Topography of the HLA-A protein enforces shared and convergent immunodominant B cell and antibody alloresponses in transplant recipients
Donor-specific antibody responses against human leukocyte antigen (HLA) proteins mismatched between transplant donors and recipients cause allograft loss, yet the structural HLA epitopes targeted by alloreactive B cells and antibodies remain largely unresolved. We profiled the HLA-A<sup>∗</sup>01:01-specific B cell response in the transplanted kidney and blood of a recipient undergoing antibody-mediated rejection and identified immunodominant B cell and antibody responses that emerged early in the alloimmune response. These responses were focused on topographically exposed mismatched HLA residues located in the α helices along the peptide-binding groove of HLA-A<sup>∗</sup>01:01. We demonstrated that the anti-HLA-A<sup>∗</sup>01:01 B cell alloresponse converged and was maintained on this same immunodominant HLA subregion, which comprises only 20% of the HLA molecule, in a diverse group of HLA-A<sup>∗</sup>01:01-mismatched transplant recipients. Thus, the B cell and antibody alloresponses appear tightly focused on a topographically defined region on the HLA-A<sup>∗</sup>01:01 crown that is conserved across individuals expressing distinct constellations of self-HLA-A.
Authors
- Troy D. Randall (ORCID: https://orcid.org/0000-0003-0643-0311)
- Song Ong (ORCID: https://orcid.org/0000-0002-4972-0776)
- R. Glenn King (ORCID: https://orcid.org/0000-0001-6522-0053)
- M. Emon Hossain
- Rubén Díaz-Avalos
- Derek Good
- A. Callahan
- John F. Kearney (ORCID: https://orcid.org/0000-0003-2569-2560)
- Frida Rosenblum (ORCID: https://orcid.org/0000-0002-2825-485X)
- James L. Kizziah (ORCID: https://orcid.org/0000-0002-2608-8595)
- Susan Kelso (ORCID: https://orcid.org/0000-0002-1759-0364)
- Aaron Lucander (ORCID: https://orcid.org/0000-0002-1292-2147)
- Christopher Fucile
- Kevin Macon
- Aarón Silva-Sánchez (ORCID: https://orcid.org/0000-0002-1882-2534)
- Jobaida Akther (ORCID: https://orcid.org/0000-0002-3096-3663)
- Todd J. Green (ORCID: https://orcid.org/0000-0003-1158-4710)
- Paige M. Porrett (ORCID: https://orcid.org/0000-0002-6895-5597)
- Frances E. Lund (ORCID: https://orcid.org/0000-0003-3083-1246)
- Betty Mousseau
- Vineeta Kumar (ORCID: https://orcid.org/0000-0002-4271-463X)
- Julie A. Houp
- Erica Ollmann Saphire (ORCID: https://orcid.org/0000-0002-1206-7451)
- John T. Killian (ORCID: https://orcid.org/0000-0002-3702-9005)
- Guang Yang (ORCID: https://orcid.org/0000-0002-8379-7478)
- Alexander F. Rosenberg
- Shihong Qiu
Institutions
- La Jolla Institute for Immunology (US)
- Emmanuel Bible College (CA)
- University of Alabama at Birmingham (US)
Publication Details
- Journal
- Immunity
- Published
- 2025-11-24
- DOI
- https://doi.org/10.1016/j.immuni.2025.10.014
- Citations
- 2
- Primary Topic
- T-cell and B-cell Immunology
- Type
- article
- Field-Weighted Citation Impact
- 1.59