Toll様受容体9

関: Toll-like receptor 9

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/04/05 07:26:13」(JST)

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TLR9はToll様受容体9番 (Toll-like receptor 9) の略称。TLR9は細菌、ウイルス由来の非メチル化CpG DNAを認識し、細菌、ウイルスからの防御で働く自然免疫系分子の一つ。

TLR9のリガンド

TLR9のリガンドは非メチル化CpG DNAである。CpGとはシトシンとグアニンがホスホジエステル結合により結びついた配列であり、これらば哺乳類ではCpGアイランドと呼ばれる領域に豊富な配列である。ただし哺乳類ではCpGがメチル化修飾を受けており、TLR9のリガンドとはならない。細菌やウイルスのDNAは非メチル化CpG DNAを有し、TLR9のリガンドとなる。合成ODNも同様に非メチル化CpG DNAであればTLR9受容体を介してシグナルが入る。

CpG DNAにはA/D型およびB/K型、C型が存在する。

タンパク質の機能

TLR9はエンドソーム内に局在し、DNAウイルスに存在するメチル化されていないCpG残基を認識することで、I型インターフェロンを産出し、ウイルスに対抗することができる。そのため、TLR9を欠損している形質細胞様樹状細胞はヘルペスウイルスに対しI型インターフェロンを作ることができない。 TLR9のリガンドであるCpGの刺激により、まず樹状細胞がIL-15を作る、その後IL-12を作り始めるのだが、先に分泌されたIL-15によりCD40とCD40リガンド（CD40LまたはCD154ともいう）の発現を誘導し樹状細胞のIL-12の産出を持続させる。IL-12は細菌に対して効果的に働くCD4T細胞を誘導する。

自己寛容破綻との関連

非メチル化CpGは病原体関連分子に特徴的なものであるが、自己分子にも多少存在している。特にアポトーシスを起こす場合には哺乳類細胞でも増加するので、過剰な細胞死などでアポトーシスした細胞断片の処理が間に合わないような場合には、CpGを認識するB細胞がB細胞受容体（BCR）を介して非メチル化CpGを取り込みTLR9と結合して補助刺激が入るので、自己反応性のB細胞を活性化させてしまう恐れがある。こうなると、活性化したB細胞は自己抗体の産生へと向かうとともに抗原提示細胞として自己反応性T細胞を活性化させてしまう。

この項目は、生物学に関連した書きかけの項目です。この記事を加筆・訂正などしてくださる協力者を求めています（プロジェクト:生命科学／Portal:生物学）。

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[Wiki en表示]

Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene.^[1] TLR9 has also been designated as CD289 (cluster of differentiation 289).

Function

TLR9 is a member of the toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are named for the high degree of conservation in structure and function seen between mammalian TLRs and the Drosophila transmembrane protein Toll. TLRs are transmembrane proteins, expressed on the cell surface and the endocytic compartment and recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents and initiate signalling to induce production of cytokines necessary for the innate immunity and subsequent adaptive immunity. The various TLRs exhibit different patterns of expression. This gene is preferentially expressed in immune cell rich tissues, such as spleen, lymph node, bone marrow and peripheral blood leukocytes. Studies in mice and human indicate that this receptor mediates cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response.^[2]

TLR9 recognizes unmethylated CpG sequences in DNA molecules. CpG sites are relatively rare (~1%) on vertebrate genomes in comparison to bacterial genomes or viral DNA. TLR9 is expressed by numerous cells of the immune system such as dendritic cells, B lymphocytes, monocytes and natural killer (NK) cells. TLR9 is expressed intracellularly, within the endosomal compartments and functions to alert the immune system of viral and bacterial infections by binding to DNA rich in CpG motifs. TLR9 signals leads to activation of the cells initiating pro-inflammatory reactions that result in the production of cytokines such as type-I interferon and IL-12.

