Disease Report: Crohn's Disease

This automatically generated dataset of diseases-related information is compiled based on literature research and is provided for informational purposes only. While efforts have been made to ensure accuracy and comprehensiveness, the dataset may include inaccuracies, omissions, or biases inherent in the source materials. It should not be used as the basis for clinical, commercial, or policy decisions. Users are advised to consult relevant experts and primary sources to verify the information.

Pathogenesis Targets

Assays and Models

1. Hypothesis Summary:

The hypothesis posits that specific genetic mutations in the NOD2, IL23R, and ATG16L1 genes are linked to an increased risk of developing Crohn's disease (CD). These genetic factors are believed to contribute to dysregulated immune responses and compromised intestinal barrier function, leading to the pathogenesis of CD.

2. Mechanism and Evidence:

NOD2: NOD2 is a pattern-recognition receptor that detects bacterial components, specifically muropeptides from peptidoglycan. Loss-of-function mutations in NOD2 impair the immune response to intestinal bacteria, leading to chronic inflammation characteristic of CD (Ogura et al., 2001, PMID: 11385577).
IL23R: IL23R is involved in the differentiation of Th17 cells, which play a crucial role in inflammatory responses. Mutations in IL23R can lead to altered immune responses, contributing to the inflammatory processes seen in CD (Van Limbergen et al., 2009, PMID: 19453248).
ATG16L1: This gene is associated with autophagy, a cellular process that helps maintain intestinal homeostasis by degrading pathogens and cellular debris. Mutations in ATG16L1 can disrupt autophagy, leading to increased susceptibility to intestinal inflammation (Bianco et al., 2015, PMID: 26604638).

3. Clinical Evidence:

Numerous studies have established a strong association between mutations in these genes and the risk of developing CD. For instance, a population-based case-control study found that carriers of the ATG16L1 mutation had an odds ratio (OR) of 1.8 for developing CD, while NOD2 mutation carriers had an OR of 4.45 (Okazaki et al., 2008, PMID: 18521914). Additionally, a comprehensive review highlighted that these genetic factors are significant contributors to the pathogenesis of CD (Gajendran et al., 2018, PMID: 28826742).

4. Genetic Targets and Evidence:

NOD2: Mutations such as 3020insC lead to a truncated protein that fails to activate NF-kappaB, impairing the immune response to bacterial components (Ogura et al., 2001, PMID: 11385577).
IL23R: Variants in IL23R have been shown to influence susceptibility to CD, with specific SNPs correlating with disease severity (Liu et al., 2015, PMID: 26192919).
ATG16L1: The SNP rs2241880 in ATG16L1 has been associated with increased risk for CD, particularly in certain populations (Zhang et al., 2014, PMID: 25048429).

5. Protein Targets and Evidence:

NOD2 Protein: The NOD2 protein's role in sensing bacterial peptidoglycan is critical for initiating immune responses. Loss-of-function mutations disrupt this sensing mechanism, leading to increased susceptibility to CD (Caruso et al., 2014, PMID: 25526305).
IL23R Protein: The IL23R protein is essential for Th17 cell differentiation. Mutations can lead to altered signaling pathways that exacerbate inflammation (Van Limbergen et al., 2009, PMID: 19453248).
ATG16L1 Protein: The ATG16L1 protein is involved in autophagy; mutations can impair this process, leading to increased intestinal inflammation (Bianco et al., 2015, PMID: 26604638).

6. Pathways and Evidence:

NOD2 Signaling Pathway: NOD2 activation leads to NF-kappaB activation, promoting pro-inflammatory cytokine production. Mutations disrupt this pathway, contributing to chronic inflammation (Gao et al., 2022, PMID: 36049483).
IL-23/Th17 Pathway: The IL-23 signaling pathway is crucial for Th17 cell differentiation, which is implicated in the pathogenesis of CD. Mutations in IL23R can lead to dysregulation of this pathway (Van Limbergen et al., 2009, PMID: 19453248).
Autophagy Pathway: ATG16L1 is essential for autophagy, and its mutations can lead to impaired clearance of pathogens, contributing to inflammation (Bianco et al., 2015, PMID: 26604638).

7. Cellular Targets and Evidence:

Immune Cells: The dysregulation of immune responses in CD is primarily mediated by T lymphocytes, particularly Th17 cells, which are influenced by IL23R mutations (Shanahan, 2002, PMID: 11809204).
Epithelial Cells: NOD2 and ATG16L1 are expressed in intestinal epithelial cells, where they play roles in maintaining barrier integrity and immune homeostasis (Caruso et al., 2014, PMID: 25526305).

8. Tissue Targets and Evidence:

Intestinal Mucosa: The intestinal mucosa is the primary site affected in CD, where mutations in NOD2, IL23R, and ATG16L1 lead to increased inflammation and barrier dysfunction (Gajendran et al., 2018, PMID: 28826742).

9. Additional Context:

The interplay between genetic predispositions and environmental factors, such as diet and microbiome composition, further complicates the pathogenesis of CD. For instance, the depletion of specific gut microbial enzymes, such as DL-endopeptidase, has been shown to exacerbate CD through NOD2 signaling pathways (Gao et al., 2022, PMID: 36049483). This highlights the multifactorial nature of CD, where genetic factors interact with environmental influences to drive disease progression.

Conclusion:

The evidence supports the hypothesis that genetic mutations in NOD2, IL23R, and ATG16L1 are associated with an increased risk of developing Crohn's disease, contributing to dysregulated immune responses and altered intestinal barrier function. However, further research is needed to fully elucidate the complex interactions between these genetic factors and environmental influences in the pathogenesis of CD.