Clin Transplant Res.  2024 Dec;38(4):294-308. 10.4285/ctr.24.0055.

A walk through the development of human leukocyte antigen typing: from serologic techniques to next-generation sequencing

• Choi H
• Choi EJ
• Kim HJ
• Baek IC
• Won A
• Park SJ
• Kim TG
• Chung YJ

• KMID: 2563952
• DOI: http://doi.org/10.4285/ctr.24.0055

Abstract

Human leukocyte antigen (HLA) is a group of glycoproteins encoded by the major his- tocompatibility complex (MHC) that plays a pivotal role in the host's immune defense. Given that the MHC represents the most polymorphic region in the human genome, HLA typing is crucial in organ transplantation. It significantly influences graft rejection, graft-versus-host disease, and the overall patient outcome by mediating the discrimination between self and nonself. HLA typing technology began with serological methods and has evolved rapidly alongside advances in molecular technologies, progressing from DNA-based typing to next- or third-generation sequencing. These advancements have increased the accuracy of HLA typing and reduced ambiguities, leading to marked improvements in transplantation outcomes. Additionally, numerous novel HLA alleles have been identified. In this review, we explore the developmental history and future prospects of HLA typing technology, which promises to further benefit the field of transplantation.

Keyword

Human leukocyte antigen; Histocompatibility testing; Transplantation; Next-generation sequencing

Figure

• 

  Fig. 1 Timeline of technological advancements in human leukocyte antigen (HLA) typing methods. This timeline shows the introduction of developing HLA typing methods from serological assays from the 1960s to third-generation sequencing technology. PCR, polymerase chain reaction.

• 

  Fig. 2 Nomenclature of HLA alleles. Each HLA allele name has a unique number of four fields. The first field describes the allele group, which often corresponds to the serological type. The second field is used to describe the specific HLA protein, and third field provide the information of synonymous mutation within the coding sequence. The fourth field describes the mutations in noncoding regions such as 3’UTR, 5’UTR, and intron. Suffixes may be added to an allele to indicate the expression status of the allele. HLA, human leukocyte antigen. Adapted from Luo et al. Nat Genet 2021;53:1504–16 with permission of Springer Nature [12].

• 

  Fig. 3 Schematic presentation of HLA class I and II gene organization and protein structure. In humans, separate clusters of HLA class I and II genes are located on chromosome 6. Three main class I genes are HLA-A, HLA-B, and HLA-C. HLA class I molecules consist of one α chain and β2microglobulin (β2m). The class II region includes the α and β chains for HLA-DR, -DP, and -DQ molecules. The most polymorphic regions are considered to reside in peptide-binding regions, which are exons 2 and 3 in HLA class I genes and exon 2 in HLA class II genes. HLA, human leukocyte antigen.

• 

  Fig. 4 The number of new alleles submissions by year to the IPD-IMGT/HLA database from 2000 to 2023. This data includes small number of human leukocyte antigen (HLA)-related genes such as MICA/B. The predominant methods for HLA typing are indicated above the bars.

• 

  Fig. 5 Ambiguous human leukocyte antigen typing results. (A) This type of ambiguity arises when the typing method cannot differentiate between the polymorphisms located on the same chromosome (cis) and that located on different chromosomes (trans). (B) Furthermore, ambiguity arises when two or more alleles differ only in the regions that are not sequenced such as introns, 3’UTR, and 5’UTR.

• 

  Fig. 6 The schematic workflow of a PacBio SMRT sequencing and Oxford Nanopore Technologies. (A) PacBio SMRT sequencing. Hairpin adaptors are ligated to both ends of the template DNA to form a single-stranded circular DNA. The addition of complementary fluorescently labeled dNTP during sequencing is recorded. (B) Oxford Nanopore sequencing. The DNA template binds to adaptors with motor protein. Sequencing is initiated by entering a nanopore attached to the motor protein. As the template DNA strand passes through the nanopore, specific change in the ionic current for each nucleotide across the membrane is detected. This specific current is further translated into nucleotide sequence. SMRT, Single-Molecule Sequencing in Real Time.

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