Peptides: the cornerstone of HLA-B27 biology and pathogenetic role in spondyloarthritis.

The association of human leukocyte antigen (HLA)-B27 to ankylosing spondylitis is one of the strongest between a major histocompatibility complex molecule and a disease. Yet, the basis for this association remains unknown. Several hypotheses, each based on a particular feature of HLA-B27, guide much of the current research on the pathogenesis of this disease, but none has yet satisfactorily explained its mechanism and the differential association of B27 subtypes to it. In this review, the pathogenetic role of HLA-B27 will be analyzed from a global perspective of its biology, emphasizing the interdependency of multiple molecular features and the likely influence of disease-modifying gene products. From this perspective, peptide binding emerges as the cornerstone of all other biological properties.

[1]  J. Shabanowitz,et al.  Differences in the Expression of Human Class I MHC Alleles and Their Associated Peptides in the Presence of Proteasome Inhibitors1 , 2001, The Journal of Immunology.

[2]  L. K. Ely,et al.  Natural HLA Class I Polymorphism Controls the Pathway of Antigen Presentation and Susceptibility to Viral Evasion , 2004, The Journal of experimental medicine.

[3]  Akira Hattori,et al.  An IFN-γ–induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I–presented peptides , 2002, Nature Immunology.

[4]  Begoña Galocha,et al.  Folding of HLA-B27 subtypes is determined by the global effect of polymorphic residues and shows incomplete correspondence to ankylosing spondylitis. , 2008, Arthritis and rheumatism.

[5]  C. Carcassi,et al.  Relevance of residue 116 of HLA‐B27 in determining susceptibility to ankylosing spondylitis , 1995, European journal of immunology.

[6]  K. Paulsson,et al.  Chaperones and folding of MHC class I molecules in the endoplasmic reticulum. , 2003, Biochimica et biophysica acta.

[7]  P. Bowness HLA B27 in health and disease: a double-edged sword? , 2002, Rheumatology.

[8]  L. Bradbury,et al.  Non-B27 MHC associations of ankylosing spondylitis , 2007, Genes and Immunity.

[9]  Christian A. Combs,et al.  Identification of ARTS-1 as a novel TNFR1-binding protein that promotes TNFR1 ectodomain shedding , 2002 .

[10]  A. Mathieu,et al.  A Sardinian patient with ankylosing spondylitis and HLA-B*2709 co-occurring with HLA-B*1403. , 2007, Arthritis and rheumatism.

[11]  R. Hammer,et al.  Additional human beta2-microglobulin curbs HLA-B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA-B27-transgenic rats. , 2006, Arthritis and rheumatism.

[12]  R. Hammer,et al.  Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlates with the level of B27 expression. , 1993, Journal of immunology.

[13]  J. Castro HLA-B27 and the Pathogenesis of Spondyloarthropathies , 2007 .

[14]  M. Vázquez,et al.  HLA-B*2704, an Allotype Associated with Ankylosing Spondylitis, Is Critically Dependent on Transporter Associated with Antigen Processing and Relatively Independent of Tapasin and Immunoproteasome for Maturation, Surface Expression, and T Cell Recognition: Relationship to B*2705 and B*27061 , 2006, The Journal of Immunology.

[15]  M. Vázquez,et al.  Similar cell surface expression of beta2-microglobulin-free heavy chains by HLA-B27 subtypes differentially associated with ankylosing spondylitis. , 2005, Arthritis and rheumatism.

[16]  R. Tampé,et al.  A critical role for tapasin in the assembly and function of multimeric MHC class I-TAP complexes. , 1997, Science.

[17]  P. Endert Role of tripeptidyl peptidase II in MHC class I antigen processing – the end of controversies? , 2008, European journal of immunology.

[18]  P. Cresswell,et al.  Tapasin and ERp57 form a stable disulfide‐linked dimer within the MHC class I peptide‐loading complex , 2005, The EMBO journal.

[19]  E. Coto,et al.  HLA-B27 polymorphism and worldwide susceptibility to ankylosing spondylitis. , 1997, Tissue antigens.

