Immunodeficiency: immunoregulation and immunogenetics.

During the past decade, our knowledge of normal immunologic development and function as well as disorders that lead to immunodeficiency has expanded rapidly as a result of the interplay between studies of the immune system in animals and studies of patients with immunodeficiency diseases or with malignancies of the cells of the lymphoid system. The study of immunodeficiency diseases has been particularly valuable in defining the critical stages in the differentiation of stem cells into mature lymphoid effector cells and the roles played by different subpopulations of cells in regulating the immune response. Our understanding of the immunodeficiency diseases has been facilitated by a number of important advances: (a) The identification of distinct surface determinants on lymphoid cells has led to improved procedures for the isolation of defined lymphoid cell subpopulations; (b) the demonstration that both T- and B-cell populations encompass subpopulations of lymphocytes with different and at times opposing functions; (c) the development of in vitro techniques to assess the functional behavior of isolated lymphoid subpopulations; and (d) the isolation and characterization of genes encoding immunoglobulin molecules and the antigen-specific T-cell receptor, thus defining at a molecular level the mechanisms leading to antibody diversity and to the organization of a recognition unit on T lymphocytes. These advances have not only been important for our understanding of the pathogenesis of immunodeficiency in patients with congenital and acquired immunodeficiency disorders, but have also provided the scientific basis for more rational approaches to the diagnosis and therapy of these disorders. This report will review (a) the defects in cellular maturation, cellular interaction, and cellular biosynthesis that have been observed in patients with immunodeficiency diseases; (b) the immunoglobulin gene rearrangements that are involved in the generation of antibody diversity; (c) the structure and genetic basis for the generation of antigen-specific T-cell receptors; and (d) potential future applications of molecular genetic approaches to the definition of the pathogenesis and to the treatment of immunodeficiency diseases.