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
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.

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]

See also

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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