Toll-like receptor 9

Last updated
TLR9
Identifiers
Aliases TLR9 , CD289, toll like receptor 9
External IDs OMIM: 605474 MGI: 1932389 HomoloGene: 68126 GeneCards: TLR9
Orthologs
SpeciesHumanMouse
Entrez

54106

81897

Ensembl

ENSG00000239732

ENSMUSG00000045322

UniProt

Q9NR96

Q9EQU3

RefSeq (mRNA)

NM_138688
NM_017442

NM_031178

RefSeq (protein)

NP_059138

NP_112455

Location (UCSC) Chr 3: 52.22 – 52.23 Mb Chr 9: 106.1 – 106.1 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Toll-like receptor 9 is a protein that in humans is encoded by the TLR9 gene. [5] TLR9 has also been designated as CD289 (cluster of differentiation 289). It is a member of the toll-like receptor (TLR) family. TLR9 is an important receptor expressed in immune system cells including dendritic cells, macrophages, natural killer cells, and other antigen presenting cells. [5] TLR9 is expressed on endosomes internalized from the plasma membrane, binds DNA (preferentially DNA containing unmethylated CpGs of bacterial or viral origin), and triggers signaling cascades that lead to a pro-inflammatory cytokine response. [6] [7] Cancer, infection, and tissue damage can all modulate TLR9 expression and activation. [7] [8] [9] [10] [11] TLR9 is also an important factor in autoimmune diseases, and there is active research into synthetic TLR9 agonists and antagonists that help regulate autoimmune inflammation. [10] [12]

Contents

Function

The TLR family 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 signaling to induce production of cytokines necessary for the innate immunity and subsequent adaptive immunity. The various TLRs exhibit different patterns of expression. [8]

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 humans indicate that this receptor mediates cellular response to unmethylated CpG dinucleotides in bacterial DNA to mount an innate immune response. [8]

TLR9 is usually activated by unmethylated CpG sequences in DNA molecules. Once activated, TLR9 moves from the endoplasmic reticulum to the Golgi apparatus and lysosomes, where it interacts with MyD88, the primary protein in its signaling pathway. [6] TLR9 is cleaved at this stage to avoid whole protein expression on cell surface, which could lead to autoimmunity. [6] 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 B lymphocytes, monocytes, natural killer (NK) cells, keratinocytes, melanocytes, and plasmacytoid dendritic 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, IL-6, TNF and IL-12. [6] There is also recent evidence that TLR9 can recognize nucleotides other than unmethylated CpG present in bacterial or viral genomes. [6] TLR9 has been shown to recognized DNA:RNA hybrids. [13]

Role in non-viral cancer

TLR9 expression progression during cancer varies greatly with the type of cancer. [6] TLR9 may even present an exciting new marker for many cancer types. Breast cancer and renal cell carcinoma have both been shown to diminish expression of TLR9. In these cases higher levels correspond with better outcomes. Conversely studies have shown higher levels of TLR9 expression in breast cancer and ovarian cancer patients, and poor prognosis is associated with higher TLR9 expression in prostate cancer. Non-small cell lung cancer and glioma have also been shown to up-regulate the expression of TLR9. While these results are highly variable, it is clear that TLR9 expression increases the capacity for invasion and proliferation. [6] Whether cancer induces modification of TLR9 expression or TLR9 expression hastens the onset of cancer is unclear, but many of the mechanisms that regulate cancer development also play a role in TLR9 expression. DNA damage and the p53 pathway influence TLR9 expression, and the hypoxic environment of tumor cells certainly induces expression of TLR9, further increases proliferation ability of the cancerous cells. Cellular stress has also been shown to relate to TLR9 expression. It is possible that cancer and TLR9 have a feed-forward relationship, where the occurrence of one leads to the up-regulation of the other. Many viruses take advantage of this relationship by inducing certain TLR9 expression patterns to first infect the cell (down-regulate) then trigger the onset of cancer (up-regulate).

Expression in oncogenic viral infection

Human papilloma virus (HPV)

Human papilloma virus is a common and widespread disease that, if left untreated, can lead to epithelial lesions and cervical cancer. [6] HPV infection inhibits the expression of TLR9 in keratinocytes, abolishing the production of IL-8. However inhibition of TLR9 by oncogenic viruses is temporary, and patients with long-lasting HPV actually show higher levels of TLR9 expression in cervical cells. In fact, the increase in expression is so severe that TLR9 could be used as a biomarker for cervical cancer. The relationship between HPV-induced epithelial lesion, cancer progression, and TLR9 expression is still under investigation.

