Tight Interdigitating Developmental Processes within the Thymus; Lessons from Primary Immunodeficiency with Autoimmunity

The underlying cause of the enigmatic coexistence of immunodeficiency and autoimmune disorders in patients with primary immunodeficiency such as Omenn syndrome is largely due to the inefficient negative selection within thymus where T cells develop. Recent advances in molecular biology and animal models answered one of the key questions on the relationship between the partially impaired T cell development at early stages and the presence of autoreactive T cells in periphery. T cell development and thymic organogenesis are tightly coupled to each other. The maturing T cells induce thymic epithelial cell development and AIRE (Autoimmune regulator) expression in thymic medullary epithelial cells. Without thymic medullary epithelial cells and AIRE protein in the patients with primary immunodeficiency, a few autoreactive T cells survive through the complete thymic selection processes and expand to form oligoclonal T cell pools in the periphery. The induction of thymic medullary epithelial cell development may be considered as an alternative therapeutic approach in addition to the current standard therapy for primary immunodeficiency stem cell transplantation.