Mechanisms of Intestine for Protection Against Pathogens
Macrophages, neutrophils, and dendritic cells express pattern recognition receptors that detect potential pathogens in the intestines. These receptors bind to peptides, carbohydrates, lipids, and nucleic acids that are common components of viruses, fungi, bacteria, and parasites. One of these receptors is called Toll-like receptors or TLR which are found at the surface of a cell and in the endosome membrane. When TLRs are activated by pathogens, they produce molecules that activate the innate immune system which mediates inflammation and defensive mechanisms. NOD protein is another type of pattern recognition receptor that can be found in the cytoplasm and recognizes peptidoglycans from bacteria during infection. Both TLR and NOD activate the NFκB pathway which leads to increased inflammatory responses by the epithelium. These inflammatory responses include the production of cytokines such as CCL1, CCL2, CXCL1, and CXCL8 which recruit macrophages and neutrophils. Inflammatory responses also include the production of CCL20 and beta-defensin which possesses antimicrobial properties and recruits dendritic cells. Mutations in NOD2, produced in epithelial cells and macrophage, recognizes muramyl dipeptide from the cell walls of a bacteria and increases the cytokine production resulting in severe Crohn’s disease. Crohn’s diseases related to the NOD2 mutation have decreased production of antimicrobial peptides which increases vulnerability to invasive bacteria. In animal studies, NOD2 variants are associated with an increased level of NF-kappaβ activation in response to muramyl dipeptide and more efficient production cytokine interleukin-1beta (IL-1β). These responses are linked to higher vulnerability to intestinal inflammation induced by bacteria.
Antigen-presenting cells in the intestinal mucosa engulf bacteria through the process of phagocytosis. After phagocytosis, the antigen-presenting cells present antigen from bacteria to the naïve T and B cells in the gut-associated lymphoid tissue (GALT). The B cells are then activated to secrete dimeric IgA antibodies which are carried into the intestinal lumen. An average of 4g of IgA is secreted into the gut lumen every day. IgA in the gut lumen neutralizes pathogenic proteins required for gut colonization and translocation. It also helps in the prevention of commensal bacteria invasion. The GALT comprises TH1 cells, TH2 cells, CD8 cytotoxic T cells, CD4 effector T cells, regulatory T cells, and TH17 cells. Cytokines interleukin (IL-2) is important for regulatory T cell function and IL-10 is an immunosuppressive cytokine. Both IL-2 and IL-10 play a role in the interaction between host and bacteria in initiating Crohn’s disease pathogenesis. Protein variants of IL-23R may confer both protection from and vulnerability to Crohn’s disease suggesting a complex role of regulatory T cells and TH17 cells in the regulation of intestinal inflammation. Effector cytokines related to TH17 cells initiate pro-inflammatory responses that contribute to the pathogenesis of Crohn’s disease which includes the calling of neutrophils through IL-8 induction, increase in IL-6, TNF-α, and IL-1β and production of metalloproteinases by fibroblast in the intestines. The severity of Crohn’s disease is increased when IL-23/TH17 pathway is altered.
The complex interaction between bacteria, gut barrier, and the local immune system maintains homeostasis and healthy intestines. One of the processes that regulate intestinal homeostasis is autophagy. Autophagy is a mechanism of cells that eliminates unnecessary and non-functional components by degrading and recycling components of a cell. This process can eliminate pathogens that escape into the cytoplasm, and it is an important mechanism of homeostasis in the immune system. If the autophagy process is dysregulated, it may affect certain aspects of the epithelial cells in the intestines and the immune system can be activated inappropriately leading to severe inflammation. ATG16L and IRGM are genes involved in the process of autophagy. Mutation in these genes affects the autophagy in Crohn’s disease. Defects in autophagy can lead to inefficient elimination of pathogens from the cytosol which further leads to extended cytokine production and Paneth cell abnormalities resulting in inflammation of the intestine. A missense mutation in ATG16L1 due to single-nucleotide polymorphism is highly related to Crohn’s disease. ATG16L1 deletion in the epithelium of intestines develops ileitis phenocopying ileal Crohn’s disease induced by stress sensor IRE1α. It has been observed that IRE1α gather in Paneth cells. ATG16L1 mutation also exhibits a higher level of IRE1α in the intestinal crypts. In IRGM, loci that are at risk in Crohn’s disease include rs13361189, rs9637876, and rs10065172. The rs13361189 minor allele carriers had reduced expression of IRGM in the terminal ileum and whole blood and increased ZNF300P1 in the ileum. ZNF300P1, a long non-coding RNA encoder, is a locus near the IRGM on chromosome 5q33.1. Minor allele carriers have altered expression of other genes which includes increased levels of lactoferrin in the ileum and TNF in blood.
Sources:
Ajayi, T. A., Innes, C. L., Grimm, S. A., Rai, P., Finethy, R., Coers, J., Wang, X., Bell, D. A., McGrath, J. A., Schurman, S. H., & Fessler, M. B. (2019). Crohn’s disease IRGM risk alleles are associated with altered gene expression in human tissues. American journal of physiology. Gastrointestinal and liver physiology, 316(1), G95–G105. https://doi.org/10.1152/ajpgi.00196.2018
Siakavellas, S. I., & Bamias, G. (2012). Role of the IL-23/IL-17 axis in Crohn’s disease. Discovery medicine, 14(77), 253–262.
Maeda, S., et. Al. (2005). Nod2 Mutation in Crohn’s Disease Potentiates NF-κB Activity and IL-1ß Processing. Science Vol. 307, Issue 5710, pp. 734-738 DOI: 10.1126/science.1103685. https://science.sciencemag.org/content/307/5710/734
Haq, S., Grondin, J., Banskota, S. et al. Autophagy: roles in intestinal mucosal homeostasis and inflammation. J Biomed Sci 26, 19 (2019). https://doi.org/10.1186/s12929-019-0512-2
Murthy, A., Li, Y., Peng, I., Reichelt, M., Katakam, A. K., Noubade, R., Roose-Girma, M., DeVoss, J., Diehl, L., Graham, R. R., & van Lookeren Campagne, M. (2014). A Crohn’s disease variant in Atg16l1 enhances its degradation by caspase 3. Nature, 506(7489), 456–462. https://doi.org/10.1038/nature13044
Ajayi, T. A., Innes, C. L., Grimm, S. A., Rai, P., Finethy, R., Coers, J., Wang, X., Bell, D. A., McGrath, J. A., Schurman, S. H., & Fessler, M. B. (2019). Crohn’s disease IRGM risk alleles are associated with altered gene expression in human tissues. American journal of physiology. Gastrointestinal and liver physiology, 316(1), G95–G105. https://doi.org/10.1152/ajpgi.00196.2018
Geha, R., Notarangelo, L. (2016). Case Studies in Immunology: A Clinical Companion 7th Edition. Garland Science New York and London.
