Wednesday, April 2, 2025
4/2/2025
Etiology of naturally-occurring anti-ABO antibodies - Summary: While ABO(H) blood group antigens were the first human polymorphisms described and corresponding anti-ABO(H) antibodies continue to be the most common immunological barrier to transfusion and transplantation, the factors responsible for anti-ABO(H) antibody development remain relatively unknown. In order to overcome barriers that result from anti-ABO(H) antibody formation, key processes that drive anti-ABO(H) antibody development need to be defined. Our long-term goal is to define the factors that regulate naturally occurring anti-ABO(H) antibody formation. Our central hypothesis is that exposure to microbes that decorate themselves with ABO(H) blood group-like antigens drives innate-like B1 B cells to produce naturally occurring anti-ABO(H) antibodies. Our hypothesis is formulated on the basis of our recent discovery that microbes that decorate themselves with carbohydrate structures that mimic blood group antigens stimulate the formation of anti-blood group antibodies capable of causing hemolytic transfusion reactions (HTRs). Our data demonstrate that anti-ABO(H) antibodies isolated from patients display unique specificity for distinct types of ABO(H) antigens and when examined against microbial glycans isolated and presented on a microbial glycan microarray, engage unique microbial determinants, strongly suggesting that microbial glycans may shape an individual's anti-ABO(H) antibody response. However, as ABO(H) blood group antigens are carbohydrate structures largely confined to humans, preclinical models capable of formally testing this have not been available. To overcome this limitation, we developed a preclinical model that recapitulates key features of naturally occurring anti-blood group antibody formation. Knocking out the enzyme required for the synthesis of the murine blood group B-like antigen (murine B or Bm), we generated blood group O-like (murine O or Om) mice that spontaneously develop varying levels of anti-Bm antibodies capable of causing Bm RBC HTRs following transfusion. Sorting and culturing anti-Bm reactive microbiota identified a strain of Klebsiella pneumonia that specifically expresses the Bm antigen, providing a possible link between the microbiota and anti-Bm antibody development. As blood group Om mice and O individuals possess innate-like B1 B cells with blood group specificity, these collective data suggest that microbial stimulation of B1 B cells drives the formation of anti-blood group antibodies capable of causing HTRs. To test this hypothesis, we will pursue the following specific aims: Aim 1. Define the role of B1 B cells and anti-blood group antibody reactive microbiota in the development of anti-ABO(H) antibodies capable of causing HTRs. Aim 2. Define the requirement for B1 B cells in microbiota-induced anti-Bm antibody formation using a preclinical model. These aims will not only define the impact of the microbiota on the development of anti-blood group antibodies, but provide a rich training opportunity for me to weld my previous training in transfusion immunology with new training in glycobiology to define the governing factors that regulate the development of the most common immunological barrier in not only transfusion, but also transplantation.
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