Severe impairment of B cell function in lpr/lpr mice expressing transgenic Fas selectively on B cells

• Published in: International immunology 1999-07, Vol.11 (7), p.1035-1042
• Main Authors: Komano, Hajime, Ikegami, Yuko, Yokoyama, Minesuke, Suzuki, Rika, Yonehara, Shin, Yamasaki, Yoshiki, Shinohara, Nobukata
• Format: Article
• Language: English
• Subjects: Animals; Autoantibodies - biosynthesis; autoantibody; Autoimmune Diseases - genetics; Autoimmune Diseases - metabolism; B cell; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; B-Lymphocytes - pathology; DNA, Complementary - genetics; DNA, Complementary - immunology; DNA, Complementary - metabolism; ds double stranded; Fas; fas Receptor - biosynthesis; fas Receptor - genetics; fas Receptor - immunology; fas Receptor - physiology; FasL Fas ligand; Female; Gene Expression; HRP horseradish peroxidase; Immunoglobulins - biosynthesis; Immunoglobulins - blood; KLH keyhole limpet hemacyanin; lpr; Lymphocyte Count; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C3H; Mice, Inbred MRL lpr; Mice, Transgenic; PE phycoerythrin; SBRC sheep red blood cell; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; TMB tetramethylbenzidine; Transgenes - immunology
• ISSN: 0953-8178; 1460-2377
• DOI: 10.1093/intimm/11.7.1035

Transgenic lpr/lpr mice expressing functional Fas selectively on B cells were produced in an attempt to elucidate the role of Fas on B cells in the regulation of autoantibody production. The homozygous lpr/lpr mice carrying the transgene did not produce anti-double-stranded DNA antibodies throughout their lives, whereas the development of abnormal lpr T cells (double negative, B220+) was not suppressed. Further analyses, however, revealed that the expression of the transgenic Fas on B cells of lpr/lpr homozygous mice resulted in severe impairment of the B cell function. The defect was characterized by a decrease in the number of mature peripheral B cells, a reduction in the serum Ig level and the total failure of B cells to mount antibody responses to stimulations of T-dependent as well as T-independent antigens. Such a defect was prominent only when the transgene was expressed on the lpr/lpr homozygous background. On the contrary, B cells of the transgenic lpr/lpr mice were shown to be capable of producing Ig when stimulated with anti-CD40 in the presence of IL-4 and IL-5. Furthermore, lpr/lpr T cells showed enhanced non-specific cytolytic activity. These observations suggested that the observed B cell defect was probably attributable to the destruction of activated B cells expressing transgenic Fas by aggressive lpr/lpr T cells.