Journal of Genetic Disorders & Genetic Reports ISSN: 2327-5790

All submissions of the EM system will be redirected to Online Manuscript Submission System. Authors are requested to submit articles directly to Online Manuscript Submission System of respective journal.

Review Article, J Genet Disor Genet Rep Vol: 2 Issue: 1

Mini Review: HLA B27 and its Immunogenetics in Ankylosing Spondylitis

Hamid Nawaz Tipu*
Classified Pathologist & Consultant Immunologist, Combined Military Hospital, KhuzdarCantt, Pakistan
Corresponding author : Dr. Hamid Nawaz Tipu, MBBS
FCPS (Immunology), Classified Pathologist & Consultant Immunologist, Combined Military Hospital, Khuzdar Cantt, Pakistan
Tel: +923335478215
E-mail: [email protected]
Received: May 14, 2013 Accepted: September 30, 2013 Published: October 07, 2013
Citation: Tipu HN (2013) Mini Review: HLA B27 and its Immunogenetics in Ankylosing Spondylitis. J Genet Disor Genet Rep 2:1. doi:10.4172/2327-5790.1000104

Abstract

Mini Review: HLA B27 and its Immunogenetics in Ankylosing Spondylitis

Human Leucocyte Antigen (HLA) B27 is one of the antigens of class I major histocompatibility complex (MHC) that has strongly been associated with development of various spondyloarthropathies [1]. The gene for HLA B27 is located on short arm of chromosome 6, at 6p21.3 [2] (Figure 1), spanning an area of 4287 base pairs (bp). It contains 7 exons and 6 introns, in addition to a TATA, a poly A and four alternate splicing signals [3] (Figure 2).Exon 1 encodes leader peptide, exon 2 and 3 encode alpha 1 & alpha 2 domains, exon 4 encodes alpha 3, exon 5 encodes the transmembrane region, and exon 6 & 7 encode cytoplasmic tail. The product of this gene is 362 amino acid protein comprising three alpha chains associated with a beta2 microglobulin chain which is encoded by chromosome 15.

Keywords:

HLA B27 Locus and Its Product

Human Leucocyte Antigen (HLA) B27 is one of the antigens of class I major histocompatibility complex (MHC) that has strongly been associated with development of various spondyloarthropathies [1]. The gene for HLA B27 is located on short arm of chromosome 6, at 6p21.3 [2] (Figure 1), spanning an area of 4287 base pairs (bp). It contains 7 exons and 6 introns, in addition to a TATA, a poly A and four alternate splicing signals [3] (Figure 2). Exon 1 encodes leader peptide, exon 2 and 3 encode alpha 1 & alpha 2 domains, exon 4 encodes alpha 3, exon 5 encodes the transmembrane region, and exon 6 & 7 encode cytoplasmic tail. The product of this gene is 362 amino acid protein comprising three alpha chains associated with a beta2 microglobulin chain which is encoded by chromosome 15. Alpha 3 chain has a transmembrane region and a cytoplasmic tail and is conserved among all HLA class I molecules. Alpha 1 and alpha 2 chains formed by amino acids 26-203 [4], form peptide binding groove. The polymorphic residues are confined to alpha 1 and alpha 2 domains. X-ray crystallographic analysis show that alpha 1 and alpha 2 chains interact to form a floor of eight stranded antiparallel beta pleated sheet supporting two parallel strands of alpha helix which are so closely opposed that only peptides of eight to ten residues can be bound to it [5]. The peptide binding groove is of alpha 1 & 2 chains is formed by six pockets named A-F. Of these, pockets A & F are important as they interact with amino and carboxyl ends of peptide respectively. Polymorphic residues in these pockets influence peptide binding of various HLA alleles to different peptides and hence influence disease susceptibility [6]. Figure 3 shows 3D structure of HLA B27 molecule with alpha 1 & 2 domains shown in pink and alpha 3 domain in blue. Peptide binding groove is clearly seen between the first two domains.
Figure 1: HLA B 27 Gene Position on Chromosome.
Figure 2: Schematic Illustration of HLA B27 Gene Depicting Exons & Introns.
Figure 3: 3D structure of HLA B27 molecule with alpha 1 & 2 domains shown in pink and alpha 3 domain in blue.
So far, more than 104 alleles of HLA-B27 have been identified based on nucleotide sequence differences. However, at the translated protein level, there are at least 91subtypes of HLA-B27 based on amino acid sequence differences as some of the mutations are located within introns and thus are silent, or they occur in exons but do not cause amino acid changes. These 91 subtypes are HLA-B*2701 to HLA-B*2792 because one of the assignments—HLA-B*2722— was subsequently withdrawn when it was found to be identical to HLA-B*2706 [7].

Disease Association and Proposed Pathogenesis

HLA B27 association with ankylosing spondylitis is among the strongest genetic associations of a gene with common human diseases, with B*2702, B*2704, B*2705, B*2707 and B*2708 carrying stronger linkage with the disease in different populations [8]. Although different subtypes of the molecule may differ from each other in a single amino acid residue, stronger association of few subtypes with diseases clearly indicates that subtype specific polymorphic residues impart different structural, thermodynamic and functional properties thus affecting peptide binding of the molecule [9]. X ray crystallographic studies and other biophysical technique used to elucidate this difference are beyond the scope of this mini-review and described elsewhere [10].
Different theories regarding its pathogenetic mechanism have been proposed. Arthritogenic peptide hypothesis among these is by far more commonly accepted one, although no such peptide has been identified yet in humans8. Peptides derived from HLA B27 have sequence homology with peptides from different micro-organisms including enterobacteria, chlamydia and cytokeratin and it has been suggested that HLA B27 derived peptides may itself play a role in initiating the inflammatory process by activating T lymphocytes [11,12].
Recently it has been found that B27 heavy chains either alone or as heavy chain homodimers can appear on the surface of cells and then interact with cells carrying killer cell immunoglobulin like receptors. It can then initiate pathogenic Th17 response [13,14]. Figure 4 shows hypothetical molecular model of heavy chain homodimer formation [15].
Figure 4: HLA B27 Heavy Chain Homodimer Formation with a Disulfide Bond at Position 67.
Unfolded protein response is a homeostatic mechanism generated by endoplasmic reticulum (ER) as a step to clear a misfolded protein and return itself to normal environment. Misfolding of B27 heavy chains in ER leads to IL23 production providing a possible link between B27 and ankylosing Spondylitis [16].
Another theory that B27 gene may be in linkage disequilibrium with another disease causing linked gene has gained little acceptance [16].
It has also been found that T lymphocyte response to peptide presentation by HLA B27 not only involves CD8 restricted T lymphocytes, but also CD4 positive T cells also, which are otherwise HLA class II restricted. These T cells produce IL17, IFN-gamma and perforin and thus may play a role in inflammatory process [17,18].

References



















Track Your Manuscript

Media Partners

Associations