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Schema Name TLR9-NOD2 Epistasis schema for Crohn's disease
Accession MS020700046.3
Gene(s) TLR9, NOD2
Schema Caption What is the mechanism for TLR9 and NOD2 as epistatic pair for Crohn's disease?
Schema Description This schema is addressing the mechanism for TLR9 and NOD2 as an epistatic pair for Crohn's disease. The synergy between NOD2 and TLR9 signaling is already reported (pmid: 16227353, 15928043). Mechanisms for this synergistic effect is not clear. One possible explanation is NOD2 activation upregulates MyD88 expression (pmid: 11254557), which is related to TLR9 schema. However, this synergy is not observed for other MyD88 dependent TLRs. It is of interesting to note that NOD2 signaling is playing different roles for adaptive immune responses depending on the presence of TLR9. NOD2 signaling alone leads to strongly polarized Th2 responses, whereas in the presence of TLR9 signaling, it is polarized towards Th1 CD4+ T cell and suppress CD8+ T cell responses. TLR9 signaling alone leads to Th1, and CD8+ T cell-mediated responses. Although we know different adaptive immune responses are operative for the presence of NOD2 or TLR9 variant, the reason for these changes is not very clear.
Author(s) Lipika R. Pal, Kunal Kundu, Lindley Darden and John Moult
Curator(s) Lipika R. Pal, John Moult
Last Modified Fri Aug 10 2018 15:52:10 GMT-0400 (Eastern Daylight Time)
Sub-state Perturbation (SSP) Annotations
Component ID: TSSP1
Stage: DNA
SSP Class: Other
Other SSP Class: SNV [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs5743836 in TLR9
Confidence Score: 3
Comment: TLR9 polymorphisms are associated with Crohn's disease. This GWAS marker is based on a small German study which is claiming the association with Crohn's disease. There is another larger study on Danish population, where they found TLR9 marker (rs187084) to be associated with IBD, but no statistical significant association with CD. Because of these conflicting information, we are using medium confidence color here. As these are GWAS marker information, where relationship with increasing disease risk is based on allele frequency, so SNV can be in either heterozygous (HET) or homozygous (HOM) mode.
For Evidence: PMID:15236225, PMID:22132241
Against Evidence: PMID:24971461
Component ID: TSSP2
Stage: RNA
SSP Class: mRNA Abundance
Other SSP Class:
Modifier: Increased
Ontology:
SSP Instance: NM_017442: c.-1237T>C
Confidence Score: 3
Comment: We are not sure whether for Crohn's patient, this altered mRNA abundance is applicable or not - so medium confidence.
For Evidence: PMID:22132241
Against Evidence:
Component ID: TSSP3
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Increased
Ontology: PLOSTHES
SSP Instance: TLR9
Confidence Score: 5
Comment: More TLR9 protein will be available - usual process.
For Evidence:
Against Evidence:
Component ID: TSSP4
Stage: Complex
SSP Class: Protein-Ligand Complex Abundance
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: Ligand bounded TLR9
Confidence Score: 5
Comment: There will be more ligand bounded TLR9
For Evidence: PMID:20490286
Against Evidence:
Component ID: TSSP5
Stage: Protein
SSP Class: Protein Conformation
Other SSP Class:
Modifier: Altered
Ontology: MESH
SSP Instance: Activated TLR9
Confidence Score: 5
Comment: Activated TLR9 is formed due to ligand binding, transport and proteolytic cleavage.
For Evidence: PMID:20490286
Against Evidence:
Component ID: TSSP6
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: TLR9-MyD88, IRAK1, TRAF6
Confidence Score: 5
Comment: Active TLR9 recruits adaptor protein MyD88, followed by further recruitment of IRAK1/TRAF6 – initiating a signaling cascade. Two major pathways get activated due to this signaling.
For Evidence: PMID:20490286
Against Evidence:
Component ID: SSP1
Stage: DNA
SSP Class: Other
Other SSP Class: IN/DEL [HET/HOM]
Modifier: NA
Ontology:
SSP Instance: rs2066847 in NOD2
Confidence Score: 5
Comment: SNPs in NOD2 have been associated with susceptibility to ileal CD with an odds ratio equal to 2.4 in heterozygote individuals and 17.1 in homozygotes or compound heterozygotes, representing the strongest association with CD to date [pmid: 15571588]. The complexity of the disease, like stricturing or fistulizing, is increased by 8% for NOD2 heterozygotes and 41% for NOD2 homozygotes or compound heterozygotes and the risk of surgery is increased by 58% with any of NOD2 mutations [pmid: 21343918]. Three main variants of NOD2 gene which are associated with CD risk, are a frameshift mutation - L1007fsC (rs2066847), and two missense SNVs - R702W (rs2066844) and G908R (rs2066845) [pmid: 11385577, 11385576, 11875755]. We start this mechanism schema with the frameshift single base insertion at 1007 position (rs2066847) which is the strongest disease predictive factor.
