Human leukocyte antigen (HLA) B27 (subtypes B*2701-2759) is a class I surface

antigen In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...

encoded by the B locus in the major histocompatibility complex (MHC) on chromosome 6 and presents antigenic

peptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. ...

s (derived from self and non-self antigens) to

T cell A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...

s. HLA-B27 is strongly associated with

ankylosing spondylitis Ankylosing spondylitis (AS) is a type of arthritis characterized by long-term inflammation of the joints of the spine typically where the spine joins the pelvis. Occasionally areas affected may include other joints such as the shoulders or hi ...

and other associated inflammatory diseases, such as

psoriatic arthritis Psoriatic arthritis is a long-term inflammatory arthritis that occurs in people affected by the autoimmune disease psoriasis. The classic feature of psoriatic arthritis is swelling of entire fingers and toes with a sausage-like appearance. Th ...

, inflammatory bowel disease, and

reactive arthritis Reactive arthritis, also known as Reiter's syndrome, is a form of inflammatory arthritis that develops in response to an infection in another part of the body (cross-reactivity). Coming into contact with bacteria and developing an infection can t ...

Prevalence

The prevalence of HLA-B27 varies markedly in the global population. For example, about 8% of Caucasians, 4% of

North Africans North Africa, or Northern Africa is a region encompassing the northern portion of the African continent. There is no singularly accepted scope for the region, and it is sometimes defined as stretching from the Atlantic shores of Mauritania in t ...

, 2–9% of

Chinese Chinese can refer to: * Something related to China * Chinese people, people of Chinese nationality, citizenship, and/or ethnicity **''Zhonghua minzu'', the supra-ethnic concept of the Chinese nation ** List of ethnic groups in China, people of ...

, and 0.1–0.5% of persons of

Japanese Japanese may refer to: * Something from or related to Japan, an island country in East Asia * Japanese language, spoken mainly in Japan * Japanese people, the ethnic group that identifies with Japan through ancestry or culture ** Japanese diaspor ...

descent possess the gene that codes for this antigen. In northern

Scandinavia Scandinavia; Sámi languages: /. ( ) is a subregion in Northern Europe, with strong historical, cultural, and linguistic ties between its constituent peoples. In English usage, ''Scandinavia'' most commonly refers to Denmark, Norway, and Swe ...

( Lapland), 24% of people are HLA-B27 positive, while 1.8% have associated ankylosing spondylitis.

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 Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...

, it does not appear to be the sole mediator in development of

disease A disease is a particular abnormal condition that negatively affects the structure or function of all or part of an organism, and that is not immediately due to any external injury. Diseases are often known to be medical conditions that a ...

. In particular, 90% of people with

(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. There are additional genes being discovered that also predispose to AS and associated diseases, and additionally there are potential environmental factors (triggers) that may also play a role in susceptible individuals. In addition to its association with ankylosing spondylitis, HLA-B27 is implicated in other types of

seronegative spondyloarthropathy Spondyloarthropathy or spondyloarthrosis refers to any joint disease of the vertebral column. As such, it is a class or category of diseases rather than a single, specific entity. It differs from spondylopathy, which is a disease of the vertebra ...

as well, such as

, certain eye disorders such as acute anterior

uveitis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and in ...

and

iritis Uveitis () is inflammation of the uvea, the pigmented layer of the eye between the inner retina and the outer fibrous layer composed of the sclera and cornea. The uvea consists of the middle layer of pigmented vascular structures of the eye and ...

, Crohn's and

ulcerative colitis Ulcerative colitis (UC) is a long-term condition that results in inflammation and ulcers of the colon and rectum. The primary symptoms of active disease are abdominal pain and diarrhea mixed with blood (hematochezia). Weight loss, fever, and ...

associated spondyloarthritis. The shared association with HLA-B27 leads to increased clustering of these diseases. HLA antigens have also been studied in relation to Autism.

Pathological mechanism

Due to its strong association with spondyloarthropathies, HLA-B27 is the most studied HLA-B allele. It is not entirely clear how HLA-B27 influences disease, however there are some prevailing theories as to the mechanism. The theories can be divided between antigen-dependent and antigen-independent categories.

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 A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pa ...

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. 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.

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 The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER) stress. It has been found to be conserved between all mammalian species, as well as yeast and worm organisms. The UPR is activated in resp ...

(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. 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. 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, 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.

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 nonprogressor Long-term nonprogressors (LTNPs), sometimes also called elite controllers, are individuals infected with HIV, who maintain a CD4 count greater than 500 without antiretroviral therapy with a detectable viral load. Many of these patients have been ...

s. The presence of HLA-B27, as well as HLA-B5701, is significantly common among this group.

References

External links

* by A. Luisa Di Lorenzo, MBBCh * * *
BASDAI and Ankylosing Spondylitis
*
National Library of Medicine - Papers on HLA B-27
https://www.ncbi.nlm.nih.gov/pubmed/?term=hla+b27
PDBe-KB
provides an overview of all the structure information available in the PDB for Human HLA class I histocompatibility antigen, B-27 alpha chain {{Authority control Immune system disorders 2 Medical mnemonics