Inflammatory effects of HLA-B27 as a Mechanism in Ankylosing Spondylitis
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Inflammatory effects of HLA-B27 as a Mechanism in Ankylosing Spondylitis

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  • Tumor Necrosis Factors = pro-inflammatory cytokines.
  • Full length wild type ERAP1 was cloned into pFastBac as a C-terminal His-10 tagged fusion protein using standard cloning techniques. ERAP1 substitution mutants were generated using site-directed mutagenesis. Recombinant proteins were purified to homogeneity on affinity Ni-NTA, and purity was assessed using SDS-PAGE/Coomassie staining.Restriction of ERAP1 to HLA-B27 positive cases of AS is consistent with the disease model that aberrant trimming/presentation of antigenic peptides is involved in the pathogenesis of the disease.
  • SNP’s at 12p13 due to effects on Lymphotoxin Beta Receptor (LTBR), TNFR1, or both.
  • TH17 cells produce IL17, a pro-inflammatory cytokine that stimulates the production of other pro-inflammatory molecules.

Inflammatory effects of HLA-B27 as a Mechanism in Ankylosing Spondylitis Presentation Transcript

  • 1. Inflammatory Effects of HLA-B27 as a Mechanism in Ankylosing Spondylitis Jordan Meyers
  • 2. • Ankylosing Spondylitis Overview• Proposed Mechanism• Roles of ERAP1 and HLA-B27• Other Possible Causes• Discovery of new AS-associated loci• Conclusion, Acknowledgements
  • 3. What is Ankylosing Spondylitis?• Arthritis that affects mainly the lower vertebrae.• Exact mechanism of the disease is unknown• Symptoms: • Inflammation • Soreness in lower back • Stiffness in lower back • Gastrointestinal irregularities• Other areas that can be affected: • Eyes • Hips • Ribs • Lungs (rarely)
  • 4. What we do know:• Of the Caucasian population with a confirmed diagnosis, >95% test positive for Human Leukocyte Antigen – B27 (HLA-B27).• This protein consists of 90 Amino Acids:• GSHSMRYFHT SVSRPGRGEP RFITVGYVDD TLFVRFDSDA ASPREEPRAP WIEQEGPEYW DRETQICKAK AQTDREDLRT LLRYYNQSEA• Most likely mechanism through which AS operates is through an aberrant processing of antigenic peptides.
  • 5. Proposed Mechanism – What causes inflammation?• HLA-B27 is one type of a major histocompatibility complex that presents antigens to CD8 lymphocytes (T-cells) on the cell’s surface.• Any type of mutation in the protein can cause an aggregation of ‘unfit’ proteins in the Endoplasmic Reticulum, which causes stress.• The immune system responds by generating pro-inflammatory cytokines and chemokines.
  • 6. Role of ERAP1• ERAP1 serves as a ‘molecular ruler’ – it cleaves proteins that have been partially processed by the proteosome into smaller peptides for association with MHC class I proteins.• MHC = Major Histocompatibility Complex, AKA Human Leukocyte Antigens (HLA’s).• Single Nucleotide Polymorphs of ERAP1 can alter its efficiency, resulting in the inability of peptides to associate with HLA-B to be presented to the cell surface.• Shown Right: mean rate of cleavage of N-Terminal Tryptophan residue in 10- mer peptide, WRVYEKCALK, by ERAP1 Wild Type, and AS associated mutants. Evans, Spencer et al, 2011
