Nucleotide sensing-TLRs (Toll-like receptors) 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 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 (Unc93B1) is a key molecule for this balancing 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 (D34A) Unc93B1 up-regulates TLR7 response and down-regulates TLR9 response (Figure 1) .
It is reported that TLR7 or TLR9 response contributes to some kinds of autoimmune disease and TLR7 overexpressed mice develop SLE like autoimmune disease [4, 5, 6, 7, 8]. 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 (Figure 2A) . Unc93b1D34A/D34A mice developed various phenotypes, for example, splenomegaly, hepatitis, glomerulonephritis, thrombocytopenia, myeloproliferative disorder (Figure 2B-2E). 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 (Figure 2).
Not only innate immune system, acquired immune system is also affected by D34A mutation. Expanded memory T cells, up-regulation of ICOS and CD69 on T cells were observed by TLR7 dependent manner and some classes of serum immunoglobulin level is increased in Unc93b1D34A/D34A mice. In addition, Th1 and Th17 cells were expanded and activated in Unc93b1D34A/D34A mice. The activation of T cells were TLR7 dependent, and mature B cell depleted Ighm-/-Unc93b1D34A/D34A mice did not induce T cell activation and moderated phenotypes (Figure 3D and 3E). It suggests that B cells are activated by TLR7 hyper-response, and the B cells activate T cells to generate phenotypes of Unc93b1D34A/D34A mice.However, thrombocytopenia was not completely recovered in Ighm-/-Unc93b1D34A/D34A mice but completely recovered in Rag2-/-Unc93b1D34A/D34A mice. Interaction between cell types and phenotypes should be confirmed as a future plan.
Fukui R, Saitoh S, Matsumoto F, Kozuka-Hata H, Oyama M, Tabeta K, Beutler B, Miyake K: Unc93B1 biases Toll-like receptor responses to nucleic acid in dendritic cells toward DNA- but against RNA-sensing. J Exp Med. 2009, 206: 1339-1350. 10.1084/jem.20082316.PubMedCentralCrossRefPubMedGoogle Scholar
Tabeta K, Hoebe K, Janssen EM, Du X, Georgel P, Crozat K, Mudd S, Mann N, Sovath S, Goode J, et al: The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nat Immunol. 2006, 7: 156-164.CrossRefPubMedGoogle Scholar
Pisitkun P, Deane JA, Difilippantonio MJ, Tarasenko T, Satterthwaite AB, Bolland S: Autoreactive B cell responses to RNA-related antigens due to TLR7 gene duplication. Science. 2006, 312: 1669-1672. 10.1126/science.1124978.CrossRefPubMedGoogle Scholar
Santiago-Raber ML, Kikuchi S, Borel P, Uematsu S, Akira S, Kotzin BL, Izui S: Evidence for genes in addition to Tlr7 in the Yaa translocation linked with acceleration of systemic lupus erythematosus. J Immunol. 2008, 181: 1556-1562.CrossRefPubMedGoogle Scholar
Asagiri M, Hirai T, Kunigami T, Kamano S, Gober HJ, Okamoto K, Nishikawa K, Latz E, Golenbock DT, Aoki K, et al: Cathepsin K-dependent toll-like receptor 9 signaling revealed in experimental arthritis. Science. 2008, 319: 624-627. 10.1126/science.1150110.CrossRefPubMedGoogle Scholar
Deane JA, Pisitkun P, Barrett RS, Feigenbaum L, Town T, Ward JM, Flavell RA, Bolland S: Control of toll-like receptor 7 expression is essential to restrict autoimmunity and dendritic cell proliferation. Immunity. 2007, 27: 801-810. 10.1016/j.immuni.2007.09.009.PubMedCentralCrossRefPubMedGoogle Scholar
Lande R, Gregorio J, Facchinetti V, Chatterjee B, Wang YH, Homey B, Cao W, Su B, Nestle FO, Zal T, et al: Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature. 2007, 449: 564-569. 10.1038/nature06116.CrossRefPubMedGoogle Scholar
Fukui R, Saitoh SI, Kanno A, Onji M, Shibata T, Ito A, Matsumoto M, Akira S, Yoshida N, Miyake K: Unc93B1 restricts systemic lethal inflammation by orchestrating toll-like receptor 7 and 9 trafficking. Immunity. 2011Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Authors and Affiliations
1.Division of Infectious Genetics, Department of Microbiology and Immunology, The Institute of Medical ScienceThe University of TokyoMinatoku, TokyoJapan
2.Laboratory of Innate Immunity, The Institute of Medical ScienceThe University of TokyoMinatoku, TokyoJapan
3.Laboratory of Developmental Genetics, Center for Experimental Medicine and Systems Biology, The Institute of Medical ScienceThe University of TokyoMinatoku, TokyoJapan
4.Department of Pathology, Faculty of MedicineKinki UniversityOsakaJapan
5.Department of Gastroenterology and MetabologyEhime University Graduate School of MedicineEhimeJapan
6.Division of Molecular Immunology, Institute for Enzyme ResearchUniversity of TokushimaTokushimaJapan
7.Laboratory of Host DefenseWorld Premier International Immunology Frontier Research CenterOsakaJapan
8.Department of Host Defense, Research Institute for Microbial DiseasesOsaka UniversityOsakaJapan