Alloreactivity and autoreactivity converge to support B cell epitope targeting in transplant rejection

Killian, J. T.; King, R. G.; Kizziah, J. L.; Fucile, C. F.; Diaz-Avalos, R.; Qiu, S.; Silva-Sanchez, A.; Mousseau, B. J.; Macon, K. J.; Callahan, A. R.; Yang, G.; Hossain, M. E.; Akther, J.; Houp, J. A.; Rosenblum, F. D.; Porrett, P. M.; Ong, S. C.; Kumar, V.; Mobley, J.; Saphire, E. O.; Kearney, J. F.; Randall, T. D.; Rosenberg, A. F.; Green, T. J.; Lund, F. E.

doi:10.1101/2023.03.31.534734

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bioRxiv · 10.1101/2023.03.31.534734

Alloreactivity and autoreactivity converge to support B cell epitope targeting in transplant rejection

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Abstract

Donor-specific antibody (DSA) responses against human leukocyte antigen (HLA) proteins mismatched between kidney transplant donors and recipients cause allograft loss. The rules governing the immunogenicity of non-self donor HLA are poorly understood. Using single-cell, molecular, structural, and proteomic techniques, we profiled the HLA-specific B cell response in the kidney and blood of a transplant recipient with antibody-mediated rejection (AMR). We observed an immunodominant B cell antibody response focused on topographically exposed, solvent-accessible mismatched HLA residues along the peptide-binding groove - a subregion comprising only 20% of the HLA molecule. We further demonstrated that, even within a diverse cohort of transplant recipients, the B cell alloresponse consistently converges on this same immunodominant subregion on the crown of the HLA molecule. Based on these findings, we propose that B cell immunodominance in transplant rejection relies on antigenic topography, and we suggest that this link could be exploited for organ matching and therapeutics.

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Killian, J. T., King, R. G., Kizziah, J. L., Fucile, C. F., Diaz-Avalos, R., Qiu, S., Silva-Sanchez, A., Mousseau, B. J., Macon, K. J., Callahan, A. R., Yang, G., Hossain, M. E., Akther, J., Houp, J. A., Rosenblum, F. D., Porrett, P. M., Ong, S. C., Kumar, V., Mobley, J., Saphire, E. O., Kearney, J. F., Randall, T. D., Rosenberg, A. F., Green, T. J., Lund, F. E.. 2023-04-02. Alloreactivity and autoreactivity converge to support B cell epitope targeting in transplant rejection. https://doi.org/10.1101/2023.03.31.534734

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