HLA-B27

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HLA-B*2705-peptide (chain A shown in green cartoon, chain B shown in yellow cartoon) complexed to a fragment of the influenza nucleoprotein NP383-391 (orange, sticks). PDB ID 2BST HLA-B*2705-peptide in complex with influenza nucleoprotein NP383-391.png
HLA-B*2705-peptide (chain A shown in green cartoon, chain B shown in yellow cartoon) complexed to a fragment of the influenza nucleoprotein NP383-391 (orange, sticks). PDB ID 2BST
B*2705-β2MG with bound peptide 2bst ​
major histocompatibility complex (human), class I, B27
AllelesB*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.

Contents

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 more than 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. Ninety percent of people with ankylosing spondylitis (AS) are HLA-B27 positive, although only a small fraction of people with HLA-B27 will develop AS. People who are HLA-B27 positive are more likely to experience early onset AS than HLA-B27 negative individuals. [6] Research is uncovering other genes that predispose to AS and associated diseases, and there are potential environmental factors that may play a role in susceptible individuals. [1] [7]

HLA-B27 is implicated in other types of seronegative spondyloarthropathy, such as reactive arthritis, acute anterior uveitis, iritis, psoriatic arthritis, Crohn's and ulcerative colitis associated spondyloarthritis. The shared association with HLA-B27 leads to increased clustering of these diseases. [8] [9] HLA antigens have 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 apparent how HLA-B27 promotes disease, theories exist and 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 cross-reacts with a HLA-B27/self-peptide pair. HLA-B27 can bind peptides at the cell surface. [12] The molecular mimicry hypothesis is similar, although it suggests that cross reactivity between some bacterial antigens and self peptide can break tolerance and lead to autoimmunity. [11]

Antigen-independent theories

Antigen-independent theories refer to the biochemical properties of HLA-B27. 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, initiating the unfolded protein response (UPR), a pro-inflammatory endoplasmic reticulum (ER) stress response. Although this mechanism has been demonstrated in vitro and in animals, there is little evidence of its occurrence in human spondyloarthritis. [12] The HLA-B27 heavy chain homodimer formation hypothesis suggests that B27 heavy chains tend to dimerise and accumulate in the ER, initiating the UPR. [11] 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.

Another 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 two, 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 three of the heavy chain when there is no longer any bound light chain, and owing to the consequent rotation around the backbone dihedral angles of residues 167/168. [13] 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

About 1 in 500 people infected with HIV can 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]

See also

Related Research Articles

<span class="mw-page-title-main">Autoimmunity</span> Immune response against an organisms own healthy cells

In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". Prominent examples include celiac disease, diabetes mellitus type 1, Henoch–Schönlein purpura (HSP), systemic lupus erythematosus (SLE), Sjögren syndrome, eosinophilic granulomatosis with polyangiitis, Hashimoto's thyroiditis, Graves' disease, idiopathic thrombocytopenic purpura, Addison's disease, rheumatoid arthritis (RA), ankylosing spondylitis, polymyositis (PM), dermatomyositis (DM), and multiple sclerosis (MS). Autoimmune diseases are very often treated with steroids.

<span class="mw-page-title-main">Major histocompatibility complex</span> Cell surface proteins, part of the acquired immune system

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are called MHC molecules.

<span class="mw-page-title-main">Human leukocyte antigen</span> Genes on human chromosome 6

The human leukocyte antigen (HLA) system or complex is a complex of genes on chromosome 6 in humans which encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histocompatibility complex (MHC) found in many animals.

<span class="mw-page-title-main">Ankylosing spondylitis</span> Type of arthritis of the spine

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. With AS, eye, bowel problems and back pain may occur. Joint mobility in the affected areas sometimes worsens over time. Ankylosing spondylitis is believed to involve a combination of genetic and environmental factors. More than 85% of people affected in the UK have a specific human leukocyte antigen known as the HLA-B27 antigen. The underlying mechanism is believed to be autoimmune or autoinflammatory. Diagnosis is based on symptoms with support from medical imaging and blood tests. AS is a type of seronegative spondyloarthropathy, meaning that tests show no presence of rheumatoid factor (RF) antibodies.

