Implications of structural and thermodynamic studies of HLA-B27 subtypes exhibiting differential association with ankylosing spondylitis.

Structural and thermodynamic properties of HLA-B27 molecules provide the basis for their function within the immune system and are probably also central for the understanding of the pathology of HLA-B27-associated diseases such as ankolysing spondylitis (AS). Several HLA-B27 alleles are AS-associated, whereas some are not, although the protein encoded by the former may differ in only a single amino acid exchange from those specified by the latter. This indicates that subtype-specific polymorphic residues play a key role in determining whether an HLA-B27 subtype is AS-associated or not and open the possibility to correlate structural, thermodynamic and functional characteristics ofa given subtype with the disease association. Our studies involved X-ray crystallography and various other biophysical techniques to examine how several different peptides are accommodated within the binding groove of the molecules. The HLA-B*2705 and HLA-B*2709 subtypes, whose products differ in only a single amino acid residue of their heavy chains from each other, were primarily chosen for these analyses, but our studies have recently also been extended to the closely related subtypes HLA-B*2703, HLA-B*2704 and HLA-B*2706. The analyses reveal that structural and thermodynamic differences between HLA-B27 complexes may exist, depending on the peptide that is displayed. Furthermore, aviralpeptide and two self-peptides were found that exhibit HLA-B27 subtype-dependent molecular mimicry, thereby providing a molecular basis to account for the subtype-dependent presence of autoreactive T-cells. Although these results do not exclude other theories for the pathogenesis of AS, they support the arthritogenic peptide hypothesis which envisages molecular mimicry between HLA-B27-presented foreign and self-peptides to explain the cross-reactivity of autoreactive T-cells that are found in HLA-B*2705-positive individuals, in particular when they suffer from AS.

[1]  W. Saenger,et al.  Purification, crystallization and preliminary X-ray diffraction analysis of the human major histocompatibility antigen HLA-B*2703 complexed with a viral peptide and with a self-peptide. , 2005, Acta crystallographica. Section F, Structural biology and crystallization communications.

[2]  P. Privalov,et al.  Scanning microcalorimetry in studying temperature-induced changes in proteins. , 1986, Methods in enzymology.

[3]  HLA-B27-transgenic rats, amyloid deposits, and spondyloarthropathies , 2008, Modern rheumatology.

[4]  D. Wiley,et al.  HLA-A2-peptide complexes: refolding and crystallization of molecules expressed in Escherichia coli and complexed with single antigenic peptides. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[5]  W. Saenger,et al.  Preliminary X-ray diffraction analysis of crystals from the recombinantly expressed human major histocompatibility antigen HLA-B*2704 in complex with a viral peptide and with a self-peptide. , 2005, Acta crystallographica. Section F, Structural biology and crystallization communications.

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

[7]  A. Barth,et al.  What vibrations tell about proteins , 2002, Quarterly Reviews of Biophysics.

[8]  Thomas E. Creighton,et al.  Protein structure : a practical approach , 1997 .

[9]  W. Saenger,et al.  X-ray diffraction analysis of crystals from the human major histocompatibility antigen HLA-B*2706 in complex with a viral peptide and with a self-peptide. , 2005, Acta crystallographica. Section F, Structural biology and crystallization communications.

[10]  D. Margulies,et al.  MHC class I molecules, structure and function. , 1999, Reviews in immunogenetics.

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

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

[13]  Wolfram Saenger,et al.  HLA-B27 Subtypes Differentially Associated with Disease Exhibit Subtle Structural Alterations* , 2002, The Journal of Biological Chemistry.

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

[15]  G. Petsko,et al.  Effects of temperature on protein structure and dynamics: X-ray crystallographic studies of the protein ribonuclease-A at nine different temperatures from 98 to 320 K. , 1993, Biochemistry.

[16]  Ian A Wilson,et al.  Structural and thermodynamic correlates of T cell signaling. , 2002, Annual review of biophysics and biomolecular structure.

[17]  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.

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

[19]  A. Rickinson,et al.  Different HLA-B27 subtypes present the same immunodominant Epstein-Barr virus peptide , 1993, The Journal of experimental medicine.

