Novel Insights into Pathophysiology of Orbital Inflammatory Diseases and Progression to Orbital Lymphoma by Pathway Enrichment Analysis
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Population
2.2. RNA Extraction
2.3. Digital Gene Expression Analysis
2.4. NanoString Data Processing
2.5. Statistical Evaluation
3. Results
3.1. Gene Set Enrichment Analysis (GSEA):
3.1.1. GSEA in Non-Specific Orbital Inflammation
- Innate immune pathways providing general response to foreign bodies:
- pertussis (normalized enrichment score, NES: 1.79; p-value: 0.001), Chagas disease (NES: 1.44; p = 0.03), Staphylococcus aureus infection (NES: 1.41; p = 0.05), phospholipase D signaling pathway (NES: 1.41; p = 0.06) and the neurotrophin signaling pathway (NES: 1.46; p = 0.04)
- Metabolic pathway part of an effector cascade:
- apoptosis (NES: 1.40; p = 0.066), Fc epsilon RI signaling pathway (NES: 1.41; p = 0.056), platelet activation (NES: 1.45; p = 0.037).
3.1.2. GSEA in MALT Lymphoma
- Focal surface regulatory pathways: protein digestion and absorption (NES: 1.95; p < 0.001), ECM (extracellular matrix)–receptor interaction (NES: 1.58; p = 0.002), complement and coagulation cascades (NES: 1.36; p = 0.054) and focal adhesion (NES: 1.28; p = 0.063), amoebiasis (NES: 1.58; p = 0.011)
- Effector pathways with systematic impact: complement and coagulation cascades (NES: 1.36; p- = 0.054), AGE-RAGE signaling pathway in diabetic complications (NES: 1.34; p = 0.055), small-cell lung cancer (NES: 1.36; p = 0.080), relaxin signaling pathway (NES: 1.38; p = 0.05)
- Focal surface regulatory pathways: B-cell receptor signaling pathway (NES: −2.37; p < 0.001), T-cell receptor signaling pathway (NES: −2.63; p < 0.001), neurotrophin signaling pathway (NES: −2.68; p < 0.001), thyroid hormone signaling pathway (NES: −2.12; p < 0.001 and Th17 cell differentiation (NES: −2.02; p < 0.001)
- Effector pathways with systematic impact: cell cycle (NES: −2.21; p < 0.001), hepatocellular carcinoma (NES: −2.22; p-value: <0.001) and FoxO signaling pathway (NES: −2.06; p < 0.001)
3.1.3. GSEA in IgG4-ROD
- Innate immune pathways providing general focal response to foreign bodies:
- NOD-like receptor signaling pathway (NES: 1.44; p = 0.043), complement and coagulation cascades (NES: 1.35; p = 0.091), ECM–receptor interaction (NES: 1.28; p = 0.126), Salmonella infection (NES: 1.26; p = 0.16) as well as cytokine–cytokine receptor interaction (NES: 1.20; p = 0.20)
- Effector pathways with systematic impact: hematopoietic cell lineage (NES: 1.29; p = 0.129) herpes simplex infection (NES: 1.44; p = 0.047), and rheumatoid arthritis (NES: 1.22; p = 0.182)
- Fc gamma R-mediated phagocytosis (NES: −1.21; p = 0.19), B-cell receptor signaling pathway (NES: −1.14; p = 0.193), T-cell receptor signaling pathway (NES: −1.21; p = 0.214), neurotrophin signaling pathway (NES: −1.15; p = 0.21), platelet activation (NES: −1.12; p = 0.34), insulin signaling pathway (NES: −1.15; p = 0.350), phospholipase D signaling pathway (NES: −1.26; p = 0.111), as well as the thyroid hormone signaling pathway (NES: −1.22; p = 0.14)
3.2. Re-Identification of Genes with Relevant Expression
ECM–Receptor Interaction and Adipocytokine Signaling Pathway
4. Discussion
4.1. ECM–Receptor Interaction and Adipocytokine Signaling Pathway
4.2. NOD-like Receptor Signaling Pathway
4.3. Outlook into B- and T-Cell Receptor Signaling
4.3.1. B-Cell Receptor Signaling in MALT
4.3.2. B-Cell Receptor Signaling in IgG4-ROD
4.3.3. T-Cell Receptor Signaling and Cytokine Induced Proliferation
4.4. Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Gene | p-Value | FDR-Adjusted p Values | Lower CI | Higher CI |
---|---|---|---|---|
Lymphoma by IGF1 | 0.0110 | 0.0224 | −349.7 | −59.2 |
Lymphoma by IGFBP4 | 0.0008 | 0.0121 | −2204.0 | −783.1 |
Lymphoma by IGFBP7 | 0.0052 | 0.0165 | −1670 | −407.3 |
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Al-Ghazzawi, K.; Mairinger, F.D.; Pförtner, R.; Horstmann, M.; Bechrakis, N.; Mohr, C.; Eckstein, A.; Oeverhaus, M. Novel Insights into Pathophysiology of Orbital Inflammatory Diseases and Progression to Orbital Lymphoma by Pathway Enrichment Analysis. Life 2022, 12, 1660. https://doi.org/10.3390/life12101660
Al-Ghazzawi K, Mairinger FD, Pförtner R, Horstmann M, Bechrakis N, Mohr C, Eckstein A, Oeverhaus M. Novel Insights into Pathophysiology of Orbital Inflammatory Diseases and Progression to Orbital Lymphoma by Pathway Enrichment Analysis. Life. 2022; 12(10):1660. https://doi.org/10.3390/life12101660
Chicago/Turabian StyleAl-Ghazzawi, Karim, Fabian D. Mairinger, Roman Pförtner, Mareike Horstmann, Nikolaos Bechrakis, Christopher Mohr, Anja Eckstein, and Michael Oeverhaus. 2022. "Novel Insights into Pathophysiology of Orbital Inflammatory Diseases and Progression to Orbital Lymphoma by Pathway Enrichment Analysis" Life 12, no. 10: 1660. https://doi.org/10.3390/life12101660