P18 Unc93 homolog B1 restricts systemic lethal irritation by orchestrating TLR7 and TLR9 response Ryutaro Fukui1, Shin Ichiroh Saitoh1, Atsuo Kanno1, Masahiro Onji1, Takuma Shibata1,2, Akihiko PDK 1 Signaling Ito4, Morikazu Onji5, Mitsuru Matsumoto6, Shizuo Akira7,8, Nobuaki Yoshida3, Kensuke Miyake1,2 1Division of Infectious Genetics, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, 4 6 1 Page 27 of 54 Shirokanedai, Minatoku, Tokyo 108 8639, Japan, 2Laboratory of Innate Immunity, The Institute of Medical Science, The University of Tokyo, 4 6 1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan, 3Laboratory of Developmental Genetics, Center for Experimental Medicine and Methods Biology, The Institute of Health care Science, The University of Tokyo, 4 6 1 Shirokanedai, Minatoku, Tokyo 108 8639, Japan, 4Department of Pathology, Faculty of Medicine, Kinki University, Osaka 589 8511, Japan, 5Department of Gastroenterology and Metabology, Ehime University Graduate College of Medication, Ehime 791 0295, Japan, 6Division of Molecular Immunology, Institute for Enzyme Exploration, University of Tokushima, Tokushima 770 8504, Japan, 7Laboratory of Host Defense, Planet Premier International Immunology Frontier Study Center, Osaka 565 0871, Japan, 8Department of Host Defense, Exploration Institute for Microbial Conditions, Osaka University, Osaka 565 0871, Japan Arthritis Investigate & Therapy 2012, 14 18 Nucleotide sensing TLRs recognize pathogen derived nucleic acids and trigger immune response.

Because of the highly conserved structure of nucleic acids, these TLRs have risk to recognize host derived nucleic acids and induce Factor Xa autoimmune disease, therefore it is important to clarify the mechanisms and control the response. We found that the responses of TLR7 and TLR9 are balanced reciprocally, and Unc93 homolog B1 is a key molecule for this baGene expression lancing system. Unc93B1 is known as an essential molecule for TLR3, TLR7, and TLR9 responses, and the function depends on its C terminal region. The balancing function of Unc93B1 is located on 34th aspartic acids from N terminal, and alanine mutant Unc93B1 up regulates TLR7 response and down regulates TLR9 response. It is reported that TLR7 or TLR9 response contributes to some kinds of autoimmune disease and TLR7 overexpressed mice develop SLE like autoimmune disease.

To investigate the significance of reciprocal TLR7/TLR9 balance in vivo, we generated Unc93b1D34A/D34A mice and observed the phenotypes. As results, Unc93b1D34A/D34A mice were born according to Mendelian rule but started to die spontaneously at 10 weeks old and over half of Unc93b1D34A/D34A mice died within 1 year. Unc93b1D34A/ D34A mice developed various phenotypes, for example, proton pump inhibitor therapy splenomegaly, hepatitis, glomerulonephritis, thrombocytopenia, myeloproliferative disorder. Especially, lethal acute hepatitis was observed in moribund mice and infiltrated myeloid cells in liver were expanded in spleen. These phenotypes are vanished by TLR7 deficient Unc93B1D34A/ D34A mice, thus TLR7 hyper response caused by TLR7/TLR9 balance disruption is factor of phenotypes in Unc93b1D34A/D34A mice. Not only innate immune system, acquired immune system is also affected by D34A mutation.