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 itself, but many conditions involve both spondylopathy and spondyloarthropathy.

<span class="mw-page-title-main">Uveitis</span> Inflammation of the uvea of the eye

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 includes the iris, ciliary body, and choroid. Uveitis is described anatomically, by the part of the eye affected, as anterior, intermediate or posterior, or panuveitic if all parts are involved. Anterior uveitis (iridocyclitis) is the most common, with the incidence of uveitis overall affecting approximately 1:4500, most commonly those between the ages of 20-60. Symptoms include eye pain, eye redness, floaters and blurred vision, and ophthalmic examination may show dilated ciliary blood vessels and the presence of cells in the anterior chamber. Uveitis may arise spontaneously, have a genetic component, or be associated with an autoimmune disease or infection. While the eye is a relatively protected environment, its immune mechanisms may be overcome resulting in inflammation and tissue destruction associated with T-cell activation.

<span class="mw-page-title-main">Reactive arthritis</span> Medical condition

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 trigger the disease. By the time the patient presents with symptoms, often the "trigger" infection has been cured or is in remission in chronic cases, thus making determination of the initial cause difficult.

<span class="mw-page-title-main">Sacroiliitis</span> Medical condition

Sacroiliitis is inflammation within the sacroiliac joint. It is a feature of spondyloarthropathies, such as axial spondyloarthritis, psoriatic arthritis, reactive arthritis or arthritis related to inflammatory bowel diseases, including ulcerative colitis or Crohn's disease. It is also the most common presentation of arthritis from brucellosis.

<span class="mw-page-title-main">Beta-2 microglobulin</span> Component of MHC class I molecules

β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells. In humans, the β2 microglobulin protein is encoded by the B2M gene.

<span class="mw-page-title-main">HLA-B</span> Protein-coding gene in the species Homo sapiens

HLA-B is a human gene that provides instructions for making a protein that plays a critical role in the immune system. HLA-B is part of a family of genes called the human leukocyte antigen (HLA) complex. The HLA complex helps the immune system distinguish the body's own proteins from proteins made by foreign invaders such as viruses and bacteria.

<span class="mw-page-title-main">Enthesitis</span> Medical condition

Enthesitis is inflammation of the entheses, the sites where tendons or ligaments insert into the bone. It is an enthesopathy, a pathologic condition of the entheses. Early clinical manifestations are an aching sensation akin to "working out too much", and it gets better with activity. It is worse in the morning. The muscle insertion hurts very focally as it joins into the bone, but there is little to no pain at all with passive motion. There are some cases of isolated, primary enthesitis which are very poorly studied and understood. It is known to be associated with other autoimmune diseases, like spondyloarthropathies and psoriasis. A common autoimmune enthesitis is at the heel, where the Achilles tendon attaches to the calcaneus.

<span class="mw-page-title-main">HLA-A</span> Protein-coding gene in the species Homo sapiens

HLA-A is a group of human leukocyte antigens (HLA) that are encoded by the HLA-A locus, which is located at human chromosome 6p21.3. HLA is a major histocompatibility complex (MHC) antigen specific to humans. HLA-A is one of three major types of human MHC class I transmembrane proteins. The others are HLA-B and HLA-C. The protein is a heterodimer, and is composed of a heavy α chain and smaller β chain. The α chain is encoded by a variant HLA-A gene, and the β chain (β2-microglobulin) is an invariant β2 microglobulin molecule. The β2 microglobulin protein is encoded by the B2M gene, which is located at chromosome 15q21.1 in humans.