Hepatitis B virus (HBV)

Hepatitis B virus down-regulates the expression of TLR9 in pDCs and B cells, destroying the production of IFNα and IL-6. [6] However, just as in HPV, as the disease progresses TLR9 expression is up-regulated. HBV induces an oncogenic transformation, which leads to a hypoxic cellular environment. This environment causes the release of mitochondrial DNA, which has CpG regions that can bind to TLR9. This induces over-expression of TLR9 in tumor cells, contrary to the inhibitory early stages of infection.

Epstein-Barr virus (EBV)

Epstein-Barr virus, like other oncogenic viruses, decreases the expression of TLR9 in B cells, diminishing production of TNF and IL-6. [6] EBV has been reported to alter expression of TLR9 at the transcription, translation, and protein level.

Polyomavirus

The viruses of the polyomavirus family destroy expression of TLR9 in keratinocytes, inhibiting the release of IL-6 and IL-8. [6] Expression is regulated at the promoter, where antigen proteins inhibit transcription. Similar to HPV and HBV infection, TLR9 expression increases as the disease progresses, probably due to the hypoxic nature of the solid tumor environment.

Clinical relevance of inflammation response

TLR9 has been identified as a major player in systemic lupus erythematosus (SLE) and erythema nodosum leprosum (ENL). [9] [10] Loss of TLR9 exacerbates progression of SLE, and leads to increased activation of dendritic cells. [10] TLR9 also controls the release of IgA and IFN-a in SLE, and loss of the receptor leads to higher levels of both molecules. In SLE, TLR9 and TLR7 have opposing effects. TLR9 regulates inflammatory response, while TLR7 promotes inflammatory response. TLR9 has an opposite effect in ENL. [9] TLR9 is expressed at high levels on monocytes of ENL patients, and is positively linked to the secretion of proinflammatory cytokines TNF, IL-6, and IL-1β. TLR9 agonists and antagonists may be useful in treatment of a variety of inflammatory conditions, and research in this area is active. Autoimmune thyroid diseases have also been shown to correlate with an increase in expression of TLR9 on peripheral blood mononuclear cells (PBMCs). [12] Patients with autoimmune thyroid diseases also have higher levels of the nuclear protein HMGB1 and RAGE protein, which together act as a ligand for TLR9. HMGB1 is released from lysed or damaged cells. HMGB1-DNA complex then binds to RAGE, and activates TLR9. TLR9 can work through MyD88, an adaptor molecule that increases the expression of NF-κB. However autoimmune thyroid diseases also increase sensitivity of MyD88 independent pathways. [12] These pathways ultimately leads to the production of pro-inflammatory cytokines in PMBCs for patients with autoimmune thyroid diseases. Autoimmune diseases can also be triggered by activated cells undergoing apoptosis and being engulfed by antigen-presenting cells. [7] Activation of cells leads to de-methylation, which exposes CpG regions of host DNA, allowing an inflammatory response to be activated through TLR9. [7] Although it is possible that TLR9 also recognizes unmethylated DNA, TLR9 undoubtedly has a role in phagocytosis-induced autoimmunity.

Role in heart health

Inflammatory responses mediated by TLR9 pathways can be activated by unmethylated CpG sequences that exist within human mitochondrial DNA. [14] [15] Usually, damaged mitochondria are digested via autophagy in cardiomyocytes, and mitochondrial DNA is digested by the enzyme DNase II. However, mitochondria that escape digestion via the lysosome/autophagy pathway can activate TLR9-induced inflammation via the NF-κB pathway. TLR9 expression in hearts with pressure overload leads to increased inflammation due to damaged mitochondria and activation of the CpG binding site on TLR9.

There is evidence that TLR9 may play a role in heart health for individuals who have already suffered a myocardial infarction. [11] In murine trials, TLR9-deficient mice had less myofibroblast proliferation, meaning cardiac muscle recovery is connected to TLR9 expression. Furthermore, class B CpG sequences induce proliferation and differentiation of fibroblasts via the NF-κB pathway, the same pathway that initiates pro-inflammatory reactions in the immune responses. TLR9 shows specific activity in post-heart attack fibroblasts, inducing them to differentiate into myofibroblasts and speed repair of left ventricle tissue. In contrast to pre-myocardial infarction, cardiomyocytes in recovering hearts do not induce an inflammation response via TLR9/NF-κB pathway. Instead, the pathway leads to proliferation and differentiation of fibroblasts.