[20]  A. Marina,et al.  Differential Association of HLA-B*2705 and B*2709 to Ankylosing Spondylitis Correlates with Limited Peptide Subsets but Not with Altered Cell Surface Stability* , 2002, The Journal of Biological Chemistry.

[21]  P. Kloetzel,et al.  HLA-B27-restricted CD8+ T cell response to cartilage-derived self peptides in ankylosing spondylitis. , 2005, Arthritis and rheumatism.

[22]  Heinz Fabian,et al.  HLA-B27 subtypes differentially associated with disease exhibit conformational differences in solution. , 2008, Journal of molecular biology.

[23]  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.

[24]  A. McMichael,et al.  Cutting edge: HLA-B27 can form a novel beta 2-microglobulin-free heavy chain homodimer structure. , 1999, Journal of immunology.

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

[26]  L. Sistonen,et al.  Enhanced intracellular replication of Salmonella enteritidis in HLA-B27-expressing human monocytic cells: dependency on glutamic acid at position 45 in the B pocket of HLA-B27. , 2004, Arthritis and rheumatism.

[27]  P I Terasaki,et al.  High association of an HL-A antigen, W27, with ankylosing spondylitis. , 1973, The New England journal of medicine.

[28]  Werner Mäntele,et al.  Infrared Spectroscopy of Proteins , 2006 .

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

[30]  P. Parham,et al.  Guilt by association: HLA-B27 and ankylosing spondylitis. , 1990, Immunology today.

[31]  Ulrike Alexiev,et al.  Differential Peptide Dynamics Is Linked to Major Histocompatibility Complex Polymorphism* , 2004, Journal of Biological Chemistry.

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

[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. Coligan,et al.  Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells. , 2002, Molecular immunology.

[35]  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.

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

[37]  M. A. Saper,et al.  Structure of the human class I histocompatibility antigen, HLA-A2 , 1987, Nature.

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

[39]  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.

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

[41]  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.

[42]  D. Madden.  The three-dimensional structure of peptide-MHC complexes. , 1995, Annual review of immunology.

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

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

[45]  A. Winter,et al.  Natural MHC class I polymorphism controls the pathway of peptide dissociation from HLA-B27 complexes. , 2007, Biophysical journal.

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

[47]  S. Yoshiya,et al.  Beta 2-microglobulin amyloid deposit in HLA-B27 transgenic rats , 2007, Modern rheumatology.

[48]  U. Alexiev,et al.  Elucidation of the nature of the conformational changes of the EF-interhelical loop in bacteriorhodopsin and of the helix VIII on the cytoplasmic surface of bovine rhodopsin: a time-resolved fluorescence depolarization study. , 2003, Journal of Molecular Biology.

[49]  D. R. Madden,et al.  The structure of HLA-B27 reveals nonamer self-peptides bound in an extended conformation , 1991, Nature.

[50]  Hill Gaston,et al.  Mechanisms of Disease: the immunopathogenesis of spondyloarthropathies , 2006, Nature Clinical Practice Rheumatology.

[51]  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.

[52]  J. Chalmers,et al.  Handbook of vibrational spectroscopy , 2002 .

[53]  J. Taurog.  The mystery of HLA-B27: if it isn't one thing, it's another. , 2007, Arthritis and rheumatism.

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

[55]  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.

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

[57]  T. Earnest,et al.  1.59 Å structure of trypsin at 120 K: Comparison of low temperature and room temperature structures , 1991, Proteins.

[58]  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.

[59]  M. Garcia-Peydró,et al.  High T cell epitope sharing between two HLA-B27 subtypes (B*2705 and B*2709) differentially associated to ankylosing spondylitis. , 1999, Journal of immunology.

[60]  Balvinder Singh,et al.  HLA‐B27 lacking associated β2‐microglobulin rearranges to auto‐display or cross‐display residues 169–181: a novel molecular mechanism for spondyloarthropathies , 2004, FEBS letters.

[61]  D Rognan,et al.  Thermodynamic stability of HLA-B*2705. Peptide complexes. Effect of peptide and major histocompatibility complex protein mutations. , 2000, The Journal of biological chemistry.

[62]  Arne Svejgaard,et al.  A functional and structural basis for TCR cross-reactivity in multiple sclerosis , 2002, Nature Immunology.

[63]  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.