<span class="mw-page-title-main">HLA-A*02</span>

HLA-A*02 (A*02) is a human leukocyte antigen serotype within the HLA-A serotype group. The serotype is determined by the antibody recognition of the α2 domain of the HLA-A α-chain. For A*02, the α chain is encoded by the HLA-A*02 gene and the β chain is encoded by the B2M locus. In 2010 the World Health Organization Naming Committee for Factors of the HLA System revised the nomenclature for HLAs. Before this revision, HLA-A*02 was also referred to as HLA-A2, HLA-A02, and HLA-A*2.

<span class="mw-page-title-main">HLA-A24</span>

HLA-A24 (A24) is a human leukocyte antigen serotype within HLA-A serotype group. The serotype is determined by the antibody recognition of α24 subset of HLA-A α-chains. For A24, the alpha, "A", chain are encoded by the HLA-A*24 allele group and the β-chain are encoded by B2M locus. This group currently is dominated by A*2402. A24 and A*24 are almost synonymous in meaning. A24 is a split antigen of the broad antigen HLA-A9 and it is a sister serotype of HLA-A23.

<span class="mw-page-title-main">HLA-F</span> Protein-coding gene in the species Homo sapiens

HLA class I histocompatibility antigen, alpha chain F is a protein that in humans is encoded by the HLA-F gene. It is an empty intracellular molecule that encodes a non-classical heavy chain anchored to the membrane and forming a heterodimer with a β-2 microglobulin light chain. It belongs to the HLA class I heavy chain paralogues that separate from most of the HLA heavy chains. HLA-F is localized in the endoplasmic reticulum and Golgi apparatus, and is also unique in the sense that it exhibits few polymorphisms in the human population relative to the other HLA genes; however, there have been found different isoforms from numerous transcript variants found for the HLA-F gene. Its pathways include IFN-gamma signaling and CDK-mediated phosphorylation and removal of the Saccharomycescerevisiae Cdc6 protein, which is crucial for functional DNA replication.

<span class="mw-page-title-main">Major histocompatibility complex, class I-related</span> Protein-coding gene in the species Homo sapiens

Major histocompatibility complex class I-related gene protein (MR1) is a non-classical MHC class I protein, that binds vitamine metabolites produced in certain types of bacteria. MR1 interacts with mucosal associated invariant T cells (MAIT).

<span class="mw-page-title-main">HLA-B39</span>

HLA-B39 (B39) is an HLA-B serotype. The serotype identifies the more common HLA-B*39 gene products.

<span class="mw-page-title-main">Enteropathic arthropathy</span> Medical condition

Enteropathic arthropathy commonly referred to as enteropathic arthritis, is a type of arthritis linked to Crohn's disease, ulcerative colitis, and chronic inflammatory bowel diseases.

<span class="mw-page-title-main">Axial spondyloarthritis</span> Medical condition

Axial spondyloarthritis is a chronic, immune-mediated disease predominantly affecting the axial skeleton. The term itself is an umbrella term characterizing a diverse disease family united by shared clinical and genetic features, such as the involvement of the axial skeleton. The 2009 introduced term axial spondyloarthritis is a preferred term nowadays and substitutes the old term ankylosing spondylitis.

<span class="mw-page-title-main">Interleukin 40</span> Mammalian cytokine

Interleukin 40 (IL-40), also known with other name C17orf99, is a protein belonging to a group of cytokines called interleukins. It is encoded by a gene that does not belong to any cytokine superfamily. This cytokine is produced primarily by human expression tissues such as bone marrow and fetal liver, and its expression can be also induced in peripheral B cells after activation. IL-40 is involved in immunoglobulin A (IgA) production, and plays an important role in humoral immune responses and B cell homeostasis and development.