As an immunotherapy target

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, [16] immunostimulation against cancer, [17] immunostimulation against pathogens, and as adjuvants in vaccines. [18]

TLR9 agonists

Protein interactions

Related Research Articles

<span class="mw-page-title-main">Toll-like receptor</span> Class of immune system proteins

Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single-spanning receptors usually expressed on sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have reached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13. Humans lack genes for TLR11, TLR12 and TLR13 and mice lack a functional gene for TLR10. The receptors TLR1, TLR2, TLR4, TLR5, TLR6, and TLR10 are located on the cell membrane, whereas TLR3, TLR7, TLR8, and TLR9 are located in intracellular vesicles.

Pattern recognition receptors (PRRs) play a crucial role in the proper function of the innate immune system. PRRs are germline-encoded host sensors, which detect molecules typical for the pathogens. They are proteins expressed mainly by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils, as well as by epithelial cells, to identify two classes of molecules: pathogen-associated molecular patterns (PAMPs), which are associated with microbial pathogens, and damage-associated molecular patterns (DAMPs), which are associated with components of host's cells that are released during cell damage or death. They are also called primitive pattern recognition receptors because they evolved before other parts of the immune system, particularly before adaptive immunity. PRRs also mediate the initiation of antigen-specific adaptive immune response and release of inflammatory cytokines.

<span class="mw-page-title-main">IRAK4</span> Protein-coding gene in humans

IRAK-4, in the IRAK family, is a protein kinase involved in signaling innate immune responses from Toll-like receptors. It also supports signaling from T-cell receptors. IRAK4 contains domain structures which are similar to those of IRAK1, IRAK2, IRAKM and Pelle. IRAK4 is unique compared to IRAK1, IRAK2 and IRAKM in that it functions upstream of the other IRAKs, but is more similar to Pelle in this trait. IRAK4 has important clinical applications.

<span class="mw-page-title-main">Interferon regulatory factors</span> Protein family

Interferon regulatory factors (IRF) are proteins which regulate transcription of interferons. Interferon regulatory factors contain a conserved N-terminal region of about 120 amino acids, which folds into a structure that binds specifically to the IRF-element (IRF-E) motifs, which is located upstream of the interferon genes. Some viruses have evolved defense mechanisms that regulate and interfere with IRF functions to escape the host immune system. For instance, the remaining parts of the interferon regulatory factor sequence vary depending on the precise function of the protein. The Kaposi sarcoma herpesvirus, KSHV, is a cancer virus that encodes four different IRF-like genes; including vIRF1, which is a transforming oncoprotein that inhibits type 1 interferon activity. In addition, the expression of IRF genes is under epigenetic regulation by promoter DNA methylation.

Plasmacytoid dendritic cells (pDCs) are a rare type of immune cell that are known to secrete large quantities of type 1 interferon (IFNs) in response to a viral infection. They circulate in the blood and are found in peripheral lymphoid organs. They develop from bone marrow hematopoietic stem cells and constitute < 0.4% of peripheral blood mononuclear cells (PBMC). Other than conducting antiviral mechanisms, pDCs are considered to be key in linking the innate and adaptive immune systems. However, pDCs are also responsible for participating in and exacerbating certain autoimmune diseases like lupus. pDCs that undergo malignant transformation cause a rare hematologic disorder, blastic plasmacytoid dendritic cell neoplasm.

Pyroptosis is a highly inflammatory form of lytic programmed cell death that occurs most frequently upon infection with intracellular pathogens and is likely to form part of the antimicrobial response. This process promotes the rapid clearance of various bacterial, viral, fungal and protozoan infections by removing intracellular replication niches and enhancing the host's defensive responses. Pyroptosis can take place in immune cells and is also reported to occur in keratinocytes and some epithelial cells.

<span class="mw-page-title-main">TICAM1</span> Protein found in humans

TIR domain containing adaptor molecule 1 is an adapter in responding to activation of toll-like receptors (TLRs). It mediates the rather delayed cascade of two TLR-associated signaling cascades, where the other one is dependent upon a MyD88 adapter.

<span class="mw-page-title-main">Toll-like receptor 7</span> Protein found in humans

Toll-like receptor 7, also known as TLR7, is a protein that in humans is encoded by the TLR7 gene. Orthologs are found in mammals and birds. It is a member of the toll-like receptor (TLR) family and detects single stranded RNA.

