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• W2007189107 abstract "Plantinga TS, Crisan TO, Oosting M, et al. Crohn’s disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2. Gut 2011;60:1229–1235.Autophagy is a critical homeostatic cell process by which eukaryotic cells remove and degrade intracellular components including organelles, proteins, and microorganisms. Importantly, with regard to chronic inflammation, the autophagy pathway also has a central and diverse role to play in aspects of immunity. Recent genome-wide association studies (GWAS) have implicated 1 particular autophagy gene, ATG16L1, in the pathogenesis of Crohn’s disease (Nat Genet 2007;39:207–211; Nat Genet 2007;39:596–604). Building on these GWAS data, mechanistic studies have highlighted a role for the intracellular pathogen recognition receptor, NOD2, in inducing autophagy through direct interaction with ATG16L1, a major protein involved in the formation of autophagosomes (Nat Immunol 2010;11:55–62). This NOD2–ATG16L1 interaction also seems to be important in the regulation of inflammatory cytokine responses (Nature 2008;456:264–268). However, at present, the few studies examining the mechanisms associated with this genetic variation and disease have tended to utilize in vitro or rodent inflammation models.In the current study, the authors investigated genetic variation in the autophagy gene ATG16L1 in the human population and the consequences for inflammatory cytokine responses after stimulation of NOD2. The authors recruited 2 independent cohorts of healthy individuals (n = 46 and n = 90) and genotyped for the ATG16L1 Thr300Ala (c.898A→rs2241880) polymorphism that has previously been associated with a greater susceptibility to Crohn’s disease. They also analyzed 1 cohort of patients with Crohn’s disease (n = 74) and selected 5 patients homozygous for the 300Thr allele, 5 patients for the 300Ala allele, and 5 heterozygous patients. From these 15 patients, peripheral blood mononuclear cells (PBMCs) were isolated for subsequent cytokine assays. Initially, they assessed the role of autophagy in the induction of the proinflammatory cytokines from PBMCs isolated from individuals in both healthy cohorts. Increased production of both interleukin (IL)-1β and IL-6, but not tumor necrosis factor-α, was observed in response to stimulation with the NOD2 ligand, muramyl dipeptide (MDP) in individuals bearing the ATG16L1 genotype. However, stimulation of PBMCs with the Toll-like receptor ligands lipopolysaccharide (LPS) and Pam3Cys did not induce any significant changes between the different genotypes. These observations were also replicated in a group of Crohn’s disease patients.To determine whether these cytokine responses were mediated through autophagy, stimulation of PBMCs with MDP and an autophagy inhibitor (3-MA) was performed. Treatment with the inhibitor abrogated this difference between the ATG16L1 genotypes, indicating a specific role for autophagy in this context. In ATG16L1 300Ala variant PBMCs, addition of 3-MA alone induced secretion of IL-1β at levels higher than MDP alone. Importantly, the authors confirmed previous research, which showed that mutations in NOD2 completely abrogated MDP-induced IL-1β production.The mechanisms underlying the effect of the ATG16L1 Thr300Ala genotype on NOD2-induced IL-1β responses were assessed at transcriptional and translational levels. Increased IL-1β mRNA and elevated intracellular pro–IL-1β were observed 24 hours after MDP stimulation of PBMCs from individuals homozygous for the ATG16L1 300Ala allele when compared with individuals heterozygous or homozygous for the 300Thr allele. In contrast, when the investigators examined caspase-1 activation in PBMCs isolated from the various genotypes, they did not observe any differences in either unstimulated or MDP-stimulated cells.Finally, the authors examined mRNA expression levels of ATG16L1 from both unstimulated and stimulated (with MDP, LPS, or Pam3Cys) PBMCs isolated from the individuals with the different ATG16L1 genotypes. When the relative mRNA expression of ATG16L1 was analyzed at 24 hours, there were no differences between unstimulated or stimulated groups or genotypes. However, Western blot analysis of cell lysates indicated changes in the amount of ATG16L1 between the genotypes. Specifically, protein expression of ATG16L1 was enhanced after 3-hour MDP, LPS, or Pam3Cys stimulation in patients carrying the 300Thr allele, in contrast with