Mechanisms underlying human genetic diversity: consequence for antigraft antibody responses

Abstract

SUMMARYThis review focuses on the emerging concept of genomewide genetic variation as basis of an alloimmune response. Chronic antibody-mediated rejection is the major cause of long-term graft loss and growing evidence supports the clinical relevance of HLA but also non-HLA related alloimmune responses. Several polymorphic gene products have been identified as minor histocompatibility antigens. The formation of donor-specific alloantibodies is driven by indirect allorecognition of donor-derived peptides representing a form of conventional T-cell response. With the availability of high-throughput sequencing and genotyping technologies, the identification of genomewide genetic variation and thus mismatches between organ donors and graft recipients has become feasible. First clinical data linking genetic polymorphism and clinical outcome have been published and larger studies are currently under way. Protein arrays have successfully been used to identify a large variety of non-HLA antibodies in kidney transplant recipients and the availability of customizable peptide arrays made screening for linear epitopes on an individual patient level feasible. This review provides a summary of the recent findings in histocompatibility matching in the field of solid organ transplantation and complements it with a clear workflow for assessing the impact of genetic differences in protein-coding genes in solid organ transplantation.

Early Acute Microvascular Kidney Transplant Rejection in the Absence of Anti-HLA Antibodies Is Associated with Preformed IgG Antibodies against Diverse Glomerular Endothelial Cell Antigens

“…These Abs might be alloantibodies directed against non-HLA polymorphic antigens that differ between the recipient and donor or autoantibodies that recognize self-antigens after a disruption of self-tolerance. 2 The identification and characterization of pathogenic antiendothelial cell Abs (AECAs) would improve our understanding of the mechanisms involved in AMRs and would enable the development of new tools for patient monitoring. Several hurdles hamper the identification of these AECAs.…”

Novel insights into non‐HLA alloimmunity in kidney transplantation

“…Identification of genome‐wide genetic variants in both donors and recipients allows for a systematic approach to identify individual level non‐HLA mismatch. This includes nsSNP that cause alteration in the amino acid sequence of proteins as well as complete loss of gene expression in the recipient (LoF variants) . In the field of hematopoietic stem cell transplantation, novel mHAs were successfully identified using similar approaches .…”

“…Especially, polymorphisms in immune‐accessible transmembrane proteins represent plausible mHAs when the donor carries an allele that is not present in the recipient (representing a non‐self/allo‐epitope). Non‐self peptides can be presented by the recipients professional APCs/B cells to indirectly alloreactive T cells . The high number of potential genome‐wide mismatches suggests that each donor and recipient pair caries a unique set of mismatched genetic variations.…”

“…For a better understanding and to put these new data into context, we will sum up the current understanding of alloimmunity in general with a focus on indirect allorecognition. We will then revisit the concept of non‐self B cell epitopes in HLA molecules (e.g., eplet mismatch) as it pertains to HLA‐DSA formation before reviewing key publications on non‐HLA alloantibodies and discussing the general difficulties in differentiating non‐HLA alloreactivity from autoreactivity that is caused by loss of self‐tolerance .…”

Editorial for the March 2018 Focus Issue ‘Omics in Transplantation’

“…Reindl–Schwaighofer and colleagues focused on the consequence of genome‐wide genetic diversity for antigraft antibody responses . Several polymorphic gene products have been identified as minor histocompatibility antigens which lead to the production of donor‐specific alloantibodies (DSA) via semi‐ and indirect allorecognition.…”