For Evidence: PMID:15571588, PMID:18824555
Against Evidence:
Component ID: SSP2
Stage: RNA
SSP Class: mRNA Abundance
Other SSP Class:
Modifier: NA
Ontology:
SSP Instance: NM_022162: c.1007insC
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:
Component ID: SSP3
Stage: Protein
SSP Class: Protein Abundance
Other SSP Class:
Modifier: Decreased
Ontology: PLOSTHES
SSP Instance: NOD2
Confidence Score: 5
Comment: NMD implies less protein product at the Protein stage.
For Evidence: PMID:26500656
Against Evidence:
Component ID: SSP4
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: NOD2-RIP2
Confidence Score: 5
Comment: Due to NMD, there will be less protein complex with RIP2.
For Evidence: PMID:28253332, PMID:26500656
Against Evidence:
Component ID: SSP5
Stage: Cell
SSP Class: Other
Other SSP Class: Regulatory Effect
Modifier: Decreased
Ontology:
SSP Instance: Negative regulation of TLR2 signaling
Confidence Score: 3
Comment: There is evidence from the mouse model that NOD2 is acting as inhibitor of TLR2 signaling [pmid: 15282558, 15220916]. However, in human cell line, a synergistic effect is observed, where this interaction is MDP dose dependent [pmid: 18340358]. This ambiguity leads to medium confidence color.
For Evidence: PMID:15282558, PMID:15220916
Against Evidence: PMID:18340358
Component ID: SSP6
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Product Abundance
Modifier: Increased
Ontology:
SSP Instance: Pro-inflammatory Cytokines, Chemokines
Confidence Score: 5
Comment: Pro-inflammatory cytokines are more due to activated NF-kB pathway.
For Evidence:
Against Evidence:
Component ID: SSP8
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Product Abundance
Modifier: Decreased
Ontology:
SSP Instance: Pro-inflammatory Cytokines
Confidence Score: 3
Comment: Less pro-inflammatory cytokine production due to deactivated NF-kB and MAPK signaling pathway.
For Evidence: PMID:28253332
Against Evidence:
Component ID: SSP9
Stage: Cell
SSP Class: Other
Other SSP Class: Cell Product Abundance
Modifier: Decreased
Ontology:
SSP Instance: Defensins in Paneth cell
Confidence Score: 3
Comment: Deactivation of NF-kB pathway also leads to less defensin in the Paneth cell (SSP9) [pmid: 19079235]. However, there is some contradiction whether lower defensin level in Crohn’s patients is dependent on NOD2 mutation or not [pmid: 18305068] – resulting into medium confidence color for SSP9.
For Evidence: PMID:19079235
Against Evidence: PMID:18305068
Component ID: SSP7
Stage: Cell
SSP Class: Other
Other SSP Class: Adaptive Immune Response
Modifier: Altered
Ontology:
SSP Instance: Lack of Th2 type response from CD4+ helper T cell
Confidence Score: 5
Comment: Adaptive immune response gets activated, leading to lack of Th2 type responses from CD4+ helper T cell. NOD2 signaling alone is strongly polarized towards Th2 responses.
For Evidence: PMID:19017983
Against Evidence:
Component ID: SSP14
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Crohn's with lower NF-kB level (less severe)
Confidence Score: 5
Comment: Crohn's patient with lower NF-kB level. NOD2 may function to both positively and negatively attenuate NF-kB signaling; thus, NOD2's function may depend on the circumstance surrounding its activation.
For Evidence: PMID:15620648
Against Evidence:
Component ID: SSP15
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Crohn's with higher NF-kB level (severe)
Confidence Score: 5
Comment: This excessive inflammation with higher NF-kB level leads to severe form of CD.
For Evidence: PMID:28753650
Against Evidence:
Component ID: SSP10
Stage: Complex
SSP Class: Protein-Protein Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: NOD2-ATG16L1
Confidence Score: 5
Comment: Due to NMD, there will be less protein complex with ATG16L1.
For Evidence: PMID:20637199
Against Evidence:
Component ID: SSP11
Stage: Complex
SSP Class: Protein-Ligand Complex Abundance
Other SSP Class:
Modifier: Decreased
Ontology:
SSP Instance: NOD2-MDP
Confidence Score: 5
Comment: Due to NMD, there will be lack of NOD2 and MDP binding.
