Abstract
Human leukocyte antigen (HLA)-DRB3 is a functional HLA class II gene, which has a limited allele diversity in the human population. Furthermore, the HLA-DRB3 gene is only present in a subset of individuals. Therefore, in organ transplantation, this HLA molecule is frequently mismatched between patient and graft donor and thus antibodies against this mismatched HLA molecule can develop. In this study, we aimed to evaluate the prevalence and reactivity of these antibodies and aimed to identify factors that underlie antibody formation against HLA-DRB3. We showed in our patient cohort that HLA-DRB3 antibodies are identified in about 7% of all patients that were screened with solid phase assays. In these assays, we observed multiple antibody reactivity patterns indicating that HLA-DRB3 harbours multiple epitopes. In those cases, where we succeeded at tracing back the induction of these antibodies to the molecular HLA typing of the immunogenic event, we noticed a different frequency of HLA-DRB1 allele groups in the donors as compared to a control group. To a certain extent this distribution (e.g. HLA-DRB1*11 individuals) could be linked to an altered expression level. However, it also appears that different HLA-DRB3 alleles (e.g. HLA-DRB3*01 group) vary in their immunogenicity without having an expression difference. In conclusion, our study provides information on the immunogenicity and reactivity patterns of antibodies against HLA-DRB3 in kidney transplantation, and it points towards the possibility of HLA expression as a factor underlying antibody formation.
Highlights
Human leukocyte antigen (HLA) class II molecules, such as HLA-DR, play an important role in the presentation of processed peptides from extracellular pathogens to the T cell receptor (TCR) of CD4+ helper T cells [1, 2]
The prevalence and Luminex Single Antigen reactivity patterns of HLA-DRB3 antibodies in the sera of organ transplant recipients
A retrospective Luminex Single Antigen (LSA) analysis of these 645 patients showed that 43 kidney patients (7%) were positive for HLA-DRB3 antibodies
Summary
Human leukocyte antigen (HLA) class II molecules, such as HLA-DR, play an important role in the presentation of processed peptides from extracellular pathogens to the T cell receptor (TCR) of CD4+ helper T cells [1, 2]. The HLA-DR molecules are heterodimers that consist of an alpha (α)-chain (encoded by HLA-DRA) that shows limited diversity and a beta (β)-chain (encoded by e.g. HLA-DRB1) that is highly polymorphic in the population [3, 5] This high diversity influences the peptide presentation and as such determines an individuals’ ability to respond to a wide variety of pathogens. The HLA-DRB1 gene was duplicated in evolution and subsequently some individuals have a second HLA-DRB gene that encodes a functional protein on a single haplotype [7, 8]. The associated HLA-DRB gene products form together with the conserved α-chain (encoded by HLA-DRA), associated HLA-DRB proteins These associated HLA-DRB proteins are not present in all individuals, but only in a subset (e.g. HLA-DRB3 is present in 43% of the caucasoid population). These associated HLA-DRB genes show allelic variation in the population, e.g. the HLA-DRB3 gene shows modest allelic diversity with 145 alleles as compared to 2103 alleles of HLA-DRB1 [10,11,12,13,14]
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