B*2705-β2MG with bound peptide 2bst​
major histocompatibility complex (human), class I, B27
Alleles	B*2701, 2702, 2703, . . .
Structure (See HLA-B)		Available 3D structures
EBI-HLA	B*2701 Archived 2009-02-20 at the Wayback Machine
	B*2702 Archived 2009-02-20 at the Wayback Machine
	B*2703 Archived 2009-02-20 at the Wayback Machine
	B*2704 Archived 2009-02-20 at the Wayback Machine
	B*2705 Archived 2009-02-20 at the Wayback Machine	2bsr​, 2bss​, 2bst​, 2a83​, 1w0v​, 1uxs​, 1ogt​, 1hsa​, 1jgd​, 1jge​
	B*2706 Archived 2009-02-20 at the Wayback Machine
	B*2709 Archived 2009-02-20 at the Wayback Machine	1w0w​, 1uxw​, 1of2​, 1k5n​

Human leukocyte antigen (HLA) B27 (subtypes B*2701-2759)^[1] is a class I surface molecule encoded by the B locus in the major histocompatibility complex (MHC) on chromosome 6 and presents antigenic peptides (derived from self and non-self antigens) to T cells. HLA-B27 is strongly associated with ankylosing spondylitis and other associated inflammatory diseases, such as psoriatic arthritis, inflammatory bowel disease, and reactive arthritis.

Prevalence

The prevalence of HLA-B27 varies markedly in the global population. For example, about 8% of Caucasians, 4% of North Africans, 2–9% of Chinese, and 0.1–0.5% of persons of Japanese descent possess the gene that codes for this antigen.^[1] Among the Sami in Northern Scandinavia (Sápmi), 24% of people are HLA-B27 positive, while 1.8% have associated ankylosing spondylitis,^[2] compared to 14-16% of Northern Scandinavians in general.^[3][4] In Finland, an estimated 14% of the population is positive for HLA-B27, while over 95% of patients with ankylosing spondylitis and approximately 70–80% of patients with Reiter's disease or reactive arthritis have the genetic marker.^[5]

Disease associations

The relationship between HLA-B27 and many diseases has not yet been fully elucidated. Though HLA-B27 is associated with a wide range of pathology, it does not appear to be the sole mediator in development of disease. In particular, 90% of people with ankylosing spondylitis (AS) are HLA-B27 positive, though only a small fraction of people with HLA-B27 ever develop AS. People who are HLA-B27 positive are also more likely to experience early onset AS than HLA-B27 negative individuals.^[6] There are additional genes being discovered that also predispose to AS and associated diseases,^[7] and additionally there are potential environmental factors (triggers) that may also play a role in susceptible individuals.^[1]

In addition to its association with ankylosing spondylitis, HLA-B27 is implicated in other types of seronegative spondyloarthropathy^[8] as well, such as reactive arthritis, certain eye disorders such as acute anterior uveitis and iritis, psoriatic arthritis, Crohn's and ulcerative colitis associated spondyloarthritis. The shared association with HLA-B27 leads to increased clustering of these diseases.^[9] HLA antigens have also been studied in relation to autism.^[10]

Pathological mechanism

HLA-B27 is the most researched HLA-B allele due to its high relationship with spondyloarthropathies. Although it is not totally apparent how HLA-B27 promotes disease, there are some prominent views. The theories can be divided between antigen-dependent and antigen-independent categories.^[11]

Antigen-dependent theories

These theories consider a specific combination of antigen peptide sequence and the binding groove (B pocket) of HLA-B27 (which will have different properties from the other HLA-B alleles). The arthritogenic peptide hypothesis suggests that HLA-B27 has a unique ability to bind antigens from a microorganism that trigger a CD8 T-cell response that then cross-reacts with a HLA-B27/self-peptide pair. Furthermore, it has been shown that HLA-B27 can bind peptides at the cell surface.^[12] The molecular mimicry hypothesis is similar, however it suggests that cross reactivity between some bacterial antigens and self peptide can break tolerance and lead to autoimmunity.^[11]

Antigen-independent theories

These theories refer to the unusual biochemical properties that HLA-B27 has. The misfolding hypothesis suggests that slow folding during HLA-B27's tertiary structure folding and association with β2 microglobulin causes the protein to be misfolded, therefore initiating the unfolded protein response (UPR)—a pro-inflammatory endoplasmic reticulum (ER) stress response. However, although this mechanism has been demonstrated both in vitro and in animals, there is little evidence of its occurrence in human spondyloarthritis.^[12] Also, the HLA-B27 heavy chain homodimer formation hypothesis suggests that B27 heavy chains tend to dimerise and accumulate in the ER, once again, initiating the UPR.^[11] Alternatively, cell surface B27 heavy chains and dimers can bind to regulatory immune receptors such as members of the killer cell immunoglobulin-like receptor family, promoting the survival and differentiation of pro-inflammatory leukocytes in disease.

One more misfolding theory, published in 2004,^[13] proposes that β2 microglobulin-free heavy chains of HLA-B27 undergo a facile conformational change in which the C-terminal end of domain 2 (consisting of a long helix) becomes subject to a helix-coil transition involving residues 169–181 of the heavy chain, owing to the conformational freedom newly experienced by domain 3 of the heavy chain when there is no longer any bound light chain (i.e., β2 microglobulin) and owing to the consequent rotation around the backbone dihedral angles of residues 167/168. The proposed conformational transition is thought to allow the newly-generated coiled region (incorporating residues 'RRYLENGKETLQR' which have also been found to be naturally bound to HLA-B27 as a 9-mer peptide) to bind to either the peptide-binding cleft of the same polypeptide chain (in an act of self-display) or to the cleft of another polypeptide chain (in an act of cross-display). Cross-display is proposed to lead to the formation of large, soluble, high molecular weight (HMW), degradation-resistant, long-surviving aggregates of the HLA-B27 heavy chain. Together with any homodimers formed either by cross-display or by a disulfide-linked homodimerization mechanism, it is proposed that such HMW aggregates survive on the cell surface without undergoing rapid degradation, and stimulate an immune response. Three previously noted features of HLA-B27, which distinguish it from other heavy chains, underlie the hypothesis: (1) HLA-B27 has been found to be bound to peptides longer than 9-mers, suggesting that the cleft can accommodate a longer polypeptide chain; (2) HLA-B27 has been found to itself contain a sequence that has also been actually discovered to be bound to HLA-B27, as an independent peptide; and (3) HLA-B27 heavy chains lacking β2 microglobulin have been seen on cell surfaces.^{[citation needed]}

HIV long-term nonprogressors

Around 1 in 500 people infected with HIV are able to remain symptom-free for many years without medication, a group known as long-term nonprogressors.^[14] The presence of HLA-B27, as well as HLA-B5701, is significantly common among this group.^[15]