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Purpose of Review: De novo HLA-DQ antibodies are the most frequently observed after solid-organ allotransplantation; and are associated with the worse adverse graft outcomes compared with all other HLA antibodies. However, the biological explanation for this observation is not yet known. Herein, we examine unique characteristics of alloimmunity directed specifically against HLA-DQ molecules., Recent Findings: While investigators attempted to decipher functional properties of HLA class II antigens that may explain their immunogenicity and pathogenicity, most early studies focused on the more expressed molecule - HLA-DR. We here summarize up-to-date literature documenting specific features of HLA-DQ, as compared to other class II HLA antigens. Structural and cell-surface expression differences have been noted on various cell types. Some evidence suggests variations in antigen-presenting function and intracellular activation pathways after antigen/antibody interaction., Summary: The clinical effects of donor-recipient incompatibility at HLA-DQ, the risk of generating de novo antibodies leading to rejection, and the inferior graft outcomes indicate increased immunogenicity and pathogenicity that is unique to this HLA antigen. Clearly, knowledge generated for HLA-DR cannot be applied interchangeably. Deeper understanding of features unique to HLA-DQ may support the generation of targeted preventive-therapeutic strategies and ultimately improve solid-organ transplant outcomes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose of Review: Accurate measurement of human leukocyte antigen antibodies is critical for making clinical decisions treating patients awaiting transplantation or monitoring them post transplantation. Single antigen bead assay results are given as Mean Fluorescence Intensity, falling short of providing the required quantitative measure., Recent Findings: Titration studies were shown to circumvent the limitation of target-saturation that affect interpretation of single antigen bead assays especially in highly sensitized patients with strong antibodies. In fact, titration information can serve to measure efficacy of antibody removal during pretransplant desensitization using plasmapheresis/intravenous immunoglobulin (PP/IVIg) approaches. Moreover, recent studies indicate that knowing the donor-specific antibody titer has prognostic value that can guide PP/IVIg desensitization treatments. Newer data demonstrates an additional layer of information obtained by titration studies allowing to stratify patients with very high cPRA (>99%) based on the strength of the antibodies present, rather than the breadth. This data can thereby identify patients that are more likely to benefit from desensitization approaches on the transplant wait-list., Summary: Titration studies have a prognostic value with regards to quantifying antibody strength. Obtaining this information does not require performing the complete set of dilutions. In fact, performing two to three specific dilutions can provide relevant information while maintaining practical cost.

Purpose of Review: A renaissance for human leukocyte antigen (HLA) testing emerged with the understanding that donor-specific HLA antibodies play a significant role in long-term allograft survival. This renewed focus on donor/recipient histocompatibility led to a recent quest to decipher antibody responses or, as introduced into the transplantation lexicon, 'HLA-epitope matching'., Recent Findings: Whether matching is at the antigen or the epitope level, in-depth understanding of how histo-incompatibility leads to activation of an immune response is required. HLA-DQ donor-specific antibody (DSA) has the highest association with poor graft survival. However, HLA-DQ antigens and antibodies are understudied and significant gaps still exist in understanding the function of HLA-DQ in immune activation. Much of our knowledge about HLA class-II molecules is derived from studies performed on HLA-DR, whether it is crystallography, antigen processing and presentation analysis, or activation of T-cell signal-transduction pathways. Indeed, HLA-DQ molecules are less amenable for laboratory testing, but the limited studies that were performed indicate that HLA-DQ might have, at least to some extent, a different role compared with HLA-DR., Summary: This review highlights qualities of HLA-DQ that may be associated with different pathways of activating an immune response. Understanding the consequences of such differences may lead to better appreciation and significance of HLA-DQ for matching purposes.

Purpose of Review: Significant interest is now focused on deciphering human leukocyte antigen (HLA) epitopes and the utilization of this new knowledge to improve donor-recipient matching in transplantation. A recently introduced concept is the appearance of antibodies against what may be considered as self-epitopes, including the introduction of the 'nonself-self paradigm'., Recent Findings: Common practice in analyzing HLA-DQ antibodies have been to separate between antibodies against the α chain and antibodies against the β chain of the molecule. This is despite the fact that the two chains have to intertwine together to be expressed stably on the cell surface. We have previously provided evidence that this practice is false. We further provide evidence to refute the use of 'self-epitopes' as an immunologically feasible terminology by delineating the historic events leading to today's misconceptions., Summary: The evidence we present supports the need for a change in current practices. HLA-DQ antigens and antibodies should be viewed as combined DQα/β complexes. This will have impact to assigning cPRA value, assigning acceptable and unacceptable antigens, and pave the way to a better understanding of true HLA epitopes as we strive to improve donor--recipient compatibility and minimize generation of de-novo HLA antibodies.

Purpose of Review: Recent reports on donor-specific antibodies documented an overwhelming frequency of antibodies to one specific locus - human leukocyte antigen DQ (HLA-DQ). This article provides a short summary of clinical observations, a historic perspective to account for the late recognition of the role of HLA-DQ antibodies as well as potential explanations., Recent Findings: The basic understanding of the complexity of HLA-DQ molecules (antigens and antibodies) existed already 3-4 decades ago. However, only more recent advancements in molecular techniques as well as solid phase platforms, that allow for testing antibody specificities against individual HLA targets, provided state-of-the-art tools that are also amenable to mass applications. Thus, the significance of the polymorphic nature of both polypeptide chains of the DQ molecule, DQα and DQβ, is only now re-emerging., Summary: HLA-DQ antibodies are real, relevant, and abundant. In order to achieve a clinically useful understanding of this phenomenon, HLA-DQ antigens and antibodies should be viewed at the level of the physiologic structure, as it appears on the cell surface, namely, one unit composed as DQαβ. Preliminary data demonstrated that such an approach is likely to lead to more equitable calculation of calculated panel reactive antibody, improving the accuracy of virtual crossmatch prediction, and increasing the likelihood of finding a compatible donor for the very highly sensitized patients.