Clinical impact of H-Y alloimmunity

Abstract

H-Y antigens are a group of minor histocompatibility antigens encoded on the Y-chromosome with homologous H-X antigens on the X-chromosome. The disparate regions of the H-Y antigens are highly immunogenic and play an important role in understanding human alloimmunity. In this review, we investigate the history of H-Y antigen discovery along with their critical contributions in transplantation and pregnancy. In hematopoietic cell transplantation, male recipients with female donors who become seropositive for B-cell responses as H-Y antibodies following transplantation have increased rates of chronic graft-versus-host disease and decreased rates of relapse. Conversely, female patients who receive male kidney allografts are more likely than other gender combinations to develop H-Y antibodies and reject their allografts. Finally, in the setting of pregnancy, mothers who initially gave birth to boys are more likely to have subsequent pregnancy complications, including miscarriages, in association with H-Y antibody development. H-Y antigens continue to serve as a model for alloimmunity in new clinical scenarios. Our development of more sensitive antibody detection and next-generation DNA sequencing promises to further advance our understanding and better predict the clinical consequences of alloimmunity.

Fig. 1

DBY seropositivity measured 3 months post-HCT predicts cGVHD development. a Heatmap representation of IgG specific for H-Y antigen DBY in 69 seropositive F → M patients. 67 seronegative patients are not shown. Overall, DBY seropositivity at 3 months was 19 and 51 % at any time point following HCT. Each row represents the results of a separate patient with the time of serum collection shown on the x-axis. The threshold for seropositivity was determined measuring 60 normal male donors. The heat reflects relative DBY antibody level relative to this threshold. Importantly, patient death is denoted by black, and missing samples are white. b The competing incidence of cGVHD development is greater in DBY seropositive patients than in DBY seronegative patients (p < 0.01)

Fig. 2

Methods for studying H-Y humoral alloimmunity. a H-Y-specific alloantibodies are quantified by protein microarray. Their immune-dominant epitopes are identified using overlapping peptides from H-Y proteins. b These immune-dominant peptides facilitate the identification of H-Y-specific B cells by fluorescence-activated cell sorting (FACS). c The B-cell receptor-binding specificity can be further elucidated by high-throughput sequencing of the immunoglobulin chain which can be used to characterize both heavy- and light-chain repertoire. The evolution of the changes in immunoglobin clonotypes over time is represented by the phylogeny tree