<span class="mw-page-title-main">Toll-like receptor 5</span> Protein found in humans

Toll-like receptor 5, also known as TLR5, is a protein which in humans is encoded by the TLR5 gene. It is a member of the toll-like receptor (TLR) family. TLR5 is known to recognize bacterial flagellin from invading mobile bacteria. It has been shown to be involved in the onset of many diseases, which includes Inflammatory bowel disease. Recent studies have also shown that malfunctioning of TLR5 is likely related to rheumatoid arthritis, osteoclastogenesis, and bone loss. Abnormal TLR5 functioning is related to the onset of gastric, cervical, endometrial and ovarian cancers.

<span class="mw-page-title-main">Toll-like receptor 4</span> Cell surface receptor found in humans

Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene.

<span class="mw-page-title-main">Toll-like receptor 6</span> Protein found in humans

Toll-like receptor 6 is a protein that in humans is encoded by the TLR6 gene. TLR6 is a transmembrane protein, member of toll-like receptor family, which belongs to the pattern recognition receptor (PRR) family. TLR6 acts in a heterodimer form with toll-like receptor 2 (TLR2). Its ligands include multiple diacyl lipopeptides derived from gram-positive bacteria and mycoplasma and several fungal cell wall saccharides. After dimerizing with TLR2, the NF-κB intracellular signalling pathway is activated, leading to a pro-inflammatory cytokine production and activation of innate immune response. TLR6 has also been designated as CD286.

<span class="mw-page-title-main">HMGB1</span> Mammalian protein found in Homo sapiens

High mobility group box 1 protein, also known as high-mobility group protein 1 (HMG-1) and amphoterin, is a protein that in humans is encoded by the HMGB1 gene.

<span class="mw-page-title-main">IRAK1</span> Protein-coding gene in humans

Interleukin-1 receptor-associated kinase 1 (IRAK-1) is an enzyme in humans encoded by the IRAK1 gene. IRAK-1 plays an important role in the regulation of the expression of inflammatory genes by immune cells, such as monocytes and macrophages, which in turn help the immune system in eliminating bacteria, viruses, and other pathogens. IRAK-1 is part of the IRAK family consisting of IRAK-1, IRAK-2, IRAK-3, and IRAK-4, and is activated by inflammatory molecules released by signaling pathways during pathogenic attack. IRAK-1 is classified as a kinase enzyme, which regulates pathways in both innate and adaptive immune systems.

<span class="mw-page-title-main">Interferon alpha-1</span> Protein-coding gene in the species Homo sapiens

Interferon alpha-1 is a protein that in humans is encoded by the IFNA1 gene.

<span class="mw-page-title-main">SIGIRR</span> Protein-coding gene in the species Homo sapiens

Single Ig IL-1-related receptor (SIGIRR), also called Toll/Interleukin-1 receptor 8 (TIR8) or Interleukin-1 receptor 8 (IL-1R8), is transmembrane protein encoded by gene SIGIRR, which modulate inflammation, immune response, and tumorigenesis of colonic epithelial cells.

Damage-associated molecular patterns (DAMPs) are molecules within cells that are a component of the innate immune response released from damaged or dying cells due to trauma or an infection by a pathogen. They are also known as danger signals, and alarmins because they serve as warning signs to alert the organism to any damage or infection to its cells. DAMPs are endogenous danger signals that are discharged to the extracellular space in response to damage to the cell from mechanical trauma or a pathogen. Once a DAMP is released from the cell, it promotes a noninfectious inflammatory response by binding to a pattern recognition receptor. Inflammation is a key aspect of the innate immune response; it is used to help mitigate future damage to the organism by removing harmful invaders from the affected area and start the healing process. As an example, the cytokine IL-1α is a DAMP that originates within the nucleus of the cell which, once released to the extracellular space, binds to the PRR IL-1R, which in turn initiates an inflammatory response to the trauma or pathogen that initiated the release of IL-1α. In contrast to the noninfectious inflammatory response produced by DAMPs, pathogen-associated molecular patterns initiate and perpetuate the infectious pathogen-induced inflammatory response. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that are released outside the cell following tissue injury. This displacement from the intracellular space to the extracellular space moves the DAMPs from a reducing to an oxidizing environment, causing their functional denaturation, resulting in their loss of function. Outside of the aforementioned nuclear and cytosolic DAMPs, there are other DAMPs originated from different sources, such as mitochondria, granules, the extracellular matrix, the endoplasmic reticulum, and the plasma membrane.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

