ReviewHLA-B27 and antigen presentation: At the crossroads between immune defense and autoimmunity
Section snippets
HLA-B27 and the puzzling mechanisms of AS
The initial discovery in 1972 of a strong association of AS with HLA-B27 has been widely confirmed over the past forty years and has become a textbook example for the association between a human disorder and a HLA gene (Brewerton et al., 1973, Schlosstein et al., 1973). Nevertheless, the precise pathogenic role of HLA-B27 is still elusive and continues to be the focus of intense investigations.
The recognition of HLA-B27 molecules by CD8+ T cells as pivotal event in the pathogenesis of AS, has
Genetic data sustain the pathogenic role of B27 antigen presentation
Genome-wide association studies (GWAS) have disclosed new susceptibility loci and offered new clues for a comprehensive view on the mechanistic role of HLA-B27 in AS. The endoplasmic reticulum amino-peptidase 1 (ERAP1) gene has been found associated with AS in HLA-B27 positive cases only (Evans et al., 2011). ERAP1 is involved in the ER-trimming of peptides, previously processed by the proteasome, allowing them to reach an optimal length (8–9 aa) before being loaded on the HLA class I
HLA-B27 positivity: a double-edged sword
The principal function of the HLA-B27 molecules is to present microbial or self-derived peptides and thereby to activate cytotoxic CD8+ T lymphocytes (CTL) in the context of adaptive immunity. In this respect, HLA-B27, together with HLA-B57, is one of the best presenting molecules since B27 carriers show a slow disease progression to AIDS (Chen et al., 2012) and, generally, a good capacity to control viral infections (HCV, Flu, EBV) through the recognition of immunodominant epitopes (
HLA-B27 peptide repertoire: sequence, length and cell compartment peptide loading
Several studies analyzed the HLA-B*2705 peptide binding repertoire increasing the collection of naturally presented peptides. This allowed to refine the B27 motif and to determine the source of these ligands (Ben Dror et al., 2010).
Besides a range of peptide lengths from 8 to 33 aa (Urban et al., 1994), the HLA-B27 peptidome comprises also a small fraction of peptides in which the primary anchor residue at P2, generally an Arg, is replaced by a Gln (Infantes et al., 2013). Interestingly, these
Structural and dynamical aspects of HLA-B27
A hallmark of HLA-B27 molecules is the presence of the unpaired, TCR-inaccessible Cys67 within the B pocket (Fig. 1) where the primary anchor residue of the peptide, usually pArg2, is located. This residue confers the capability to form β2m-free disulfide-linked heavy chain (HC) B27-homodimers (Allen et al., 1999). Other alleles of the HLA-B locus share this cysteine (B14, B15, B38, B39, B73) and, notably, some of them, namely B14, B38 and B39, are risk factors for AS independently from HLA-B27
Conclusions
It is amazing how the clue of the well-established association between HLA-B27 and AS, the first time described four decades ago, is still elusive. Since the physiological function of HLA class I molecules is to present antigenic peptides to CD8+ T cells, this immediately appeared as the most likely molecular mechanism for this association. However, the lack of conclusive evidence prompted to consider further explanations. Recently, the report of the epistatic effects between ERAP1 and HLA-B27
Conflicts of interest
No competing financial interests exist.
Acknowledgments
Our work has been supported by the Istituto Pasteur-Fondazione Cenci Bolognetti, by Sapienza through Progetti di Ateneo, by VolkswagenStiftung and by the German Science Foundation (DFG BO 2963/1-1). We sincerely thank Prof. A. Mathieu and Dr. A. Cauli for fruitful and long-lasting collaboration.
References (47)
- et al.
The Cys-67 residue of HLA-B27 influences cell surface stability, peptide specificity, and T-cell antigen presentation
Journal of Biological Chemistry
(2001) - et al.
Guilt by association: HLA-B27 and ankylosing spondylitis
Immunology Today
(1990) - et al.
Ankylosing spondylitis and HL-A 27
Lancet
(1973) - et al.
HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution
Journal of Molecular Biology
(2008) - et al.
Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human beta 2m: an animal model of HLA-B27-associated human disorders
Cell
(1990) - et al.