  • 7. Other possible causes of AS• The IL-23 – IL-23R – IL-17 is also suspect in the mechanism of AS.• Studies have shown that an overexpression of Tumor Necrosis Factor Receptor 1 (TNFR1) is sufficient to induce spondyloarthritis in mice.• Further research is required to determine if SNPs at the locus involved in production of TNFR1 (12p13) are associated with AS. Iwakura and Ishigame, 2006
  • 8. Discovery of new AS-associated loci• SNPs at the RUNX3 loci may induce AS through lowered CD8+ lymphocyte counts• RUNX3 is a key gene that encodes a transcription factor involved in CD8+ lymphocyte differentiation• CARD9, PTGER4 • CARD9 – mediates signals from dectin-1 and -2, which are immunity receptors for β-glucan. Mice treated with higher amounts of β-glucan developed spondyloarthritis. • PGE2 acts through PTGER4 to promote expansion of TH17 cell counts (Evans et al, 2011).
  • 9. Conclusion• Most likely mechanism through with AS develops is through an aberrant processing of antigenic peptides, or their presentation to CD8+ lymphocytes on the cell surface.• HLA-B27 plays a predominant role in the pathogenesis of the disease, but AS can still develop even in cases in which HLA-B27 is not present.• Genes strongly associated with pathogenesis of AS: IL23R, RUNX3, KIF21B, 2p15, IL12B, ERAP1, HLA-B, LBTR-TNFR1, and 21q22 (Evans et al, 2011).• Further 4 loci identified: ANTXR2, PTGER4, CARD9, TBKBP1 (Evans et al, 2011).
  • 10. Literature CitedEvans, David M.; Spencer, Chris C A.; Pointon, Jennifer J.; Su, Zhan;Harvey, David; Kochan, Grazyna; Oppermann, Udo; Dilthey, Alexander;Pirinen, Matti; Stone, Millicent A; Appleton, Louise;Moutsianas, Loukas; Leslie, Stephen; Wordsworth, Tom; Kenna, Tony J;Karaderi, Tugce; Thomas, Gethin P; Ward, Michael M;Weisman, Michael H; Farrar, Claire; Bradbury, Linda A; Danoy, Patrick;Inman, Robert D; Maksymowych, Walter; Gladman, Dafna;Rahman, Proton; Morgan, Ann; Marzo-Ortega, Helena; Bowness, Paul;Gaffney, Karl; Gaston, J S Hill; Smith, Malcolm; Bruge-Armas, Jacome;Couto, Ana-Rita; Sorrentino, Rosa; Paladini, Fabiana; Ferreira, ManuelA; Xu, Huji; Liu, Yu; Jiang, Lei; Lopez-Larrea, Carlos; Diaz-Pena, Roberto;Lopez-Vazquez, Antonio; Zayats, Tetyana; Band, Gavin;Bellenguez, Celine; Blackburn, Hannah; Blackwell, Jenefer M.;Bramon, Elvira; Bumpstead, Suzannah J.; Casas, Juan P.; Corvin, Aiden;Craddock, Nicholas; Deloukas, Panos; Dronov, Serge;Duncanson, Audrey; Edkins, Sarah; Freeman, Colin; Gillman, Matthew;Gray, Emma; Gwilliam, Rhian; Hammond, Naomi; Hunt, Sarah E.;Jankowski, Janusz; Jayakumar, Alagurevathi; Langford, Cordelia;Liddle, Jennifer; Markus, Hugh S; Mathew, Christopher G.;McCann, Owen T.; McCarthy, Mark I.; Palmer, Colin N A.;Peltonen, Leena; Plomin, Robert; Potter, Simon C.; Rautanen, Anna;Ravindrarajah, Radhi; Ricketts, Michelle; Samani, Nilesh;Sawcer, Stephen J.; Strange, Amy; Trembath, Richard C.;Viswanathan, Ananth C.; Waller, Matthew; Weston, Paul;Whittaker, Pamela; Widaa, Sara; Wood, Nicholas W.; McVean, Gilean;Reveille, John D.; Wordsworth, B Paul; Brown, Matthew A.;Donnelly, Peter. 2011. “Interaction between ERAP1 and HLA-B27 in ankylosing spondylitis implicates peptide handlingin the mechanism for HLA-B27 in disease susceptibility.”Nature Genetics. Vol. 43:8. Pp 761-767.
  • 11. Acknowledgments• UMD Chemistry and Biochemistry Department