[20]  C. Angelini,et al.  Identification of previously unrecognized predisposing factors for ankylosing spondylitis from analysis of HLA-B27 extended haplotypes in Sardinia. , 2007, Arthritis and rheumatism.

[21]  J. Cragnolini,et al.  Identification of Endogenously Presented Peptides from Chlamydia trachomatis with High Homology to Human Proteins and to a Natural Self-ligand of HLA-B27*S , 2008, Molecular & Cellular Proteomics.

[22]  R. Brunham,et al.  Immunoproteomic Discovery of Novel T Cell Antigens from the Obligate Intracellular Pathogen Chlamydia1 , 2008, The Journal of Immunology.

[23]  M. Marcilla,et al.  Proteasome-independent HLA-B27 Ligands Arise Mainly from Small Basic Proteins*S , 2007, Molecular & Cellular Proteomics.

[24]  D. Rognan,et al.  Molecular Mimicry of an HLA-B27-derived Ligand of Arthritis-linked Subtypes with Chlamydial Proteins* , 2002, The Journal of Biological Chemistry.

[25]  B. Loll,et al.  Implications of structural and thermodynamic studies of HLA-B27 subtypes exhibiting differential association with ankylosing spondylitis. , 2009, Advances in experimental medicine and biology.

[26]  W. Saenger,et al.  Thermodynamic and structural equivalence of two HLA-B27 subtypes complexed with a self-peptide. , 2005, Journal of molecular biology.

[27]  Simon C. Potter,et al.  Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants , 2007, Nature Genetics.

[28]  P. Bowness,et al.  Jekyll and Hyde: the transformation of HLA-B27. , 2000, Immunology today.

[29]  E. Camafeita,et al.  Identification of Novel HLA-B27 Ligands Derived from Polymorphic Regions of Its Own or Other Class I Molecules Based on Direct Generation by 20 S Proteasome* , 2001, The Journal of Biological Chemistry.

[30]  D. Rognan,et al.  Long‐range effects in protein–ligand interactions mediate peptide specificity inl the human major histocompatibility antigen HLA‐B27 (B*2701) , 1999, Protein science : a publication of the Protein Society.

[31]  J. Harley,et al.  A hypothesis for the HLA-B27 immune dysregulation in spondyloarthropathy: contributions from enteric organisms, B27 structure, peptides bound by B27, and convergent evolution. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[32]  A. Goldberg,et al.  26S proteasomes and immunoproteasomes produce mainly N‐extended versions of an antigenic peptide , 2001, The EMBO journal.

[33]  J. Drijfhout,et al.  Cutting Edge: HLA-B27 Acquires Many N-Terminal Dibasic Peptides: Coupling Cytosolic Peptide Stability to Antigen Presentation1 , 2006, The Journal of Immunology.

[34]  J. Fernández-Morera,et al.  Association of ankylosing spondylitis with HLA-B*1403 in a West African population. , 2002, Arthritis and rheumatism.

[35]  J. Albar,et al.  HLA-B27 (B*2701) specificity for peptides lacking Arg2 is determined by polymorphism outside the B pocket. , 1997, Tissue antigens.

[36]  H. Rammensee,et al.  Misfolding of HLA-B27 as a result of its B pocket suggests a novel mechanism for its role in susceptibility to spondyloarthropathies. , 1999, Journal of immunology.

[37]  Rosa Sorrentino,et al.  Allele-dependent Similarity between Viral and Self-peptide Presentation by HLA-B27 Subtypes* , 2005, Journal of Biological Chemistry.

[38]  J. Goodall,et al.  Spondylarthritis-associated and non-spondylarthritis-associated B27 subtypes differ in their dependence upon tapasin for surface expression and their incorporation into the peptide loading complex. , 2006, Arthritis and rheumatism.

[39]  A. van Leeuwen,et al.  Guilt by association: HLA-B27 and ankylosing spondylitis. , 1990, Immunology today.

