Natural Autoreactive B Cells in Transgenic Mice Reproduce an Apparent Paradox to the Clonal Tolerance Theory

• Published in: The Journal of immunology (1950) 2001-02, Vol.166 (3), p.1463-1470
• Main Authors: Koenig-Marrony, Severine, Soulas, Pauline, Julien, Sylvie, Knapp, Anne-Marie, Garaud, Jean-Claude, Martin, Thierry, Pasquali, Jean-Louis
• Format: Article
• Language: English
• Subjects: Animals; Autoantibodies - biosynthesis; Autoantibodies - genetics; Autoantigens - genetics; Autoantigens - immunology; B-Lymphocyte Subsets - cytology; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Clonal Anergy - genetics; Clonal Deletion - genetics; DNA, Single-Stranded - immunology; Female; Genetic Vectors - immunology; Genetic Vectors - metabolism; Humans; Hybridomas; Immunity, Innate - genetics; Immunoglobulin Constant Regions - biosynthesis; Immunoglobulin Constant Regions - genetics; Immunoglobulin delta-Chains - biosynthesis; Immunoglobulin delta-Chains - genetics; Immunoglobulin Heavy Chains - biosynthesis; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Variable Region - biosynthesis; Immunoglobulin Variable Region - genetics; Immunology; Life Sciences; Lymphocyte Activation - genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Antigen, B-Cell - physiology; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - immunology; Self Tolerance - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.3.1463

Naturally occurring autoreactive B cells are thought to be physically eliminated or rendered functionally silent through different mechanisms of tolerance. However, multireactive low affinity natural autoantibody-producing B cells seem to escape these mechanisms in normal adults and could constitute the B cell pool from which pathological autoantibodies can emerge. To analyze this apparent paradox to the clonal tolerance theory, we have made two transgenic mouse lines (mu(k), mudelta(k)) producing a natural low affinity multireactive human autoantibody. These models enable us to test both the central tolerance mechanisms (reactivity with single-stranded DNA) and the peripheral tolerance mechanisms after Ag administration. Not only are the multireactive B cells not deleted in the bone marrow, they circulate and remain in the periphery even after the prolonged administration of Ag, the presence of membrane IgD increasing the number of mature autoreactive B cells. Self-reactive B cells are shown to be autoantigen ignorant both in vivo and in vitro, but they are not anergic because they can be easily activated through both B cell receptor-dependent and -independent pathways. Thus, these mouse lines reproduce an apparent paradox to the clonal tolerance theory meriting further investigation of the biological significance of this phenomenon.