Why HLA-DQ?

HLA-DQ was formally introduced into the HLA community in 1975 during the 6^th International Histocompatibility Workshop – though it was referred to at the time as HLA-D (and HLA-DC before that). HLA-D, which included all of the class II molecules, was first described in the early 1970’s as a family of molecules belonging to the human major histocompatibility complex (MHC) that were genetically distinct from the already named HLA-A and -B loci. The name HLA-D didn’t last long, however, as the individual class II antigens were identified in the following years and given the names that we are familiar with today: -DR, -DQ, and -DP.

It was around this time that HLA-DR was identified as an important factor in assessing compatibility between donors and recipients and predicting graft outcomes. Further studies revealed higher expression of HLA-DR in mixed lymphocyte cultures compared to HLA-DQ, and attempts at obtaining X-Ray crystallography structures of the class II molecules proved much easier for HLA-DR due to its monomorphic α-chain and more evident peptide-binding motif. Thus, much of our understanding of the class II antigens has been limited to the DR locus.

One of the major differences between the two classes of HLA antigens is the fact that class I antigens are encoded by a single polymorphic α-chain and ꞵ₂-microglobulin, whereas class II antigens consist of polymorphic alpha and beta subunits. That said, while the α-chain for HLA-DQ and -DP contains considerable heterogeneity, the HLA-DRα chain is virtually monomorphic, with nearly all genetic variability lying within its ꞵ-chain. Consequently, this has led to a significant shortcoming in how the antigens are identified. Serological naming convention for Class II antigens is based on the ꞵ-chain typing of the molecule, and while this has been appropriate for DR molecules due to its invariant α-chain, it can be problematic for DQ and DP. Namely, serological nomenclature for HLA-DQ and -DP does not specify which α-chain the molecule carries

It was established over 40 years ago that mismatches at the HLA-DR locus can be detrimental to graft survival. Meanwhile, early studies investigating the impact of DQ mismatches on graft outcomes found that it had little to no effect. It was therefore common practice in many transplant centers to focus on matching solid organ donors and recipients at only the HLA-DR locus for class II. It wasn’t until the past decade that the prevalence of HLA-DQ antibodies and their impact on graft survival became fully appreciated.

There are several reasons for this. Genetically, the HLA loci are found in close proximity on chromosome 6 and are inherited as a haplotype, leading to significant linkage disequilibrium among the HLA antigens, particularly -DR and -DQ. This made it challenging for early investigators to distinguish between antibody reactivity against HLA-DR versus -DQ on cell surfaces and hindered the discovery of new DQ phenotypes. So much so, that the full spectrum of DQ serologic specificities that we recognize today were not identified until the late 1980’s.

The introduction of the single-antigen bead (SAB) assay changed all that. With the ability to isolate individual HLA molecules onto separate beads, researchers were able to identify and measure antibodies against specific HLA alleles. In addition to having an enormous impact on clinical testing, the SAB assay also played a role in revealing the full extent of antibodies against HLA-DQ. Prior to the SAB assay, most class II antibodies were reported as against HLA-DR. With the help of SABs, however, we were able to show that >40% of the patients at our center sensitized against class II antigens had antibodies against HLA-DQ. Several subsequent studies at other centers reported high incidences of de novo HLA-DQ donor-specific antibodies (DSA), as well as HLA-DQ DSA being associated with increased risk of antibody-mediated rejections (AMR) and graft loss. This growing list of evidence indicated that HLA-DQ DSA were more prevalent than previously thought, and that they are likely associated with poor graft outcomes.