Abstract: Common variable immunodeficiency (CVID) is the most frequent clinically relevant primary immunodeficiency in humans. CVID is a mixed group of heterogeneous conditions linked by lack of immunoglobulin production against pathogens. CVID in human patients has challenged the field of clinical immunology in regards to etiology and, consequently, therapeutic intervention;only a minor percentage of the affected patients are known to have genetic mutations that result in dysfunctional adaptive humoral responses. In addition to its heterogeneous nature, a striking aspect of this disorder relates to its manifestation later in life, confounding the study of putative genetic disorders. The goal of this proposal is to introduce and investigate the mechanism of disease in a natural equine model of CVID, for direct application in diagnostics and management of human patients with primary humoral immunodeficiencies. My hypothesis is that B cell differentiation is impaired at pro-B cell stage in equine patients with B cell lymphopenia due to essential gene silencing. Deregulation of mechanisms that control chromatin modification lead to inappropriate expression or silencing of genes involved in cell differentiation and development that could be involved in progressive B cell depletion in equine patients with CVID. My research proposal is uniquely suited to the New Innovator Award program because it offers a natural horse model of disease, and and non- conventional approach and therory for the etiology of primary immunodeficiencies in humans. Although there is accumulating evidence of epigenetic mechanisms involved in many diseases, tradition and well-defined other genetic primary immunodeficiency disorders may have overshadowed this possibility in the study of CVID in human patients to date. Public Health Relevance: Common variable immunodeficiency (CVID) in horses is a primary humoral immunodeficiency characterized by late-onset recurrent bacterial infections, hypo- or agammaglobulinemia, and B cell lymphopenia or depletion. We propose the CVID horse as a model of study for CVID in humans because they share numerous similarities in clinical disease and patient care. Horses with CVID offer a rare opportunity to study abnormal B cell differentiation and development in a natural setting, with direct applications to the understanding of mechanisms of disease and diagnostics in human patients.
