Massive upregulation of the Fas ligand in lpr and gld mice: implications for Fas regulation and the graft-versus-host disease-like wasting syndrome.
Fas-deficient lpr and gld mice develop lymphadenopathy due to the accumulation of T cells with an unusual double negative (DN) (CD4-CD8-) phenotype. Previous studies have shown that these abnormal cells are capable of inducing redirected lysis of certain Fc receptor-positive target cells. Since the Fas ligand (FasL) has recently been shown to be partly responsible for T cell-mediated cytotoxicity, lymph node cells from lpr and gld mice were examined for the expression of FasL mRNA. Northern blot analysis revealed that lymph node cells obtained from lpr and gld mice had a striking increase in the level of expression of FasL mRNA predominantly due to expression in the DN T cells. Furthermore, lpr, but not gld lymph node cells killed the B cell line, A20, in a Fas-dependent manner. These findings indicate that Fas mutations result in a massive up-regulation of FasL which, most likely, results from repetitive exposure to (self) antigen. This phenomenon could explain the lpr-induced wasting syndrome observed when lpr bone marrow-derived cells are adoptively transferred to wild-type recipients.
Chu
J L
JL
Specialized Center of Research in Systemic Lupus Erythematosus, Hospital for Special Surgery-Cornell University Medical Center, New York 10021.
Ramos
P
P
Rosendorff
A
A
Nikolić-Zugić
J
J
Lacy
E
E
Matsuzawa
A
A
Elkon
K B
KB
D000367:Age Factors; D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D001327:Autoimmune Diseases / Q000503:physiopathology; D001483:Base Sequence; D002100:Cachexia / Q000503:physiopathology*; D003602:Cytotoxicity, Immunologic; D017931:DNA Primers / Q000737:chemistry; D053222:Fas Ligand Protein; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000503:physiopathology*; D008206:Lymphatic Diseases / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D019014:fas Receptor
D000954:Antigens, Surface; D017931:DNA Primers; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D019014:fas Receptor