For Evidence: PMID:24336102, PMID:26500656
Against Evidence:
Component ID: SSP12
Stage: Cell
SSP Class: Other
Other SSP Class: Pathogen Abundance
Modifier: Increased
Ontology:
SSP Instance: Bacteria in epithelial cell
Confidence Score: 5
Comment: Less defensin production in Paneth cell, reduced xenophagy and lack of bacterial cell-wall recognition – all are leading to one event – excess load of bacteria in the epithelial cell (SSP12).
For Evidence:
Against Evidence:
Component ID: SSP13
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Ileal Crohn's disease
Confidence Score: 3
Comment: Excessive bacterial translocation is leading to Ileal CD for NOD2 mutations [pmid: 27703457]. However, this is not clearly understood that why NOD2 mutations are leading to only Ileal CD (as opposed to colonic one) – what type of mechanisms are operative here that is not known yet, resulting into the medium confidence color (orange) for SSP13.
For Evidence: PMID:27703457
Against Evidence:
Component ID: TSSP7
Stage: Cell
SSP Class: Other
Other SSP Class: Adaptive Immune Response
Modifier: Altered
Ontology:
SSP Instance: Lack of CD8+ T cell activation & Th1 response
Confidence Score: 5
Comment: TLR9 signaling alone leads to lack of Th1 and CD8+ T cell mediated responses.
For Evidence: PMID:24688022, PMID:19597998
Against Evidence:
Component ID: SSP18
Stage: Cell
SSP Class: Other
Other SSP Class: Adaptive Immune Response
Modifier: Altered
Ontology:
SSP Instance: Lack of Th1 type response & abrogation of CD8+ T cell activation
Confidence Score: 3
Comment: NOD2 signaling plays different roles for adaptive immune responses depending on the presence of TLR9 [DOI: 10.1002/adfm.201603563]. In presence of TLR9 signaling, it is polarized towards Th1 CD4+ T cell and suppress CD8+ T cell responses. We are not sure why this change in adaptive immune response is happening for NOD2-TLR9 epistatic scenario.
For Evidence: PMID:19017983
Against Evidence:
Component ID: TSSP8
Stage: Phenotype
SSP Class: Other
Other SSP Class: Disease Risk
Modifier: Increased
Ontology:
SSP Instance: Crohn's disease
Confidence Score: 5
Comment: TLR9 is related to crohn's disease risk.
For Evidence: PMID:28753650
Against Evidence:
Biomarker(s) Annotations
Mechanism Module (MM) Annotations
Component ID: TMM1
Mechanism Class Name: Transcription
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance: Increased Transcription
Confidence Score: 3
Comment: For rs5743836 variant, the minor allele shows upregulation of mRNA expression [pmid: 22132241] and also from GTEX portal data (accessed on 16 Dec 2017), we can see this upregulation in expression for TLR9. There is some evidence that in Ulcerative Colitis patients, TLR9 mRNA expression is increased [pmid: 25780451], however there is no change in expression for CD patients [Table 3, pmid: 29155256]. Because of this ambiguity, we gave a medium confidence code (orange color) in this part of the chain.
For Evidence: PMID:22132241, PMID:25780451
Against Evidence: PMID:29155256
Component ID: TMM2
Mechanism Class Name: Translation
Other Mechanism Class Name:
Modifer: Increased
Ontology:
Mechanism Instance: Increased Translation
Confidence Score: 5
Comment: Usual process of getting increased translation from increased mRNA abundance
For Evidence:
Against Evidence:
Component ID: TMM3
Mechanism Class Name: Binding with CpG-DNA of bacteria
Other Mechanism Class Name:
Modifer: NA
Ontology: NCIT
Mechanism Instance: Binding with CpG-DNA of bacteria
Confidence Score: 5
Comment: TLR9 will bind with the unmethylated CpG-DNA of bacteria or pathogens.
For Evidence: PMID:20490286
Against Evidence:
Component ID: TMM4
Mechanism Class Name: Transport from ER to endosome & cleavage
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance: Transport from ER to endosome & cleavage
Confidence Score: 5
Comment: During this ligand recognition process, TLR9 got transported from Endoplasmic Reticulum to endosome via a shuttle protein UNC93b1, followed by a proteolytic cleavage to form active TLR9.
For Evidence: PMID:20490286
Against Evidence:
Component ID: TMM5
Mechanism Class Name: Signaling
Other Mechanism Class Name:
Modifer: Increased
Ontology: GO
Mechanism Instance:
Confidence Score: 5
Comment: Activated TLR9 intiates a signaling cascade by recruiting other proteins.
