Immune Response to RBC Antigens

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ABSTRACT Autoimmune hemolytic anemia (AIHA) causes significant morbidity and mortality; however, we still do not fully understand how immune tolerance to red blood cells (RBCs) is established or broken. Given that RBCs are required for life, are abundant, and have essential functions (e.g., tissue oxygenation), one would predict stringent immune tolerance; however, tolerance failure occurs frequently. Indeed, 0.1% of healthy blood donors and ~8% of hospitalized patients have detectable RBC autoantibodies. These autoantibodies can be clinically significant, by inducing RBC clearance, hemolysis, antigen modulation, and increased risk for future AIHA or cancer. Patients with AIHA present with pallor, fatigue, hemoglobinuria, splenomegaly, and/or life-threatening hemolysis. Treatment strategies have variable success, with high relapse rates and mortality in ~11% of cases. Supportive care using RBC transfusions is challenging as most autoantibodies recognize ubiquitous RBC antigens; thus, virtually all donor units are crossmatch incompatible. The etiology of AIHA is generally unknown and up to 50% of AIHA cases have no identifiable cause (“primary”). Secondary AIHA is frequently associated with other autoimmune diseases and has been recently observed as a complication of checkpoint inhibitor immunotherapies in the treatment of cancer. Thus, loss of tolerance to RBC autoantigens is an important medical and scientific problem. To elucidate RBC tolerance mechanisms, we developed an innovative primary AIHA murine model, which closely reflects human disease, a subset of mice develops age-onset hemolytic RBC autoantibodies, anemia, splenomegaly, and reticulocytosis. Using this model, we pinpointed a 3-week developmental timeframe during which RBC autoreactive recent thymic emigrants encounter RBC antigens and become tolerized. Transcriptomic analysis identified novel pathways whose activity correlates with autoreactive T cell tolerization, including 1) checkpoint molecules, 2) IL-10, and 3) purinergic signaling. Because AIHA is the most frequently reported hematological adverse event due to cancer immunotherapy, we developed a novel secondary AIHA model with checkpoint inhibitors. Loss of tolerance in the primary and secondary AIHA mouse models is associated with an imbalance between regulatory T cells (Tregs) and proinflammatory TH17 T cells, as well as a distinct population of CD39+ T cells. Herein, we leverage our preclinical AIHA mouse models to determine which signaling molecules and/or pathways (i.e., checkpoint molecules, IL-10, or purinergic signaling molecules) are required for T cell tolerance and AIHA prevention, and elucidate how biological factors, such as sex and age, affect these requirements. The function of unique T cell populations (i.e., recent thymic emigrants, Treg subsets, and CD39+ T cells) will also be defined. Understanding how the immune system responds to RBC antigens will provide insight into not only autoimmunity to RBCs but may also have applicability to other autoantigens present at high concentrations (e.g., platelet autoantigens, dsDNA) thereby making this a powerful platform to study the requirements for tolerance to self-antigens in general.