Renal allograft rejection is often associated with graft-infiltrating lymphocytes which form tertiary lymphoid structures. Although such B cell infiltration has been shown to be associated with poor clinical outcomes, their roles in renal allograft rejection are poorly understood.
To characterize graft-infiltrating B cells, we sorted intrarenal CD19+CD38+ B cells from five patients and subjected them to single-cell RNA-seq. When compared to tonsil B cells, class switched intrarenal B cells had a characteristic gene expression profile with an upregulation of innate immune receptors and their downstream genes. In addition, intrarenal B cells upregulated inflammatory cytokines and cytokine receptors whose ligand/receptor counterparts are expressed in rejected renal tissues. These data suggest specific cross-talk pathways and circuits between B cells and other cell populations within the rejected kidney.
Finally, we cloned and expressed antibodies from the intrarenal B cells to test their reactivity. Remarkably more than half, 47 out of 87, expressed antibodies were polyreactive. Furthermore, 30 antibodies were reactive with HLA and, of these, 24 antibodies were also polyreactive. Anti-HLA antibodies were expressed even in a patient without detectable serum anti-HLA reactivity. These data suggest that in renal allograft rejection, there is strong in situ selection for B cells expressing polyreactive, anti-HLA antibodies. Overall, our studies define a unique population of pathogenic intrarenal B cells that likely contribute to renal allograft rejection through multiple mechanisms.
Yuta Asano– Department of Medicine, Section of Rheumatology and The Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL, USA
Joe Daccache– Transplantation Research Center, Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
Dharmendra Jain– Section of Transplant, Department of Surgery, The University of Chicago, Chicago, IL, USA
Anita Chong– Section of Transplant, Department of Surgery, The University of Chicago, Chicago, IL, USA
Shiv Pillai– Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology, and Department of Medicine, Harvard University, Cambridge, MA, USA
Marcus Clark– Department of Medicine, Section of Rheumatology and The Knapp Center for Lupus and Immunology Research, The University of Chicago, Chicago, IL, USA