Donor HLA DQ reactive B cells clonally expand under chronic immunosuppression and include atypical CD21lowCD27- B cells with high avidity germline B cell receptors.

Russum, S.; Sayin, I.; Shwetar, J.; Baughan, E.; Jeong, J. C.; Kim, A.; Reyentovich, A.; Moazami, N.; Zeevi, A.; Chong, A. S.; Habal, M.

doi:10.1101/2024.12.06.627284

bioRxiv · 10.1101/2024.12.06.627284

Donor HLA DQ reactive B cells clonally expand under chronic immunosuppression and include atypical CD21lowCD27- B cells with high avidity germline B cell receptors.

Russum, S.·Sayin, I.·Shwetar, J.·Baughan, E.·Jeong, J. C.·Kim, A.·Reyentovich, A.·Moazami, N.·Zeevi, A.·Chong, A. S.·Habal, M.

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Abstract

Long-term allograft survival is limited by humoral-associated chronic allograft rejection, suggesting inadequate constraint of humoral alloimmunity by contemporary immunosuppression. Heterogeneity in alloreactive B cells and the incomplete definition of which B cells participate in chronic rejection in immunosuppressed transplant recipients limits our ability to develop effective therapies. Using a double-fluorochrome single-HLA tetramer approach combined with single-cell in vitro culture, we investigated the B-cell receptor (BCR) repertoire characteristics, avidity, and phenotype of donor HLA-DQ reactive B cells in a transplant recipient with end-stage donor specific antibody (DSA)-associated cardiac allograft vasculopathy while receiving maintenance immunosuppression (tacrolimus, mycophenolate mofetil, prednisone). Donor DQB1*03:02/DQA1*03:01 (DQ8)-reactive IgG+ B cells were enriched for minimally mutated and germline encoded high avidity BCRs (median KD 4.26x10-09) with an atypical, antigen-experienced and proliferative phenotype (CD27-CD21lowCD71+CD11c+/-). These B cells coexisted with a smaller subset of more highly mutated, affinity matured IgG+CD27+ B cells. Circulating donor-reactive B cells and DSA remained detectable after rituximab, contrasting with the marked reduction in DSA after allograft explant and retransplant. Together, these findings define the persistence of germline high-avidity HLA-DQ alloreactive B cells and their co-existence with affinity matured clones that were both driven by the allograft despite conventional immunosuppression.

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Russum, S., Sayin, I., Shwetar, J., Baughan, E., Jeong, J. C., Kim, A., Reyentovich, A., Moazami, N., Zeevi, A., Chong, A. S., Habal, M.. 2024-12-10. Donor HLA DQ reactive B cells clonally expand under chronic immunosuppression and include atypical CD21lowCD27- B cells with high avidity germline B cell receptors.. https://doi.org/10.1101/2024.12.06.627284

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