OR11 Comparison of arthritogenic peptide binding to DRB1*01:01 and DRB1*01:02

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• 作者：Christina L. Roark¹ ; ² ; Kirsten M. Anderson² ; Michael T. Aubrey¹ ; Edward F. Rosloniec³ ; Brian M. Freed¹ ; ²
• 刊名：Human Immunology
• 出版年：2015
• 出版时间：October 2015
• 年：2015
• 卷：76
• 期：supp_S
• 页码：22
• 全文大小：171 K

文摘

Susceptibility to rheumatoid arthritis (RA) has been shown to be associated with DRB1*04 and *01 alleles due to the presence of the QRRAA “shared epitope” in amino acids 70–74. However, despite both DRB1*01:01 and *01:02 having the QRRAA shared epitope, DRB1*01:01 is more strongly associated with RA. The purpose of this study was to determine if the binding of citrullinated and non-citrullinated peptides to DRB1*01:01, *01:02 and *01:03 (as a negative control) could be used to dissect the role of the shared epitope and other amino acids in RA susceptibility.

Methods

Binding of type II collagen^259–273 (CII), citrullinated and native vimentin^66–78, and citrullinated and native 5bfd6c5891de9d449e61e5ace3" title="Click to view the MathML source">α$\alpha$-enolase^11–25 was measured on cell lines expressing DRB1*01:01, *01:02 and *01:03 by flow cytometry. Single site mutagenesis was performed to examine how the differences between these alleles affect peptide binding and T cell responses.

Results

DRB1*01:01 exhibited an 8.2-fold preference for binding citrullinated vimentin^66–78 over its native form, compared to 7.8-fold for *01:02 and 0.68-fold (preference for binding native) for *01:03. DRB1*01:01 also exhibited a 2-fold preference for binding citrullinated 5bfd6c5891de9d449e61e5ace3" title="Click to view the MathML source">α$\alpha$-enolase^11–25 over native, compared to 1.0-fold (no preference) for *01:02 and 0.49-fold (preference for native) for *01:03. In addition, DRB1*01:01 bound more type II collagen (CII)^259–273 (3.7-fold over background) than *01:02 (1.1-fold) and *01:03 (1.7-fold). Mutating G86 in DRB1*01:01 to the residue found in DRB1*01:02 (V86) abolished citrullinated 5bfd6c5891de9d449e61e5ace3" title="Click to view the MathML source">α$\alpha$-enolase^11–25 and CII^259–273 binding and decreased citrullinated vimentin^66–78 binding (1.7-fold).

Conclusion

The difference in susceptibility between DRB1*01:01 and *01:02 for RA may be explained by the effect of position 86 on peptide binding.