Figure 2.

The role of gene-expressed mismatch antigens in GVHD or rejection following transplantation. (a) Donor-recipient GEMA mismatch in myeloablative HCT: GVHD can occur in an HCT recipient with normal GEMA expression when he or she is transplanted with cells derived from a donor without normal GEMA protein expression. Since GEMAs are ‘self-expressed' antigens, GEMA-derived peptides can be presented in the context of both class I and class II MHC receptors found on recipient cells following HCT. Allorecognition of host MHC molecules presenting GEMA-derived peptides subsequently triggers donor-derived T cells that are not ‘tolerized' to GEMA-derived peptides to attack host cells, resulting in clinical manifestations of GVHD. In addition, because GEMAs such as UGT2B17 can be cell-surface antigens, their antigenicity is not MHC-restricted like most autosomally encoded minor histocompatibility antigens. Like H-Y antigens, a B-cell mediated response to the ‘foreign' GEMA expression can result in the production of autoantibodies by donor-derived B cells that target the host-cell expressed GEMA proteins on the cell surface. McCarroll et al. first demonstrated the clinical significance of GEMA mismatch in HCT by following up on the results from a large genome-wide association study (GWAS)-based screen for homozygous deletion copy number variations (hdCNVs) that appear to be tolerated and are found frequently in an appreciable percentage of the human population. Based on the hypothesis that hdCNVs overlapping a gene-encoding region would cause gene expression mismatch between HCT donors and recipients, McCarroll screened ∼400 HCT recipients and their HLA-matched siblings for six candidate GEMAs. They identified that D−/R+ status for one particular GEMA UGT2B17 increased the risk of Grade 2+ GVHD, a finding that was later replicated in two independent cohorts, together totaling over 1300 patients (combined OR of 2.5).¹⁸ In addition, McCarroll et al showed that UGT2B17+ HCT recipients, who received hematopoeitic cells from UGT2B17^−/− donors were seropositive for anti-UGT2B17 antibodies. Moreover, they were able to isolate MHC-bound UGT2B17-derived peptides from the sera of these UGT2B17 mismatched. Given that the average human genome has at least several thousand CNVs greater than 1 kb (which is likely to be an underestimate due to current limitations in CNV detection platforms¹⁹) and contains ∼100 loss of function (LoF) mutations (with ∼20 in both copies) ²⁰, other GEMAs are likely to exist. By coupling large-scale RNA-seq and SGS data, a genome-wide search for other GEMAs may reveal hundreds of other such loci across the genome. (b) Donor-recipient GEMA mismatch in the context of reduced-intensity conditioning/non-myeloablative HCT or solid organ transplantation: rejection of donor cells or tissue occurs due to the absence of GEMA protein expression (eg, UGT2B17) in the recipient. Complementary to the scenario illustrated in (a), recipient tissues do not express GEMA proteins. Thus, potentially GEMA-reactive T- and B-cell clones are not eliminated from the host immune repertoire. Following transplantation, immune competent recipient T cells can attack donor stem cells expressing GEMA and inhibit engraftment or cause acute graft rejection.