A signal adaptor SLAM-associated protein regulates spontaneous autoimmunity and Fas-dependent lymphoproliferation in MRL-Faslpr lupus mice.
Autoantibody production and lymphadenopathy are common features of systemic autoimmune disease. Targeted or spontaneous mutations in the mouse germline have generated many autoimmune models with these features. Importantly, the models have provided evidence for the gene function in prevention of autoimmunity, suggesting an indispensable role for the gene in normal immune response and homeostasis. We describe here pathological and genetic characterizations of a new mutant strain of mice, the mutation of which spontaneously occurred in the Fas-deficient strain, MRL/Mp.Faslpr (MRL/lpr). MRL/lpr is known to stably exhibit systemic lupus erythematosus-like diseases. However, the mutant mice barely displayed autoimmune phenotypes, though the original defect in Fas expression was unchanged. Linkage analysis using (mutant MRL/lpr x C3H/lpr)F2 mice demonstrated a nucleotide insertion that caused loss of expression of small adaptor protein, signaling lymphocyte activation molecule (SLAM)-associated protein (SAP). SAP is known to be a downstream molecule of SLAM family receptors and to mediate the activation signal for tyrosine kinase Fyn. Recent studies have shown pleiotropic roles of SAP in T, B, and NK cell activations and NKT cell development. The present study will provide evidence for an essential role for SAP in the development of autoimmune diseases, autoantibodies, and lymphadenopathy in MRL/lpr lupus mice.
Komori
Hiroaki
H
Department of Pathology, Ehime University School of Medicine, Toon, Japan.
Furukawa
Hiroshi
H
Mori
Shiro
S
Ito
Mitsuko R
MR
Terada
Miho
M
Zhang
Ming-Cai
MC
Ishii
Naoto
N
Sakuma
Nobuhiro
N
Nose
Masato
M
Ono
Masao
M
D000595:Amino Acid Sequence; D000818:Animals; D015551:Autoimmunity / Q000235:genetics*; D015153:Blotting, Western; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D008040:Genetic Linkage; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology; D008206:Lymphatic Diseases / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008969:Molecular Sequence Data; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D019014:fas Receptor / Q000378:metabolism
D047908:Intracellular Signaling Peptides and Proteins; D019014:fas Receptor