Kidney transplant is well known to be the best possible therapy for patients with end-stage kidney failure; however, allograft rejection remains a major obstacle despite the advent of modern immunosuppression regimens. Despite the well-established role of donorspecific antibodies directed at anti-HLA-A, -B, -DR, and -DQ antigens, the particular role of anti-HLA-C donorspecific antibodies in allograft longevity is not yet clear. Recently, preformed anti-native HLA-C donorspecific antibodies were reported to be possibly linked to poor allograft outcome. In addition, inclusion of HLA-C in all transplant allocation regimens has been suggested. Moreover, possible relevance of HLA-C has been shown in other fields (eg, transfusion and obstetrics). Its reduced expression could explain the diminished immunogenicity of the anti-HLA-C antibodies with subsequent lowered strength and prevalence. Furthermore, the"missed self" theory has gained interest. Here, we investigated HLA-C donorspecific antibody immunogenicity, pathogenicity, cellsurface expression, antibody heterogenicity, and possible management tools.

In solid organ transplantation (SOT), the clinical relevance of donor-specific antibodies (DSA) directed at anti-HLA-A, -B, -DR and -DQ antigens is largely recognized while it is still a matter of debate for DSA directed at HLA-C. In this review, we summarize the peculiarities of HLA-C among class I HLA antigens as well as their immunogenicity, which underlie the clinical relevance of HLA-C locus and anti-HLA-C DSA in SOT. Many factors, both intrinsic and extrinsic to the HLA-C gene and HLA-C protein, explain its lower expression in comparison with HLA-A and -B. This lower expression can explain the apparent lower immunogenicity of HLA-C leading to a lower prevalence and strength of anti-HLA-C antibodies. Nevertheless, HLA-C antigens are truly immunogenic and preformed anti-HLA-C DSA are clinically relevant. Indeed, anti-HLA-C DSA are able to bind donor cells and to activate the complement pathway both ex vivo and in vivo. In line with this, numerous clinical studies now show that preformed DSA directed at native HLA-C molecules induce poorer graft outcomes. We then plead for the inclusion of HLA-C in all transplant allocation systems and we propose a strategy to cope with anti-HLA-C DSA in SOT. Beyond SOT, anti-HLA-C antibodies generate a growing interest in the allo-HCT, transfusion and obstetrics fields, while new concepts such as the role of the "missing-self" in solid organ rejection places HLA-C as an inescapable actor in transplant tolerance.

Detection of donor-specific antibodies (DSA) is an essential part of diagnosing antibody-mediated renal allograft rejection (ABMR). The role of solitary preformed, or post-transplant HLA-C antigens in solid organ transplantation is unclear, due to the less sensitive nature of the historical assays, lack of data, low expression level on the cell surface, and their co-existence with other anti-HLA DSA. Herein, we present the case of a 39-year-old African American man, without prior history of pre-transplant sensitization that was diagnosed with biopsy-proven ABMR due to de novo donor-specific anti-HLA-C antibodies. This case report illustrates the role of HLA-C antibodies in causing ABMR if generated toward immunogenic-shared epitopes and demonstrates the need for their recognition in the pre- and post-transplant period. Another interesting aspect of this case is the incidental finding of Fabry-like zebra bodies, which we eventually determined to be of unclear etiology.