Regulatory B cells (Bregs or Breg cells) represent a small population of B cells that participates in immunomodulation and in the suppression of immune responses. The population of Bregs can be further separated into different human or murine subsets such as B10 cells, marginal zone B cells, Br1 cells, GrB+B cells, CD9+ B cells, and even some plasmablasts or plasma cells. Bregs regulate the immune system by different mechanisms. One of the main mechanisms is the production of anti-inflammatory cytokines such as interleukin 10 (IL-10), IL-35, or transforming growth factor beta (TGF-β). Another known mechanism is the production of cytotoxic Granzyme B. Bregs also express various inhibitory surface markers such as programmed death-ligand 1 (PD-L1), CD39, CD73, and aryl hydrocarbon receptor. The regulatory effects of Bregs were described in various models of inflammation, autoimmune diseases, transplantation reactions, and in anti-tumor immunity.

The interleukin-1 receptor (IL-1R) associated kinase (IRAK) family plays a crucial role in the protective response to pathogens introduced into the human body by inducing acute inflammation followed by additional adaptive immune responses. IRAKs are essential components of the Interleukin-1 receptor signaling pathway and some Toll-like receptor signaling pathways. Toll-like receptors (TLRs) detect microorganisms by recognizing specific pathogen-associated molecular patterns (PAMPs) and IL-1R family members respond the interleukin-1 (IL-1) family cytokines. These receptors initiate an intracellular signaling cascade through adaptor proteins, primarily, MyD88. This is followed by the activation of IRAKs. TLRs and IL-1R members have a highly conserved amino acid sequence in their cytoplasmic domain called the Toll/Interleukin-1 (TIR) domain. The elicitation of different TLRs/IL-1Rs results in similar signaling cascades due to their homologous TIR motif leading to the activation of mitogen-activated protein kinases (MAPKs) and the IκB kinase (IKK) complex, which initiates a nuclear factor-κB (NF-κB) and AP-1-dependent transcriptional response of pro-inflammatory genes. Understanding the key players and their roles in the TLR/IL-1R pathway is important because the presence of mutations causing the abnormal regulation of Toll/IL-1R signaling leading to a variety of acute inflammatory and autoimmune diseases.