Clinical significance

There are new immunomodulatory treatments undergoing testing which involve the administration of artificial DNA oligonucleotides containing the CpG motif. CpG DNA has applications in treating allergies such as asthma,^[3] immunostimulation against cancer,^[4] immunostimulation against pathogens, and as adjuvants in vaccines.^[5]

Protein interactions

TLR9 has been shown to interact with RNF216.^[6]

References

^ Du X, Poltorak A, Wei Y, Beutler B (Dec 2000). "Three novel mammalian toll-like receptors: gene structure, expression, and evolution". Eur Cytokine Netw 11 (3): 362–71. PMID 11022119.
^ "Entrez Gene: TLR9 toll-like receptor 9".
^ Kline JN (July 2007). "Eat dirt: CpG DNA and immunomodulation of asthma". Proc Am Thorac Soc 4 (3): 283–8. doi:10.1513/pats.200701-019AW. PMC 2647631. PMID 17607014.
^ Thompson JA, Kuzel T, Bukowski R, Masciari F, Schmalbach T (July 2004). "Phase Ib trial of a targeted TLR9 CpG immunomodulator (CPG 7909) in advanced renal cell carcinoma (RCC)". Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 22 (14S).
^ Klinman DM (2006). "Adjuvant activity of CpG oligodeoxynucleotides". Int. Rev. Immunol. 25 (3-4): 135–54. doi:10.1080/08830180600743057. PMID 16818369.
^ Chuang TH, Ulevitch RJ (May 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nat. Immunol. 5 (5): 495–502. doi:10.1038/ni1066. PMID 15107846.

External links

TLR9 protein, human at the US National Library of Medicine Medical Subject Headings (MeSH)

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This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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1. Toll様受容体：疾患および治療における役割 toll like receptors roles in disease and therapy
2. 全身性エリテマトーデスの疫学および病因 epidemiology and pathogenesis of systemic lupus erythematosus
3. 分類不能型低ガンマグロブリン血症の病因 pathogenesis of common variable immunodeficiency
4. ヘルパーT細胞サブセット：疾患における分化および役割 t helper subsets differentiation and role in disease
5. 糸球体の免疫障害の機序 mechanisms of immune injury of the glomerulus

English Journal

TLR9 and BAFF: Their expression in patients with IgA nephropathy.

Li W, Peng X, Liu Y, Liu H, Liu F, He L, Liu Y, Zhang F, Guo C, Chen G, Zhang L, Dong Z, Peng Y.
Molecular medicine reports.Mol Med Rep.2014 Sep;10(3):1469-74. doi: 10.3892/mmr.2014.2359. Epub 2014 Jul 1.
Since it was first described in 1968, immunoglobulin (Ig)A nephropathy (IgAN) has become the most commonly diagnosed form of primary glomerular disease worldwide. A number of reports have shown that toll‑like receptor 9 (TLR9) and B‑cell activating factor (BAFF) may be associated with IgAN; how
PMID 24993857

The Gammaherpesviruses Kaposi's Sarcoma-Associated Herpesvirus and Murine Gammaherpesvirus 68 Modulate the Toll-Like Receptor-Induced Proinflammatory Cytokine Response.

Bussey KA1, Reimer E1, Todt H1, Denker B1, Gallo A2, Konrad A3, Ottinger M4, Adler H5, Stürzl M3, Brune W2, Brinkmann MM6.
Journal of virology.J Virol.2014 Aug 15;88(16):9245-9259. Epub 2014 Jun 4.
The human pathogen Kaposi's sarcoma-associated herpesvirus (KSHV), the etiological agent of Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease, establishes lifelong latency upon infection. Murine gammaherpesvirus 68 (MHV68) is a well-established model for KSHV. Toll-li
PMID 24899179

Macrophage endocytosis of high-mobility group box 1 triggers pyroptosis.

Xu J1, Jiang Y2, Wang J1, Shi X3, Liu Q4, Liu Z1, Li Y5, Scott MJ5, Xiao G6, Li S7, Fan L8, Billiar TR9, Wilson MA10, Fan J11.
Cell death and differentiation.Cell Death Differ.2014 Aug;21(8):1229-39. doi: 10.1038/cdd.2014.40. Epub 2014 Apr 25.
Macrophages can be activated and regulated by high-mobility group box 1 (HMGB1), a highly conserved nuclear protein. Inflammatory functions of HMGB1 are mediated by binding to cell surface receptors, including the receptor for advanced glycation end products (RAGE), Toll-like receptor (TLR)2, TLR4,
PMID 24769733

Japanese Journal

IgA腎症の発症と粘膜免疫 (AYUMI IgA腎症 : 研究と臨床Update)

