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TitleTopography of the HLA-A protein enforces shared and convergent immunodominant B cell and antibody alloresponses in transplant recipients.
Journal, issue, pagesImmunity, Vol. 58, Issue 12, Page 3040-3060.e12, Year 2025
Publish dateDec 9, 2025
AuthorsJohn T Killian / R Glenn King / Aaron C K Lucander / James L Kizziah / Christopher F Fucile / Ruben Diaz-Avalos / Shihong Qiu / Aaron Silva-Sanchez / Betty J Mousseau / Kevin J Macon / Amanda R Callahan / Guang Yang / M Emon Hossain / Jobaida Akther / Daryl B Good / Susan Kelso / Julie A Houp / Frida Rosenblum / Paige M Porrett / Song C Ong / Vineeta Kumar / Erica Ollmann Saphire / John F Kearney / Troy D Randall / Alexander F Rosenberg / Todd J Green / Frances E Lund /
PubMed AbstractDonor-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 ...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-A01:01-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-A01:01. We demonstrated that the anti-HLA-A01:01 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-A01:01-mismatched transplant recipients. Thus, the B cell and antibody alloresponses appear tightly focused on a topographically defined region on the HLA-A01:01 crown that is conserved across individuals expressing distinct constellations of self-HLA-A.
External linksImmunity / PubMed:41289995 / PubMed Central
MethodsEM (single particle) / X-ray diffraction
Resolution3.14 - 3.84 Å
Structure data

41072

8t6m

EMDB-41072, PDB-8t6m:
Human leukocyte antigen bound by two alloreactive antibody Fabs
Method: EM (single particle) / Resolution: 3.14 Å

PDB-8t7r:
Crystal structure of human leukocyte antigen A*0101 in complex with the Fab of alloreactive antibody E07
Method: X-RAY DIFFRACTION / Resolution: 3.84 Å

Source
  • homo sapiens (human)
  • cytomegalovirus
KeywordsIMMUNE SYSTEM / antibody / human leukocyte antigen / graft rejection / HLA / HLA class I / antibodies / autoimmunity / Fab / alloreactive

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