Murine models of autoimmune hemolytic anemia

Abstract

Purpose of review: Pathogenic autoantibodies directed against red blood cells (RBCs) may lead to autoimmune hemolytic anemia (AIHA), a severe and sometimes fatal disease. Much of what is known about the etiology and pathogenesis of AIHA has been learned from observations made in human patients and murine models, but many questions remain; importantly, it is still unclear why some people generate RBC-specific autoantibodies. The combination of technological advancements applied to existing models and the development of new AIHA murine models will continue to provide considerable insight into the initiation of AIHA and provide a platform for the design of more effective therapies.

Recent findings: Advancements in well described murine models of AIHA show that reticulocytes are preferentially targeted by anti-RBC autoantibodies and an increase in oxidative stress may trigger autoantibody production. Additionally, a new murine model of erythrocyte autoreactivity demonstrates that T cell tolerance is the stopgap for autoimmunity. Moreover, unlike many self-antigens, data suggest that RBC self-antigens are not presented in the thymus thereby escaping the scrutiny of T cell central tolerance mechanisms and placing emphasis on peripheral tolerance instead. Information gained from this new model provide novel insight into how the immune system responds to RBC autoantigens and provides a tractable platform to discover new therapies for AIHA.

Summary: Murine models of AIHA have provided significant understanding into the risk factors for AIHA. The application of new technologies and models of erythrocyte autoreactivity is a pathway with the potential to elucidate how tolerance to RBC autoantigens is established, maintained, and broken down.

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FIGURE 1

The HOD model of erythrocyte autoreactivity. (a) The HOD mouse expresses an RBC-restricted triple fusion protein consisting of hen egg lysozyme (HEL), ovalbumin (OVA), and human blood group Duffy. (b) HOD crossed to IgHEL, SwHEL, and OTII to generate new models of AIHA. In HOD+IgHEL+ mice (top), IgM HEL-specfic B cells cannot undergo receptor editing or class-switching, which leads to a deletion of B-2 B cells and an enrichment of peritoneal B-1 B cells. HOD+SwHEL+ mice (middle) produce B cells that can undergo receptor rearrangement and class-switching. In this model, deletion of B-1 and B-2 B cell subsets is observed. Both HOD+IgHEL+ and HOD+SwHEL+ develop anti-RBC autoantibodies, however only HOD+IgHEL+ mice develop decreased hematocrit and hemoglobin. HOD+OTII+ mice (bottom) have CD4 T cells that are specific for OVA. Upon aging, a subset of HOD+OTII+ mice develop erythrocyte autoantibodies, which correlated with splenomegaly and anemia. Similar to other autoimmunity models and observations in humans, autoimmune mice were mostly female.