Human Hepatitis B Viral Infection Outcomes Are Linked to Naturally Occurring Variants of HLA-DOA That Have Altered Function.

The Journal of Immunology : Official Journal of the American Association of Immunologists
Austin M GravesLisa K Denzin

Abstract

HLA molecules of the MHC class II (MHCII) bind and present pathogen-derived peptides for CD4 T cell activation. Peptide loading of MHCII in the endosomes of cells is controlled by the interplay of the nonclassical MHCII molecules, HLA-DM (DM) and HLA-DO (DO). DM catalyzes peptide loading, whereas DO, an MHCII substrate mimic, prevents DM from interacting with MHCII, resulting in an altered MHCII-peptide repertoire and increased MHCII-CLIP. Although the two genes encoding DO (DOA and DOB) are considered nonpolymorphic, there are rare natural variants. Our previous work identified DOB variants that altered DO function. In this study, we show that natural variation in the DOA gene also impacts DO function. Using the 1000 Genomes Project database, we show that ∼98% of individuals express the canonical DOA*0101 allele, and the remaining individuals mostly express DOA*0102, which we found was a gain-of-function allele. Analysis of 25 natural occurring DOα variants, which included the common alleles, identified three null variants and one variant with reduced and nine with increased ability to modulate DM activity. Unexpectedly, several of the variants produced reduced DO protein levels yet efficiently inhibited DM activity. Finally, ...Continue Reading

References

Jun 29, 1995·Nature·V S SloanD M Zaller
Sep 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·P A RocheE O Long
Mar 3, 1999·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·S A VillanoD L Thomas
Feb 23, 2000·Journal of Virology·T V Golovkina
Jun 3, 2000·Annual Review of Immunology·C Alfonso, L Karlsson
Jul 21, 2000·The Journal of Immunology : Official Journal of the American Association of Immunologists·D J TaxmanJ P Ting
Nov 9, 2000·Immunity·R C DoebeleE D Mellins
Jan 11, 2000·Nucleic Acids Research·S T SherryK Sirotkin
Feb 2, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Uma M NagarajanJeremy M Boss
Apr 17, 2002·The Journal of Experimental Medicine·Kim S GlazierLisa K Denzin
Dec 21, 2002·Tissue Antigens·H KhalilJ Thibodeau
Mar 2, 2005·Nature Reviews. Immunology·Barbara Rehermann, Michelina Nascimbeni
Apr 26, 2005·Proceedings of the National Academy of Sciences of the United States of America·Francis DeshaiesJacques Thibodeau
Mar 30, 2007·Proceedings of the National Academy of Sciences of the United States of America·Jan M PestkaThomas F Baumert
Dec 7, 2010·Nature Immunology·Anne-Kathrin AndersKai W Wucherpfennig
Nov 16, 2011·Proceedings of the National Academy of Sciences of the United States of America·Corrie A PainterLawrence J Stern
Jun 27, 2012·Proceedings of the National Academy of Sciences of the United States of America·Taejin YoonElizabeth D Mellins
Dec 12, 2012·Nature Structural & Molecular Biology·Abigail I GuceLawrence J Stern
Jan 10, 2013·Annual Review of Immunology·Janice S BlumPeter Cresswell
Jul 10, 2013·Trends in Immunology·Wouter PosKai W Wucherpfennig
Oct 23, 2013·Frontiers in Immunology·Liusong Yin, Lawrence J Stern
Jan 16, 2014·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·William O OsburnStuart C Ray
Nov 22, 2014·Nucleic Acids Research·James RobinsonSteven G E Marsh
Dec 17, 2014·The Journal of Immunology : Official Journal of the American Association of Immunologists·Miguel Álvaro-BenitoChristian Freund
Feb 28, 2015·Nature Reviews. Immunology·Paul A Roche, Kazuyuki Furuta
Oct 4, 2015·Nature·UNKNOWN 1000 Genomes Project ConsortiumGonçalo R Abecasis
Aug 19, 2016·Open Biology·Miguel Alvaro-BenitoChristian Freund
Aug 19, 2016·Nature·Monkol LekUNKNOWN Exome Aggregation Consortium
Nov 24, 2018·Cellular & Molecular Immunology·Miguel Álvaro-BenitoChristian Freund
Dec 24, 2018·Molecular & Cellular Proteomics : MCP·Padma P NanawareLawrence J Stern

❮ Previous
Next ❯

Citations

Oct 2, 2020·Journal of Virology·Emily CullumTatyana Golovkina
Jul 6, 2021·Frontiers in Genetics·Jana StichtStefan Konigorski
Jun 18, 2021·The Journal of Immunology : Official Journal of the American Association of Immunologists·Emily CullumTatyana Golovkina

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antibody Repertoire Diversity

Antibody repertoire diversity and its role during natural infection is a prerequisite for molecular and structural elucidation of functionally protective immunity. Discover the latest insights into antibody diversity here.