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HLA-B27

January 05, 2024

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.

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 2009-02-20 at the Wayback Machine
B*2702 2009-02-20 at the Wayback Machine
B*2703 2009-02-20 at the Wayback Machine
B*2704 2009-02-20 at the Wayback Machine
B*2705 2009-02-20 at the Wayback Machine 2bsr​, 2bss​,
2bst​, 2a83​,
1w0v​, 1uxs​,
1ogt​, 1hsa​,
1jgd​, 1jge​
B*2706 2009-02-20 at the Wayback Machine
B*2709 2009-02-20 at the Wayback Machine 1w0w​, 1uxw​,
1of2​, 1k5n​

Prevalence edit

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 edit

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 edit

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 edit

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 edit

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 edit

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 edit

References edit

  1. ^ a b c 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). . 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. ^ a b c 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. ^ a b 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. ^ . 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.

External links edit

  • HLA-B27 Syndromes at eMedicine by A. Luisa Di Lorenzo, MBBCh
  • Bowness, P. (1 August 2002). "HLA B27 in health and disease: a double-edged sword?". Rheumatology. 41 (8): 857–868. doi:10.1093/rheumatology/41.8.857. PMID 12154202.
  • Online Mendelian Inheritance in Man (OMIM): 142830
  • HLA-B27 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  • BASDAI and Ankylosing Spondylitis
  • National Library of Medicine - Papers on HLA B-27

January 05, 2024
human, leukocyte, antigen, subtypes, 2701, 2759, class, surface, molecule, encoded, locus, major, histocompatibility, complex, chromosome, presents, antigenic, peptides, derived, from, self, self, antigens, cells, strongly, associated, with, ankylosing, spondy. 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 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 2BSTB 2705 b2MG with bound peptide 2bst major histocompatibility complex human class I B27Alleles B 2701 2702 2703 Structure See HLA B Available3D structuresEBI HLA B 2701 Archived 2009 02 20 at the Wayback MachineB 2702 Archived 2009 02 20 at the Wayback MachineB 2703 Archived 2009 02 20 at the Wayback MachineB 2704 Archived 2009 02 20 at the Wayback MachineB 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 MachineB 2709 Archived 2009 02 20 at the Wayback Machine 1w0w 1uxw 1of2 1k5n Contents 1 Prevalence 2 Disease associations 2 1 Pathological mechanism 2 1 1 Antigen dependent theories 2 1 2 Antigen independent theories 2 2 HIV long term nonprogressors 3 See also 4 References 5 External linksPrevalence editThe 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 Sapmi 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 editThe 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 edit 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 edit 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 edit 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 b2 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 b2 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 b2 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 b2 microglobulin have been seen on cell surfaces citation needed HIV long term nonprogressors edit 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 editHuman leukocyte antigenReferences edit a b c 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 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 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 Bjelle Anders Cedergren Bertil Rantapaa 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 Vaasa laboratorio ohjekirja Ly Kudosantigeeni B27 Vaasa laboratory manual Ly Tissue antigen B27 in Finnish 2014 07 21 Retrieved 2023 04 13 Feldtkeller Ernst Khan Muhammad van der Heijde Desiree van der Linden Sjef Braun Jurgen 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 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 Elizabeth D Agabegi Agabegi Steven S 2008 Step Up to Medicine Step Up Series Hagerstwon MD Lippincott Williams amp Wilkins ISBN 978 0 7817 7153 5 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 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 a b c Hacquard Bouder Cecile 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 a b Bowness Paul 21 March 2015 HLA B27 Annual Review of Immunology 33 1 29 48 doi 10 1146 annurev immunol 032414 112110 PMID 25861975 Luthra Guptasarma Manni Singh Balvinder 24 September 2004 HLA B27 lacking associated b2 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 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 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 External links editHLA B27 Syndromes at eMedicine by A Luisa Di Lorenzo MBBCh Bowness P 1 August 2002 HLA B27 in health and disease a double edged sword Rheumatology 41 8 857 868 doi 10 1093 rheumatology 41 8 857 PMID 12154202 Online Mendelian Inheritance in Man OMIM 142830 HLA B27 at the U S National Library of Medicine Medical Subject Headings MeSH BASDAI and Ankylosing Spondylitis National Library of Medicine Papers on HLA B 27 Retrieved from https en wikipedia org w index php title HLA B27 amp oldid 1189373560, wikipedia, wiki, book, books, library,

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