Topography of the HLA-A protein enforces shared and convergent immunodominant B cell and antibody alloresponses in transplant recipients

作者：John T. Killian, R. Glenn King, Aaron Lucander, James L. Kizziah, Christopher Fucile, Rubén Díaz-Avalos, Shihong Qiu, Aarón Silva-Sánchez, Betty Mousseau, Kevin Macon, A. Callahan, Guang Yang, Md Emon Hossain, Jobaida Akther, Daryl B. Good, Susan Kelso, Julie A. Houp, Frida Rosenblum, Paige M. Porrett, Song Ong, Vineeta Kumar, Erica Ollmann Saphire, John F. Kearney, Troy D. Randall, Alexander F. Rosenberg, Todd J. Green, Frances E. Lund · 发表于：Immunity · 年份：2025 · DOI：10.1016/j.immuni.2025.10.014 · 被引用次数：3 · 研究领域：T-cell and B-cell Immunology、Renal Transplantation Outcomes and Treatments、vaccines and immunoinformatics approaches

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 ∗ 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 ∗ 01:01. We demonstrated that the anti-HLA-A ∗ 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 ∗ 01:01-mismatched transplant recipients. Thus, the B cell and antibody alloresponses appear tightly focused on a topographically defined region on the HLA-A ∗ 01:01 crown that is conserved across individuals expressing distinct constellations of self-HLA-A.