Abstract
The HLA-DRB3/4/5 loci are closely linked to the HLA-DRB1 gene. Mismatches in these loci occur with a frequency of about 8%–12% in otherwise 10/10 HLA-matched transplant pairs. There is preliminary evidence that these disparities may associate with increased acute graft-versus-host disease (GvHD) rates. The aim of this study was to analyze a large cohort of German patients and their donors for HLA-DRB3/4/5 compatibility and to correlate the HLA-DRB3/4/5 matching status with the outcome of unrelated hematopoietic stem cell transplantation (uHSCT). To this end, 3,410 patients and their respective donors were HLA-DRB3/4/5 and HLA-DPB1 typed by amplicon-based next-generation sequencing (NGS). All patients included received their first allogeneic transplant for malignant hematologic diseases between 2000 and 2014. Mismatches in the antigen recognition domain (ARD) of HLA-DRB3/4/5 genes were correlated with clinical outcome. HLA-DRB3/4/5 incompatibility was seen in 12.5% (n = 296) and 17.8% (n = 185) of the 10/10 and 9/10 HLA-matched cases, respectively. HLA-DRB3/4/5 mismatches in the ARD associated with a worse overall survival (OS), as shown in univariate (5-year OS: 46.1% vs. 39.8%, log-rank p = 0.038) and multivariate analyses [hazard ratio (HR) 1.25, 95% CI 1.02–1.54, p = 0.034] in the otherwise 10/10 HLA-matched subgroup. The worse outcome was mainly driven by a significantly higher non-relapse mortality (HR 1.35, 95% CI 1.05–1.73, p = 0.017). In the 9/10 HLA-matched cases, the effect was not statistically significant. Our study results suggest that mismatches within the ARD of HLA-DRB3/4/5 genes significantly impact the outcome of otherwise fully matched uHSCT and support their consideration upon donor selection in the future.
Highlights
HLA-DRB3/4/5 genes are closely linked to the HLA-DRB1 locus [1]
The three loci HLA-DRB3, HLA-DRB4, and HLA-DRB5 show a lower expression as compared to HLA-DRB1 but are still detectable by serological methods on account of which they are designated as HLA-DR52, -DR53, and -DR51 antigens, respectively [3]
Non-expressed alleles are quite frequent within the HLA-DRB3/ 4/5 genes, HLA-DRB4*01:03:01:02N, which is the most frequent HLA-null allele recognized with an overall allele frequency of about 3.5% [5, 6]
Summary
HLA-DRB3/4/5 genes are closely linked to the HLA-DRB1 locus [1] They exhibit a strong linkage disequilibrium in often conserved HLA-class II haplotypes [2]. Within such haplotypes, the HLA-DRB1 antigen determines the presence or absence of an HLA-DRB3/4/5 gene. Alleles from the HLA-DRB1*01, *08, and *10 antigen groups do not associate with any of the HLA-DRB3/4/5 genes [4]. Despite the strong linkage disequilibrium, unusual HLA-DRB1-DRB3/4/5 associations do occur, leading to unexpected absence or presence of an HLADR52/53/51 antigen. This is sometimes observed in HLADRB1*01 that occasionally associates with HLA-DRB5 [7]. HLA-DRB3/4/5 typing can be challenging due to the presence of unusual associations and non-expressed variants caused by polymorphisms in non-coding regions (e.g., HLADRB4*01:03:01:02N or HLA-DRB4*01:14N) [8, 9]
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