Chinese (2-8%), Arabs (2-5%), African Americans (2-4%), and Japanese (0.4%) . In indigenous peoples of South America, equatorial and southern Africa, and Australian aborigines, HLA-B27 is virtually absent. Thus, the prevalence of sondylarthritis is also commensurate with the distribution of HLA-B27 alleles in different populations (Bodis G et al. 2018).

Similar to other MHC class I molecules, HLA-B27 is a heterotrimer composed of a heavy chain encoded by the HLA genes, a light β2-microglobulin chain, and the presented peptide. HLA-B27 differs from other HLA-B molecules in that it has a free cysteine at residue 67 (Cys67). This allows the molecule to form stable homodimers in the absence of β2-microglobulin through the formation of disulfide bonds (Bodis G et al. 2018).

In its function for the immune system, HLA-B27 appears to be particularly effective in binding certain viral antigens compared to other class 1 HLA proteins. It has been shown that HIV-infected individuals with HLA-B27 positivity exhibit a significantly delayed onset of AIDS. Components of influenza A viruses are also bound particularly well by HLA-B27. Conversely, this functional property could also explain the associations with certain autoimmune diseases.

Among others, the HLA-B27 protein is frequently detectable in people with:

• Reiter's syndrome (70-80%)
• Rheumatoid arthritis (10%)
• Psoriatic arthritis (60-70%)
• Juvenile idiopathic arthritis (75)
• Crohn's disease
• Whipple 's disease (28%)
• ankylosing spondylitis (ankylosingspondylitis ) (90%)
• and ocular inflammation (uveitis and iritis/50%).

For example, approximately 3 to 6% of HLA-B*27 carriers develop ankylosing spondylitis. On the other hand, about 90% of all ankylosing spondylitis patients are carriers of this tissue antigen.

One of the advantages of genetic HLA-B27 testing is that it can more reliably and reproducibly determine the different subtypes, all of which are associated with disease to varying degrees. The B*27:05 subtype is most common in Caucasians, and other subtypes have evolved from this ancestral type through gene conversion, reciprocal combination, and point mutation. However, it is not likely to be associated with spondylarthritis in the African population. B*27:02 shows a strong association in the Mediterranean population, whereas B*27:04 is a common subtype in Asian spondyloarthritis patients . A recent meta-analysis involving 8993 AS patients and 19 254 healthy controls confirmed the significant association of B*27:02 and B*27:04 with AS. B*27:03, *27:06, and *27:09 are considered protective subtypes, although spondylarthritis cases have been reported in patients with these subtypes. B*27:03 and B*27:06 are common in Southeast Asia, whereas *27:09 is common in Sardinia and Italy. Some rare subtypes also appear to contribute to the risk of spondyloarthritis, including B*27:01, B*27:07, B*27:08, B*27:10, B*27:13, B*27:14, B*27:15, B*27:19, and B*27:25. Variations in the primary structure of the HLA-B27 protein may explain the different disease associations, particularly those involving the antigen-binding cleft and, consequently, possibly peptide specificity. A difference of two amino acids between the F-pockets of the peptide binding groove of B*27:06 and B*27:04 and a difference of one amino acid between B*27:09 and B*27:05 were detected. These minor changes in amino acid sequences result in significantly different risk profiles.