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Inflammatory bowel disease
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Giovanni Monteleone, Markus F. Neurath, Britta Siegmund
ATG16L1 is expressed in intestinal epithelial cells, T and B lymphocytes, and antigen-presenting cells. Very little is known about the function of the disease-associated ATG16L1 gene product. However, it has recently been shown that macrophages isolated from mice deficient in Atg16l1 produce elevated levels of IL-1 in response to lipopolysaccharide (LPS) and commensal bacteria such as E. coli, and mice develop more severe experimental colitis when the hematopoietic system is ATG16L1-deficient. Mice deficient for Atg16l1, and humans with a disease-associated risk variant, show decreased autophagy in the ileum and abnormalities in Paneth-cell granule structure with a pro-inflammatory phenotype including an increased expression of genes involved in peroxisome proliferator-activated receptor pathways and adipokines, such as leptin and adiponectin, which are known to be increased in IBD. Furthermore, NOD2 engagement by peptidoglycans induces autophagy and bacterial clearance. This process is dependent on the ability of NOD2 to recruit the autophagy protein ATG16L1 to the plasma membrane at the site of bacterial entry. IRGM, the human homolog of the mouse Irgm/Lrg47, encodes a GTP-binding protein that induces autophagy and is involved in the elimination of intracellular bacteria, including Mycobacterium tuberculosis. Taken together, these findings suggest that reduced function and/or activity of NOD2/ATG16L1/IRGM proteins could alter the innate immune response to luminal bacteria, thereby leading to persistence of intracellular bacteria and the development of pathogenic intestinal inflammation (Figure 34.3).
Linkage analysis identifies novel genetic modifiers of microbiome traits in families with inflammatory bowel disease
Published in Gut Microbes, 2022
Arunabh Sharma, Silke Szymczak, Malte Rühlemann, Sandra Freitag-Wolf, Carolin Knecht, Janna Enderle, Stefan Schreiber, Andre Franke, Wolfgang Lieb, Michael Krawczak, Astrid Dempfle
Our analysis of the relationship between intra-familial genetic similarity at IBD risk loci and microbiome dissimilarity, measured by β diversity, revealed one significant association for SNP rs11741861. IBD-discordant pairs of relatives who were genetically more similar at the respective IBD risk locus tended to be less similar in terms of their microbiome composition. This observation is consistent with similar findings in monozygotic IBD-discordant twins16 and supports the idea that a genetic disposition to IBD may only lead to manifest disease in the presence of a susceptible microbiome. What is more, SNP rs11741861 is an intronic variant of the IRGM (immunity-related GTPase M) and ZNF300 (zinc finger protein 300) genes on chromosome 5. Notably, altered levels of IRGM expression have been shown before to affect bacterial autophagy,33 which in turn is linked to CD susceptibility. Moreover, IBD risk variants, including rs11741861, are known to influence the gut microbiota of healthy individuals in the form of a reduction in abundance of the butyrate producing genus Roseburia.6
Bacterial imbalance and gut pathologies: Association and contribution of E. coli in inflammatory bowel disease
Published in Critical Reviews in Clinical Laboratory Sciences, 2019
Shahanavaj Khan, Ahamad Imran, Abdul Malik, Anis Ahmad Chaudhary, Abdur Rub, Arif Tasleem Jan, Jakeera Begum Syed, Christian Rolfo
Autophagy promotes homeostasis in eukaryotic cells through lysosomal pathways [53]. It also protects cells by inhibiting or decreasing the growth of intracellular pathogens including bacterial pathovars [54]. Therefore, dysregulation of autophagy may lead to persistent bacterial infection. A key relationship between CD and two autophagy gene variants (autophagy-related like 1 [ATG16L1] and IRGM) was identified. A Thr300Ala substitution in the ATG16L1 gene was linked with ileal CD [44,54]. Immunity-related GTPase family M (IRGM), another autophagy gene, has also been detected in CD susceptible patients [55].
Immune Mediators against Toxoplasma Gondii during Reactivation of Toxoplasmic Retinochoroiditis
Published in Ocular Immunology and Inflammation, 2019
Marcelo Rudzinski, Carina Argüelles, Cristóbal Couto, José R. Oubiña, Silvia Reina
Toxoplasma gondii (T. gondii) infects approximately one-third of the population worldwide. In most cases, the infection course is asymptomatic. The retina, neurons, and muscle fibers are target cells in humans. Symptoms arise when the infected tissue becomes inflamed. The initial recognition of T. gondii by dendritic cells and cells of the mononuclear phagocytic system stimulates the release of interleukin-12 (IL-12) by both cell types and also tumor necrosis factor-α (TNF-α) by the dendritic cells.1 IL-12 stimulates NK cells as well as CD4+ and CD8+ T cells to release interferon-γ (IFN-γ). This is the main mediator of the immune system against T. gondii.2 Its release may be inhibited by IL-10. IFN-γ decreases the number of parasites inside mononuclear phagocytic cells by increasing the intracellular levels of nitric oxide and reactive oxygen species. In mice, IFN-γ increases the transcription of Immune-Related GTPases(IRGs) and guanine-binding proteins, both of which are localized at the parasitophorous vesicle, mediating its destruction. Although many studies have investigated the role of the immune response in several mouse models, it should be taken into account that they do not necessarily reflect the human infection, since significant differences have been observed between them. In this regard, the dramatically enhanced susceptibility of AIDS patients and those on immunodepletion therapy indicates that the adaptive immune system plays a key role in immunity to human toxoplasmosis. In contrast, it is much more difficult to define the role of the innate response in this host. As an example, both TLR-11 and -12 play a crucial role in mouse resistance against T. gondii,3 while such receptors are absent in humans. Furthermore, the number (>20) of murine IFN-inducible immunity-related GTPase (IRG) genes contrasts sharply with the dearth of IRG genes in humans, since a single syntenic truncated (compared to mouse) IRGM copy and IRGC (presumably not playing a key role in immunity) have been described.4,5 In humans, IRGM has been associated with protection against intracellular bacteria, such as Mycobacterium tuberculosis, while some of the IRGM haplotypes are related to Crohn’s disease susceptibility. In both diseases, IRGM modulates autophagy.6,7