医学のあゆみ 255(11), 1089-1093, 2015-12-12
NAID 40020675706

Hot tub lungの病態

呼吸器内科 27(1), 72-76, 2015-01
NAID 40020335344

自己免疫疾患におけるT細胞-B細胞相互作用の重要性

日本臨床免疫学会会誌 38(5), 398-402, 2015
NAID 130005116549

Related Pictures

TLR9 - TLR9 - JapaneseClass.jp Images of TLR9 - JapaneseClass.jp Toll-Like Receptor 9 Frontiers | Toll-Like Receptor Signaling Pathways | Immunology

★リンクテーブル★

リンク元	「Toll様受容体9」
関連記事	「TL」

「Toll様受容体9」

Toll-like receptor 9
Identifiers
Symbols	TLR9; CD289
External IDs	OMIM: 605474 MGI: 1932389 HomoloGene: 68126 ChEMBL: 5804 GeneCards: TLR9 Gene
Gene Ontology
Molecular function	• interleukin-1 receptor binding; • siRNA binding;
Cellular component	• Golgi membrane; • extracellular region; • cytoplasm; • lysosome; • endosome; • endoplasmic reticulum; • endoplasmic reticulum membrane; • plasma membrane; • endosome membrane; • integral to membrane; • basolateral plasma membrane; • apical plasma membrane; • early phagosome; • endolysosome membrane;
Biological process	• response to molecule of bacterial origin; • inflammatory response; • I-kappaB phosphorylation; • insulin receptor signaling pathway; • maintenance of gastrointestinal epithelium; • negative regulation of NF-kappaB transcription factor activity; • negative regulation of interleukin-6 production; • negative regulation of interleukin-8 production; • positive regulation of chemokine production; • positive regulation of interferon-beta production; • positive regulation of interleukin-10 production; • positive regulation of interleukin-12 production; • positive regulation of interleukin-18 production; • positive regulation of interleukin-6 production; • positive regulation of interleukin-8 production; • positive regulation of tumor necrosis factor production; • negative regulation of toll-like receptor signaling pathway; • positive regulation of toll-like receptor signaling pathway; • positive regulation of NF-kappaB import into nucleus; • defense response to bacterium; • positive regulation of I-kappaB kinase/NF-kappaB cascade; • positive regulation of JUN kinase activity; • positive regulation of interferon-gamma biosynthetic process; • innate immune response; • positive regulation of interferon-alpha biosynthetic process; • positive regulation of interferon-beta biosynthetic process; • positive regulation of transcription from RNA polymerase II promoter; • positive regulation of JNK cascade; • positive regulation of inflammatory response; • positive regulation of NF-kappaB transcription factor activity; • positive regulation of nitric-oxide synthase biosynthetic process;
	Sources: Amigo / QuickGO
Orthologs
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英: Toll-like receptor 9、TLR9
関: Toll様レセプター9

「TL」

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[pmid11022119-1] Du X, Poltorak A, Wei Y, Beutler B (Dec 2000). "Three novel mammalian toll-like receptors: gene structure, expression, and evolution". Eur Cytokine Netw 11 (3): 362–71. PMID 11022119.

[2] "Entrez Gene: TLR9 toll-like receptor 9".

[pmid17607014-3] Kline JN (July 2007). "Eat dirt: CpG DNA and immunomodulation of asthma". Proc Am Thorac Soc 4 (3): 283–8. doi:10.1513/pats.200701-019AW. PMC 2647631. PMID 17607014.

[Thompson_2004-4] Thompson JA, Kuzel T, Bukowski R, Masciari F, Schmalbach T (July 2004). "Phase Ib trial of a targeted TLR9 CpG immunomodulator (CPG 7909) in advanced renal cell carcinoma (RCC)". Journal of Clinical Oncology, 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition) 22 (14S).

[pmid16818369-5] Klinman DM (2006). "Adjuvant activity of CpG oligodeoxynucleotides". Int. Rev. Immunol. 25 (3-4): 135–54. doi:10.1080/08830180600743057. PMID 16818369.

[pmid15107846-6] Chuang TH, Ulevitch RJ (May 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nat. Immunol. 5 (5): 495–502. doi:10.1038/ni1066. PMID 15107846.

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TLR9