Loss of humoral tolerance to red blood cells (RBCs) can lead to
autoimmune hemolytic anemia (AIHA), a severe, and sometimes fatal disease. Patients with AIHA present with pallor,
fatigue, decreased hematocrit, and
splenomegaly. While secondary AIHA is associated with
lymphoproliferative disorders,
infections, and more recently, as an adverse event secondary to
cancer immunotherapy, the etiology of primary AIHA is unknown. Several therapeutic strategies are available; however, there are currently no licensed treatments for AIHA and few
therapeutics offer treatment-free durable remission. Moreover, supportive care with RBC transfusions can be challenging as most
autoantibodies are directed against ubiquitous RBC
antigens; thus, virtually all RBC donor units are incompatible. Given the severity of AIHA and the lack of treatment options, understanding the cellular and molecular mechanisms that facilitate the breakdown in tolerance would provide insight into new
therapeutics. Herein, we report a new murine model of primary AIHA that reflects the biology observed in patients with primary AIHA. Production of anti-erythrocyte
autoantibodies correlated with sex and age, and led to RBC
antigen modulation,
complement fixation, and
anemia, as determined by decreased hematocrit and
hemoglobin values and increased reticulocytes in peripheral blood. Moreover,
autoantibody-producing animals developed
splenomegaly, with altered splenic architecture characterized by expanded white pulp areas and nearly diminished red pulp areas. Additional analysis suggested that compensatory extramedullary erythropoiesis occurred as there were increased frequencies of RBC progenitors detectable in the spleen. No significant correlations between AIHA onset and inflammatory status or microbiome were observed. To our knowledge, this is the first report of a murine model that replicates observations made in humans with idiopathic AIHA. Thus, this is a tractable murine model of AIHA that can serve as a platform to identify key cellular and molecular pathways that are compromised, thereby leading to
autoantibody formation, as well as testing new
therapeutics and management strategies.