[40]  M. Garcia-Peydró,et al.  Quantitative and Qualitative Influences of Tapasin on the Class I Peptide Repertoire1 , 2001, The Journal of Immunology.

[41]  E. Ren,et al.  Possible protective role of HLA-B*2706 for ankylosing spondylitis. , 1997, Tissue antigens.

[42]  Ying Wang,et al.  A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 , 2005, Nature Immunology.

[43]  C. Carcassi,et al.  Two distinctive HLA haplotypes harbor the B27 alleles negatively or positively associated with ankylosing spondylitis in Sardinia: implications for disease pathogenesis. , 2003, Arthritis and rheumatism.

[44]  R. Colbert,et al.  HLA-B27 Misfolding Is Associated with Aberrant Intermolecular Disulfide Bond Formation (Dimerization) in the Endoplasmic Reticulum* , 2002, The Journal of Biological Chemistry.

[45]  J. Albar,et al.  Modulation of peptide binding by HLA‐B27 polymorphism in pockets A and B, and peptide specificity of B*2703 , 1995, European journal of immunology.

[46]  James McCluskey,et al.  Optimization of the MHC class I peptide cargo is dependent on tapasin. , 2002, Immunity.

[47]  J. Shabanowitz,et al.  Proteasomes can either generate or destroy MHC class I epitopes: evidence for nonproteasomal epitope generation in the cytosol. , 1998, Journal of immunology.

[48]  Feras Hawari,et al.  An Aminopeptidase, ARTS-1, Is Required for Interleukin-6 Receptor Shedding* , 2003, Journal of Biological Chemistry.

[49]  S. Mizutani,et al.  Human Leukocyte-derived Arginine Aminopeptidase , 2003, Journal of Biological Chemistry.

[50]  A. Ziegler,et al.  Ankylosing spondylitis: a beta2m-deposition disease? , 2003, Trends in immunology.

[51]  J. Goodall,et al.  The recognition of abnormal forms of HLA-B27 by CD4+ T cells. , 2004, Current molecular medicine.

[52]  R. Hammer,et al.  The Specificity of Peptides Bound to Human Histocompatibility Leukocyte Antigen (HLA)-B27 Influences the Prevalence of Arthritis in HLA-B27 Transgenic Rats , 1998, The Journal of experimental medicine.

[53]  M. Preuss,et al.  Redox regulation of peptide receptivity of major histocompatibility complex class I molecules by ERp57 and tapasin , 2007, Nature Immunology.

[54]  M. Marcilla,et al.  B*2707 differs in peptide specificity from B*2705 and B*2704 as much as from HLA‐B27 subtypes not associated to spondyloarthritis , 2006, European journal of immunology.

[55]  R. Colbert,et al.  HLA-B27 Misfolding in Transgenic Rats Is Associated with Activation of the Unfolded Protein Response1 , 2005, The Journal of Immunology.

[56]  M. Vázquez,et al.  HLA-B27: a registry of constitutive peptide ligands. , 2004, Tissue antigens.

[57]  L. Punzi,et al.  Distribution of HLA-B27 subtypes in Sardinia and continental Italy and their association with spondylarthropathies. , 2005, Arthritis and rheumatism.

[58]  S. Rowland-Jones,et al.  Differences in peptide presentation between B27 subtypes: the importance of the P1 side chain in maintaining high affinity peptide binding to B*2703. , 1994, Immunity.

[59]  Dean R. Madden,et al.  The three-dimensional structure of HLA-B27 at 2.1 Å resolution suggests a general mechanism for tight peptide binding to MHC , 1992, Cell.

[60]  J. Harley,et al.  HLA-B27 binding of peptide from its own sequence and similar peptides from bacteria: implications for spondyloarthropathies , 1995, The Lancet.

[61]  Michael J. Wilson,et al.  Cutting Edge: Leukocyte Receptor Complex-Encoded Immunomodulatory Receptors Show Differing Specificity for Alternative HLA-B27 Structures1 , 2001, The Journal of Immunology.

[62]  H. Pahl,et al.  The ER-overload response: activation of NF-kappa B. , 1997, Trends in biochemical sciences.