For Evidence: PMID:20490286
Against Evidence:
Component ID: MM1
Mechanism Class Name: Transcription Rate
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment:
For Evidence:
Against Evidence:
Component ID: MM3
Mechanism Class Name: Le Chatelier
Other Mechanism Class Name:
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Effect of chemical equilibrium.
For Evidence:
Against Evidence:
Component ID: MM2
Mechanism Class Name:
Other Mechanism Class Name: Nonsense mediated decay
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: The frameshift implies nonsense-mediated decay (NMD) at the RNA stage, but there is no direct evidence for that, hence the medium confidence color (orange) here.
For Evidence:
Against Evidence:
Component ID: MM4B
Mechanism Class Name:
Other Mechanism Class Name: Deactivation of NF-kB, MAPK signaling
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 3
Comment: Less NOD2-RIP2 complex is supposed to be followed by deactivated NF-kB pathway and reduced MAPK signaling – resulting into less cytokine production (SSP8) [pmid: 28253332] and consequently less inflammation (MM8) for Crohn’s patients. However, there is evidence of Crohn’s patients with higher levels of NF-kB proteins [pmid: 15620648]. Discrepancy in this observation is leading towards ‘OR’ branching of mechanism modules coming out from SSP4 and medium confidence color (orange) for MM4B and SSP8.
For Evidence: PMID:28253332
Against Evidence:
Component ID: MM5
Mechanism Class Name:
Other Mechanism Class Name: Activation of NF-kB pathway
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: When there is defect in the inhibitory role for NOD2, TLR2 signaling gets activated, leading to activation of NF-kB pathway [pmid: 15282558] and more production of cytokines or chemokines. Here at this point TLR9 and NOD2 schema are merging as both are activating NF-kB pathway.
For Evidence: PMID:15282558
Against Evidence:
Component ID: MM8
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Decreased inflammation due to decreased abundance of pro-inflammatory cytokines.
For Evidence:
Against Evidence:
Component ID: MM9
Mechanism Class Name:
Other Mechanism Class Name: Bacterial removal
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Lower defensin level at the paneth cell will lead to decreased removal of bacteria.
For Evidence:
Against Evidence:
Component ID: MM7
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Excessive inflammation for Crohn's patients.
For Evidence:
Against Evidence:
Component ID: MM10
Mechanism Class Name:
Other Mechanism Class Name: Xenophagy
Modifer: Decreased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Decreased abundance of NOD2-ATG16L1 complex leads to reduced xenophagy.
For Evidence: PMID:19966812, PMID:25497060
Against Evidence:
Component ID: MM11
Mechanism Class Name:
Other Mechanism Class Name: MDP recognition by NOD2
Modifer: Decreased
Ontology: NCIT
Mechanism Instance:
Confidence Score: 5
Comment: Due to NMD, there will be less recognition of bacterial cell wall by NOD2.
For Evidence: PMID:24336102
Against Evidence:
Component ID: MM12
Mechanism Class Name:
Other Mechanism Class Name: Bacterial translocation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Excessive bacterial translocation is leading to Ileal CD for NOD2 mutations [pmid: 27703457].
For Evidence: PMID:27703457
Against Evidence:
Component ID: TMM7
Mechanism Class Name:
Other Mechanism Class Name: Inflammation
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Due to altered adaptive immune response, inflammation should be increased.
For Evidence:
Against Evidence:
Component ID: MM6
Mechanism Class Name:
Other Mechanism Class Name: IFN-γ production
Modifer: Increased
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: When IL-12 pro-inflammatory cytokines will be activated, more IFN-gamma will be produced which is coming from Th-1 type cytokine response.
For Evidence: PMID:9505196
Against Evidence:
Component ID: TMM6
Mechanism Class Name:
Other Mechanism Class Name: T reg/T eff cell disequilibrium
Modifer: NA
Ontology:
Mechanism Instance:
Confidence Score: 5
Comment: Mice deficient with TLR9 displayed increased frequencies of CD4+ Foxp3+ regulatory T (Treg) cells within intestinal effector sites and reduced constitutive IL-17 and IFN-gamma producing effector T (T eff) cells.
For Evidence: PMID:18835196
Against Evidence:
Unknown Mechanism Module (MM) Annotations
Component ID: MM4A
Comment: It is not very clear yet, how NOD2 is playing the inhibitory role for TLR2 – we used a blackbox here. There is some suggestion that this interaction is also controlled by RIP2 complex [pmid: 11894098, 16227353].
For Evidence: PMID:11894098, PMID:16227353
Against Evidence:
Environmental Factor Annotations
Therapeutic Interventions Annotations