References

  1. 1 2 3 M. A. Khan (2010). "HLA and spondyloarthropathies". In Narinder K. Mehra (ed.). The HLA Complex in Biology and Medicine. New Delhi, India: Jayppee Brothers Medical Publishers. pp. 259–275. ISBN   978-81-8448-870-8.
  2. ↑ Johnsen, K.; Gran, J. T.; Dale, K.; Husby, G. (October 1992). "The prevalence of ankylosing spondylitis among Norwegian Samis (Lapps)". The Journal of Rheumatology. 19 (10): 1591–1594. ISSN   0315-162X. PMID   1464873.
  3. ↑ Gran, J. T.; Mellby, A. S.; Husby, G. (January 1984). "The Prevalence of HLA-B27 in Northern Norway". Scandinavian Journal of Rheumatology. 13 (2): 173–176. doi:10.3109/03009748409100382. ISSN   0300-9742.
  4. ↑ Bjelle, Anders; Cedergren, Bertil; Rantapää Dahlqvist, Solbritt (January 1982). "HLA B 27 in the Population of Northern Sweden". Scandinavian Journal of Rheumatology. 11 (1): 23–26. doi:10.3109/03009748209098109. ISSN   0300-9742.
  5. ↑ "Vaasa, laboratorio-ohjekirja Ly-Kudosantigeeni B27 (Vaasa, laboratory manual Ly-Tissue antigen B27)" (in Finnish). 2014-07-21. Retrieved 2023-04-13.
  6. ↑ Feldtkeller, Ernst; Khan, Muhammad; van der Heijde, Désirée; van der Linden, Sjef; Braun, Jürgen (March 2003). "Age at disease onset and diagnosis delay in HLA-B27 negative vs. positive patients with ankylosing spondylitis". Rheumatology International. 23 (2): 61–66. doi:10.1007/s00296-002-0237-4. PMID   12634937. S2CID   6020403.
  7. ↑ Thomas, Gethin P.; Brown, Matthew A. (January 2010). "Genetics and genomics of ankylosing spondylitis". Immunological Reviews. 233 (1): 162–180. doi:10.1111/j.0105-2896.2009.00852.x. PMID   20192999. S2CID   205223192.
  8. ↑ Elizabeth D Agabegi; Agabegi, Steven S. (2008). Step-Up to Medicine (Step-Up Series) . Hagerstwon, MD: Lippincott Williams & Wilkins. ISBN   978-0-7817-7153-5.
  9. ↑ Kataria, RK; Brent LH (June 2004). "Spondyloarthropathies". American Family Physician. 69 (12): 2853–2860. PMID   15222650. Archived from the original on 2008-07-09. Retrieved 2009-06-29.
  10. ↑ Torres, Anthony; Jonna Westover (February 2012). "HLA Immune Function Genes in Autism". Autism Research and Treatment. 2012 (12): 2853–2860. doi: 10.1155/2012/959073 . PMC   3420779 . PMID   22928105.
  11. 1 2 3 Hacquard-Bouder, Cécile; Ittah, Marc; Breban, Maxime (March 2006). "Animal models of HLA-B27-associated diseases: new outcomes". Joint Bone Spine. 73 (2): 132–138. doi:10.1016/j.jbspin.2005.03.016. PMID   16377230.
  12. 1 2 Bowness, Paul (21 March 2015). "HLA-B27". Annual Review of Immunology. 33 (1): 29–48. doi: 10.1146/annurev-immunol-032414-112110 . PMID   25861975.
  13. ↑ Luthra-Guptasarma, Manni; Singh, Balvinder (24 September 2004). "HLA-B27 lacking associated β2-microglobulin rearranges to auto-display or cross-display residues 169-181: a novel molecular mechanism for spondyloarthropathies". FEBS Letters. 575 (1–3): 1–8. doi: 10.1016/j.febslet.2004.08.037 . PMID   15388324.
  14. ↑ "HIV+ Long-Term Non-Progressor Study". National Institute of Allergy and Infectious Diseases. June 23, 2010. Archived from the original on July 19, 2011. Retrieved July 5, 2011.
  15. ↑ Deeks, Steven G.; Walker, Bruce D. (September 2007). "Human Immunodeficiency Virus Controllers: Mechanisms of Durable Virus Control in the Absence of Antiretroviral Therapy". Immunity. 27 (3): 406–416. doi: 10.1016/j.immuni.2007.08.010 . PMID   17892849.
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