[63]  L. Schomburg,et al.  Concerted peptide trimming by human ERAP1 and ERAP2 aminopeptidase complexes in the endoplasmic reticulum , 2005, Nature Immunology.

[64]  R. Hammer,et al.  Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and human β 2m: An animal model of HLA-B27-associated human disorders , 1990, Cell.

[65]  J. Taurog,et al.  HLA-B27 in Transgenic Rats Forms Disulfide-Linked Heavy Chain Oligomers and Multimers That Bind to the Chaperone BiP1 , 2004, The Journal of Immunology.

[66]  P. Cresswell,et al.  Selective loading of high-affinity peptides onto major histocompatibility complex class I molecules by the tapasin-ERp57 heterodimer , 2007, Nature Immunology.

[67]  M. Ramos,et al.  HLA-B27 and the pathogenesis of spondyloarthritis. , 2002, Tissue antigens.

[68]  R. Colbert,et al.  HLA-B27 misfolding: a solution to the spondyloarthropathy conundrum? , 2000, Molecular medicine today.

[69]  I. Olivieri,et al.  The HLA-B*2709 subtype in a woman with early ankylosing spondylitis. , 2007, Arthritis and rheumatism.

[70]  Rosa Sorrentino,et al.  Conformational Dimorphism of Self-peptides and Molecular Mimicry in a Disease-associated HLA-B27 Subtype* , 2006, Journal of Biological Chemistry.

[71]  S Uebel,et al.  Recognition principle of the TAP transporter disclosed by combinatorial peptide libraries. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[72]  J. A. López de Castro,et al.  HLA-B27 and the pathogenesis of spondyloarthropathies. , 2007, Immunology letters.

[73]  R D Sturrock,et al.  Ankylosing spondylitis and HL-A 27. , 1973, Lancet.

[74]  M. Brown,et al.  Breakthroughs in genetic studies of ankylosing spondylitis. , 2007, Rheumatology.

[75]  Feras Hawari,et al.  Shedding of the Type II IL-1 Decoy Receptor Requires a Multifunctional Aminopeptidase, Aminopeptidase Regulator of TNF Receptor Type 1 Shedding , 2003, The Journal of Immunology.

[76]  G. Kyriakides,et al.  HLA-B27 in the Greek Cypriot population: distribution of subtypes in patients with ankylosing spondylitis and other HLA-B27-related diseases. The possible protective role of B*2707. , 2004, Human immunology.

[77]  R. Colbert,et al.  HLA-B27 up-regulation causes accumulation of misfolded heavy chains and correlates with the magnitude of the unfolded protein response in transgenic rats: Implications for the pathogenesis of spondylarthritis-like disease. , 2007, Arthritis and rheumatism.

[78]  M. Mann,et al.  ER‐60, a chaperone with thiol‐dependent reductase activity involved in MHC class I assembly , 1998, The EMBO journal.

[79]  T. Elliott,et al.  Lymphoblastoid cells express HLA‐B27 homodimers both intracellularly and at the cell surface following endosomal recycling , 2003, European journal of immunology.

[80]  P Wordsworth,et al.  Susceptibility to ankylosing spondylitis in twins: the role of genes, HLA, and the environment. , 1997, Arthritis and rheumatism.

[81]  B. Suarez-Alvarez,et al.  Contribution of KIR3DL1/3DS1 to ankylosing spondylitis in human leukocyte antigen-B27 Caucasian populations , 2006, Arthritis research & therapy.

[82]  Günter J. Hämmerling,et al.  Selectivity of MHC-encoded peptide transporters from human, mouse and rat , 1994, Nature.

[83]  N. Morrice,et al.  A role for the thiol-dependent reductase ERp57 in the assembly of MHC class I molecules , 1998, Current Biology.

[84]  T. Dick Assembly of MHC class I peptide complexes from the perspective of disulfide bond formation , 2004, Cellular and Molecular Life Sciences CMLS.

[85]  Rosa Sorrentino,et al.  Dual, HLA-B27 Subtype-dependent Conformation of a Self-peptide , 2004, The Journal of experimental medicine.

