DARC and Anti-Duffy Antibodies in the Line of Fire: The Challenges in Pinpointing the Etiology of Microcirculation Inflammation to a Distinct Entity

Antibody-mediated rejection (ABMR) due to non-HLA alloantibodies has gained substantial attention in transplantation research. One candidate for such non-HLA reactivity is the Duffy blood group carrier molecule DARC, which is not only expressed on erythrocytes, but also on kidney microvascular endothelial cells and is postulated as a potential transplantation-relevant alloantigen. However, <i>in vivo</i> observation of anti-Duffy antibodies as trigger of microvascular inflammation (MVI) is lacking. Here we propose a direct relationship between preformed anti-Duffy (anti-Fy^a) antibodies, complement deposition (C4d) in peritubular capillaries (PTC), and MVI. Double immunofluorescence for DARC and C4d in sequential biopsies revealed a striking overlap of DARC expression and C4d staining that was completely restricted to the peritubular capillaries. Remarkably, MVI was confined to PTC with complete absence of glomerulitis and lack of preformed anti-HLA DSA. Retrospective analysis revealed a self-limiting posttransplant flare of a low-level anti-DQ8 DSA after blood transfusions and a high missing-self KIR ligand constellation. Concomitant occurrence of non-HLA and anti-HLA reactivities next to missing-self constellations substantially complicates the assessment of individual contributions for the development and propagation of MVI. Due to the strictly confined distribution of DARC to PTC our report provides <i>in vivo</i> evidence that anti-Fy^a alloantibodies may associate with MVI.