Epigenetics of autoimmune disorders is the role that epigenetics play in autoimmune diseases. Autoimmune disorders are a diverse class of diseases that share a common origin. These diseases originate when the immune system becomes dysregulated and mistakenly attacks healthy tissue rather than foreign invaders. These diseases are classified as either local or systemic based upon whether they affect a single body system or if they cause systemic damage.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000239732 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000045322 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Du X, Poltorak A, Wei Y, Beutler B (September 2000). "Three novel mammalian toll-like receptors: gene structure, expression, and evolution". European Cytokine Network. 11 (3): 362–71. PMID   11022119.
  6. 1 2 3 4 5 6 7 8 9 10 11 Martínez-Campos C, Burguete-García AI, Madrid-Marina V (March 2017). "Role of TLR9 in Oncogenic Virus-Produced Cancer". Viral Immunology. 30 (2): 98–105. doi:10.1089/vim.2016.0103. PMID   28151089.
  7. 1 2 3 4 Notley CA, Jordan CK, McGovern JL, Brown MA, Ehrenstein MR (February 2017). "DNA methylation governs the dynamic regulation of inflammation by apoptotic cells during efferocytosis". Scientific Reports. 7: 42204. Bibcode:2017NatSR...742204N. doi:10.1038/srep42204. PMC   5294421 . PMID   28169339.
  8. 1 2 3 "Entrez Gene: TLR9 toll-like receptor 9".
  9. 1 2 3 Dias AA, Silva CO, Santos JP, Batista-Silva LR, Acosta CC, Fontes AN, Pinheiro RO, Lara FA, Machado AM, Nery JA, Sarno EN, Pereira GM, Pessolani MC (September 2016). "DNA Sensing via TLR-9 Constitutes a Major Innate Immunity Pathway Activated during Erythema Nodosum Leprosum". Journal of Immunology. 197 (5): 1905–13. doi: 10.4049/jimmunol.1600042 . PMID   27474073.
  10. 1 2 3 4 Christensen SR, Shupe J, Nickerson K, Kashgarian M, Flavell RA, Shlomchik MJ (September 2006). "Toll-like receptor 7 and TLR9 dictate autoantibody specificity and have opposing inflammatory and regulatory roles in a murine model of lupus". Immunity. 25 (3): 417–28. doi: 10.1016/j.immuni.2006.07.013 . PMID   16973389.
  11. 1 2 Omiya S, Omori Y, Taneike M, Protti A, Yamaguchi O, Akira S, Shah AM, Nishida K, Otsu K (December 2016). "Toll-like receptor 9 prevents cardiac rupture after myocardial infarction in mice independently of inflammation". American Journal of Physiology. Heart and Circulatory Physiology. 311 (6): H1485–H1497. doi:10.1152/ajpheart.00481.2016. PMC   5206340 . PMID   27769998.
  12. 1 2 3 Peng S, Li C, Wang X, Liu X, Han C, Jin T, Liu S, Zhang X, Zhang H, He X, Xie X, Yu X, Wang C, Shan L, Fan C, Shan Z, Teng W (December 2016). "Increased Toll-Like Receptors Activity and TLR Ligands in Patients with Autoimmune Thyroid Diseases". Frontiers in Immunology. 7: 578. doi: 10.3389/fimmu.2016.00578 . PMC   5145898 . PMID   28018345.
  13. ↑ Rigby, Rachel E. et al. “RNA:DNA hybrids are a novel molecular pattern sensed by TLR9.” The EMBO journal vol. 33,6 (2014): 542-58. doi:10.1002/embj.201386117
  14. ↑ Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K (May 2012). "Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure". Nature. 485 (7397): 251–5. Bibcode:2012Natur.485..251O. doi:10.1038/nature10992. PMC   3378041 . PMID   22535248.
  15. ↑ Nakayama H, Otsu K (November 2013). "Translation of hemodynamic stress to sterile inflammation in the heart". Trends in Endocrinology and Metabolism. 24 (11): 546–53. doi:10.1016/j.tem.2013.06.004. PMID   23850260. S2CID   11951308.
  16. ↑ Kline JN (July 2007). "Eat dirt: CpG DNA and immunomodulation of asthma". Proceedings of the American Thoracic Society. 4 (3): 283–8. doi:10.1513/pats.200701-019AW. PMC   2647631 . PMID   17607014.
  17. ↑ 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). Archived from the original on 2012-03-08. Retrieved 2010-07-12.
  18. ↑ Klinman DM (2006). "Adjuvant activity of CpG oligodeoxynucleotides". International Reviews of Immunology. 25 (3–4): 135–54. doi:10.1080/08830180600743057. PMID   16818369. S2CID   41625841.
  19. ↑ MOLOGEN AG: First patient recruited in combination study with lefitolimod and Yervoy. July 2016
  20. ↑ "Dynavax Presents Updated Data for SD-101 in Combination with KEYTRUDA(R) (pembrolizumab) Highlighting an ORR in 7 out of 7 Patients Naive to an Anti-PD-1 or Anti-PD-L1 Therapy (NASDAQ:DVAX)". investors.dynavax.com. Archived from the original on 2018-02-26. Retrieved 2017-06-06.
  21. ↑ Intratumoral IMO-2125 in combination with ipilimumab demonstrating an ORR of 44% in melanoma patients refractory to anti-PD1 therapy vs 10-13% response rate with ipilimumab monotherapy
  22. ↑ U.S. FDA Grants Fast Track Designation for Idera Pharmaceuticals’ tilsotolimod in Combination with Ipilimumab for Treatment of PD-1 Refractory Metastatic Melanoma
  23. ↑ Chuang TH, Ulevitch RJ (May 2004). "Triad3A, an E3 ubiquitin-protein ligase regulating Toll-like receptors". Nature Immunology. 5 (5): 495–502. doi:10.1038/ni1066. PMID   15107846. S2CID   39773935.
  24. ↑ Veleeparambil M, Poddar D, Abdulkhalek S, Kessler PM, Yamashita M, Chattopadhyay S, Sen GC (April 2018). "Constitutively Bound EGFR-Mediated Tyrosine Phosphorylation of TLR9 Is Required for Its Ability To Signal". Journal of Immunology. 200 (8): 2809–2818. doi:10.4049/jimmunol.1700691. PMC   5893352 . PMID   29531172.

[1]

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

  1. ↑ Rigby, Rachel E; Rehwinkel, Jan; Ramiscal, Roymond R; Zhang, Yongzhi; Summersgill, Helen R; Matikainen, Sampsa; Freeman, Tiffany C (2014). "RNA:DNA hybrids are a novel molecular pattern sensed by TLR9". The EMBO Journal. 33 (6): 542–58. doi:10.1002/embj.201386117. PMC   3923970 . PMID   24493648.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.