Clinical relevance of donor‐specific antibodies directed at HLA‐C: A long road to acceptance

Abstract

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.

Study on the Relationship between Unexplained Recurrent Abortion and HLA-DQ Gene Polymorphism

“…Fetal blood enters the maternal circulation when exchanging blood with the mother through the placenta, and the maternal immune system is able to recognize paternal HLA antigens carried by the blood; excessive sharing of HLA antigens between the couple can lead to insufficient production of blocking antibodies and finally to recurrent miscarriage. The literature [ 16 ] suggests that excessive sharing of HLA antigens between couples can lead to low maternal responsiveness to paternal antigens, which is an important mechanism leading to recurrent miscarriage. The literature [ 17 ] suggests that antipaternal HLA antibodies may not be harmful in healthy pregnancies but rather may even be beneficial.…”

Characterization of the novel HLA‐C*05:01:01:81Q allele by sequencing‐based typing

“…We were very confident in the phasing as the sample displayed a mean read length of 304 base pairs over all the loci, the mismatched G base was attributed 229 times to the new HLA‐C*05 allele and can be only attributed to this allele because it was possible to discriminate from the associated HLA‐C*16:01:01:01 allele by virtue of 2 variant positions each distant by less than 100 base pairs. C*05:01:01:81Q was not evaluated easily with T or B cell flow cytometry crossmatch (FCXM) 3,4 . Furthermore none LCT Typing kit is available to demonstrate the lack of expression of this antigen.…”

Virtual crossmatching and epitope analysis in kidney transplantation: What the physician involved in kidney transplantation should know?

“…The clinical impact of DSA directed at anti‐HLA‐A, ‐B, ‐DR, as well as ‐DQ antibodies is well recognized, as HLA typing in KTX was limited to HLA‐A, ‐B, ‐DR, and ‐DQ loci for a long time. Antibodies against HLA‐C loci have also been reported to affect graft prognosis 30,31 . Although the impact of antibodies against HLA‐DP loci remains controversial, there are some reports recognizing its effect 30,32 …”

“…Antibodies against HLA-C loci have also been reported to affect graft prognosis. 30,31 Although the impact of antibodies against HLA-DP loci remains controversial, there are some reports recognizing its effect. 30,32 Furthermore, in the situation involving the presence of a rejected kidney graft in a patient willing re-transplantation, we should be aware of DSA absorption by the graft.…”