Natural HLA-B*2705 ligands with glutamine as anchor motif: implications for HLA-B27 association to spondyloarthropathy
Journal of Biological Chemistry
(2013) - et al.
Characterization of a proteasome and TAP-independent presentation of intracellular epitopes by HLA-B27 molecules
Journal of Biological Chemistry
(2012) - et al.
Dynamical characterization of two differentially disease associated MHC class I proteins in complex with viral and self-peptides
Journal of Molecular Biology
(2012) - et al.
HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system
European Journal of Cell Biology
(2012) - et al.
Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure
Journal of Immunology
(1999)
Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover
Journal of Experimental Medicine
Variants in RUNX3 contribute to susceptibility to psoriatic arthritis exhibiting further common ground with ankylosing spondylitis
Arthritis & Rheumatism
The solvent-inaccessible Cys67 residue of HLA-B27 contributes to T cell recognition of HLA-B27/peptide complexes
Journal of Immunology
Immunohistologic analysis of zygapophyseal joints in patients with ankylosing spondylitis
Arthritis & Rheumatism
The HLA-B*2705 peptidome
Arthritis & Rheumatism
The C terminus of the nucleoprotein of influenza A virus delivers antigens transduced by Tat to the trans-Golgi network and promotes an efficient presentation through HLA class I
Journal of Virology
Preferential HLA usage in the influenza virus-specific CTL response
Journal of Immunology
Different HLA-B27 subtypes present the same immunodominant Epstein–Barr virus peptide
Journal of Experimental Medicine
Identification of previously unrecognized predisposing factors for ankylosing spondylitis from analysis of HLA-B27 extended haplotypes in Sardinia
Arthritis & Rheumatism
TCR clonotypes modulate the protective effect of HLA class I molecules in HIV-1 infection
Nature Immunology
Predominance of CD8+ T lymphocytes in psoriatic arthritis
Journal of Rheumatology
Relevance of residue 116 of HLA-B27 in determining susceptibility to ankylosing spondylitis
European Journal of Immunology
Old and new HLA associations with ankylosing spondylitis
Tissue Antigens
Cited by (36)
The enigma of sclera-specific autoimmunity in scleritis
2024, Journal of AutoimmunityAntigen-specific immune reactions by expanded CD8<sup>+</sup> T cell clones from HLA-B*27-positive patients with spondyloarthritis
2022, Journal of AutoimmunityCitation Excerpt :Strikingly, the highly homologous alleles B*27:06 and B*27:09 do not confer any risk. The only major differences in the HLA binding groove and the T cell receptor (TCR) recognition area between risk- and non-risk-conferring alleles are at amino acid positions 114 and 116 in the floor of the peptide-binding groove of HLA-B*27, which contribute to peptide binding pockets D and F [6–8]. Further, the second strongest susceptibility gene for SpA is endoplasmic reticulum aminopeptidase 1 (ERAP1), which trims peptides in the lumen of the endoplasmic reticulum to a proper length [9–11].
ERAP1 shapes just part of the immunopeptidome
2019, Human ImmunologyThe association of HLA-B27 and Klebsiella pneumoniae in ankylosing spondylitis: A systematic review
2018, Microbial PathogenesisGastrointestinal and Hepatic Disease in Spondyloarthritis
2018, Rheumatic Disease Clinics of North AmericaCitation Excerpt :In the B27 rat model, disease-specific dysbiosis occurs in parallel with metabolic and mucosal immune changes associated with developing inflammation,45,46 further supporting the role of the microbiome in triggering altered T-cell responses relevant to the pathogenesis of SpA. Although the specific mechanisms have yet to be defined, a general model of the gut-joint hypothesis is suggested by current data: Compounded by genetic polymorphisms, a state of microbial dysbiosis, and localized intestinal inflammation, a Th17 response and generation of autoreactive T and B cells is thought to emerge.47–49 Locally activated lymphocytes and macrophages, expressing intestinal markers, such as invariant T-cell receptors,50 IL-23R, interleukin-17a, αEβ7, α4β7, and CD16322,47 then circulate to other tissues, such as the joint, where they engage self-antigens and initiate inflammation.
Born to run: The paradox of biomechanical force in spondyloarthritis from an evolutionary perspective
2017, Best Practice and Research: Clinical Rheumatology