[86]  W. Saenger,et al.  Thermodynamic and Structural Analysis of Peptide- and Allele-dependent Properties of Two HLA-B27 Subtypes Exhibiting Differential Disease Association* , 2004, Journal of Biological Chemistry.

[87]  A. Ziegler,et al.  Ankylosing spondylitis: a β2m–deposition disease? , 2003 .

[88]  S. Opat,et al.  The Recognition of HLA-B27 by Human CD4+ T Lymphocytes1 , 2001, The Journal of Immunology.

[89]  H. Rammensee,et al.  Naturally occurring A pocket polymorphism in HLA-B*2703 increases the dependence on an accessory anchor residue at P1 for optimal binding of nonamer peptides. , 1997, Journal of immunology.

[90]  M. Fiorillo,et al.  CD8(+) T-cell autoreactivity to an HLA-B27-restricted self-epitope correlates with ankylosing spondylitis. , 2000, The Journal of clinical investigation.

[91]  P. Cresswell,et al.  The thiol oxidoreductase ERp57 is a component of the MHC class I peptide-loading complex , 1998, Current Biology.

[92]  A. Marina,et al.  The Peptide Repertoires of HLA-B27 Subtypes Differentially Associated to Spondyloarthropathy (B*2704 and B*2706) Differ by Specific Changes at Three Anchor Positions* , 2002, The Journal of Biological Chemistry.

[93]  Jürgen Braun,et al.  Ankylosing spondylitis. , 2007, Lancet.

[94]  A. Goldberg,et al.  Degradation of cell proteins and the generation of MHC class I-presented peptides. , 1999, Annual review of immunology.

[95]  P. Cresswell,et al.  Roles for calreticulin and a novel glycoprotein, tapasin, in the interaction of MHC class I molecules with TAP. , 1996, Immunity.

[96]  J. Neefjes,et al.  Allelic differences in the relationship between proteasome activity and MHC class I peptide loading. , 1998, Journal of immunology.

[97]  L. Wedderburn,et al.  Expansion and enhanced survival of natural killer cells expressing the killer immunoglobulin-like receptor KIR3DL2 in spondylarthritis. , 2005, Arthritis and rheumatism.

[98]  S Kunmartini,et al.  HLA-B27 subtypes positively and negatively associated with spondyloarthropathy. , 1997, The Journal of rheumatology.

[99]  N. Shastri,et al.  ERAAP customizes peptides for MHC class I molecules in the endoplasmic reticulum , 2002, Nature.

[100]  M. Jackson,et al.  The molecular chaperone calnexin facilitates folding and assembly of class I histocompatibility molecules. , 1996, The EMBO journal.

[101]  J. Castro HLA-B27-Bound Peptide Repertoires: Their Nature, Origin and Pathogenetic Relevance , 2009 .

[102]  E. Märker-Hermann,et al.  HLA‐B27‐restricted T cells from patients with ankylosing spondylitis recognize peptides from B*2705 that are similar to bacteria‐derived peptides , 2003, Clinical and experimental immunology.

[103]  P Chiewsilp,et al.  HLA-B27 subtypes in Asian patients with ankylosing spondylitis. Evidence for new associations. , 1995, Tissue antigens.

[104]  N. Shastri,et al.  ER aminopeptidases generate a unique pool of peptides for MHC class I molecules , 2001, Nature Immunology.

[105]  A Sette,et al.  The peptide-binding motif for the human transporter associated with antigen processing , 1995, The Journal of experimental medicine.

[106]  A. McMichael,et al.  Cell-surface expression and immune receptor recognition of HLA-B27 homodimers. , 2002, Arthritis and rheumatism.

[107]  J. Yewdell,et al.  The generation of MHC class I-associated peptides is only partially inhibited by proteasome inhibitors: involvement of nonproteasomal cytosolic proteases in antigen processing? , 1997, Journal of immunology.

[108]  D. Brewerton,et al.  Reiter's disease and HL-A 27. , 1973, Lancet.