Thymus microenvironment in human primary immunodeficiency diseases.
Severe combined immunodeficiencies represent a heterogeneous group of genetic disorders affecting genes of both early and late steps in lymphocytes development, a process tightly controlled by thymic epithelial cells. Detailed analysis of thymic morphology aids to the assessment of the severity of the immune disorder and may be critical to the understanding of the role of the genetic defects in the pathophysiology of these diseases. In this review, we highlight recent advancements in the characterization of the thymic microenvironment in primary immunodeficiencies. Crosstalk between thymocytes and thymic epithelial cells is essential to preserve thymic architecture and function, and therefore to promote T-cell maturation and development of self-tolerance. Early severe defects in T-cell development result in profound abnormalities of thymic epithelial cells differentiation with loss of AIRE expression and severe reduction of thymic dendritic and T-regulatory cells. Differently, later defects in T-cell development that are permissive for normal thymocytes development allow cortico-medullary differentiation with partially preserved AIRE expression and dendritic/T-regulatory cells distribution. Hypomorphic mutations in the same genes partially permissive to T-cell development may result in a more complex phenotype with immunodysreactivity and peculiar thymic alterations. Although the molecular and genetic bases of primary immunodeficiencies directly aid to both diagnosis and management of the patients, the detailed analysis of thymic morphology critically contributes to unveil the pathophysiology of these diseases.