Activation and differentiation of autoreactive B-1 cells by interleukin 10 induce autoimmune hemolytic anemia in Fas-deficient antierythrocyte immunoglobulin transgenic mice.
The Fas (CD95) gene is among critical genetic factors in some autoimmune diseases, which are characterized by autoantibody (autoAb) productions. In mice, mutations in the Fas gene cause lymphoproliferation (lpr) which predominantly develops glomerulonephritis, whereas the mutations in human cause autoimmune lymphoproliferative syndrome (ALPS) characterized by autoimmune hemolytic anemia (AIHA) and thrombocytopenia. Although the mechanism of antinuclear Ab in Fas-deficient background has been well characterized, that of antierythrocyte Ab production in ALPS has been still unclear. To investigate this mechanism, we developed a mouse line by crossing the antierythrocyte antibody transgenic mice (H+L6 mice) and Fas-deficient mice. Although Fas deficiency did not break tolerance of autoreactive B-2 cells in H+L6 mice, autoreactive B-1 cells in Fas-deficient H+L6 homozygous mice became activated and differentiated into autoAb-producing cells in mesenteric lymph nodes and lamina propria of intestine, resulting in severe anemia. In addition, serum levels of interleukin (IL)-10 significantly increased in Fas-/- x H+L6 homozygous mice and administration of anti-IL-10 Ab prevented exacerbation of autoAb production and AIHA. These results suggest that activation of B-1 cells is responsible for induction of AIHA in Fas-deficient condition and that IL-10 plays a critical role in terminal differentiation of B-1 cells in these mice.
Watanabe
Norihiko
N
Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan.
Ikuta
Koichi
K
Nisitani
Sazuku
S
Chiba
Tsutomu
T
Honjo
Tasuku
T
D000740:Anemia / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001323:Autoantibodies / Q000235:genetics / Q000276:immunology*; D015551:Autoimmunity / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002454:Cell Differentiation / Q000276:immunology*; D003433:Crosses, Genetic; D004912:Erythrocytes / Q000276:immunology; D006579:Heterozygote; D006720:Homozygote; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D007378:Interleukins / Q000097:blood; D008198:Lymph Nodes / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology*; D008643:Mesentery / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019014:fas Receptor / Q000235:genetics*
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D007136:Immunoglobulins; D007378:Interleukins; D019014:fas Receptor; D016753:Interleukin-10