those patients carrying the 300Ala allele, where ATG16L1 expression remained unchanged. Overall, there were also higher amounts of absolute ATG16L1 protein in the 300Thr genotype compared with the 300Ala genotype after stimulation.In summary, this study shows that the human ATG16L1 polymorphism, which confers an increased susceptibility to Crohn’s disease, leads to an increased production of the inflammatory cytokines, IL-1β and IL-6 in response to NOD2 stimulation.CommentComplex interactions involving gut microorganisms, host immune responses, and environmental factors play a role in the pathogenesis of Crohn’s disease. Importantly, a genetic contribution is also central to disease pathobiology, in tandem with the dysregulation of these individual components. Crohn’s disease is considered a polygenic disorder, with 10%–15% of patients having affected family members. Advances in high-throughput genetic tools have contributed enormously to our appreciation of the complex genetic associations and subsequent susceptibilities involved in Crohn’s disease. Recent GWAS studies have indicated a strong link with mutations in autophagy genes, specifically ATG16L1, with a higher susceptibility to this disease. Moreover, recent meta-analysis indicates a female gender-specific Crohn’s disease association in the ATG16L1 polymorphism, owing in large part to different allele distributions in healthy male and female control subjects (Inflamm Bowel Dis 2011; DOI: 10.1002/ibd.21781).Impairments in the integrity and function of the intestinal epithelium are major factors associated with the pathogenesis of Crohn’s disease. Initial research on the ATG16L1 mutation confirmed that ATG16L1 was indeed an autophagy protein, and, interestingly, along with another autophagy protein, ATG5, was also involved in the biology of Paneth cells. Mice deficient for ATG16L1 were defective in the generation and secretion of antimicrobial peptides, as well as other regulatory proteins from these specialized epithelial cells. Notably, when Crohn’s disease patients homozygous for the ATG16L1 risk allele were examined, these individuals also displayed similar granule pathway abnormalities (Nature 2008;456:259–263).There is increasing evidence suggesting a critical interaction between the autophagy protein ATG16L1 and NOD2 in defense and subsequent generation of immunity to intracellular/invasive bacteria. Polymorphisms in NOD2, an intracellular pathogen recognition receptor, are also associated with an increased susceptibility to Crohn’s disease (Nature 2001;411:599–603; Nature 2001;411:603–606). One particular study demonstrated that mutant NOD2 failed to recruit ATG16L1 to the plasma membrane and that engulfing of invading bacteria by autophagosomes was impaired (Nature Immunol 2010;11:55–62). It also seems that this autophagy effect requires the NOD2 signaling mediator RIPK-2 along with other autophagy proteins including PI3K, ATG5, and ATG7 (Nature Med 2010;16:90–97). Furthermore, dendritic cells isolated from Crohn’s disease patients expressing either NOD2 or ATG16L1 risk alleles were found to be defective in autophagy induction, which led to impairment in antigen processing and presentation to CD4+ T cells via MHCII (Nat Med 2010;16:90–97). Importantly for the pathogenesis of Crohn’s disease, these specific polymorphisms, in tandem with pathogenic bacterial infection, could prevent clearance, subsequently leading to persistence of the bacterium and ultimately, the generation of chronic intestinal inflammation. Moreover, deregulation of mucosal immune responses, occurring because of a breakdown in self-recognition of commensal bacteria, is a possible mechanism that can lead to the intestinal inflammation fundamental to Crohn’s disease. Future studies need to determine if these Crohn’s disease risk alleles may also play a pathogenic role after sampling of gut microbiota.Knowledge of the complex and diverse modulatory functions of autophagy in immunity and chronic inflammation continues to grow after a recent study, which demonstrated that macrophages isolated from ATG16L1 knockout mice produce elevated levels of IL-1β and IL-18 in response to stimulation by LPS (Nature 2008;456:264–268). Paneth cells from ATG16L1-deficient mice also show enhanced transcription of proinflammatory cytokines as well as adipokines (Nature 2008;456:259–263). Although this autophagy-mediated effect on inflammation occurs at the level of the inflammasome, the precise mechanisms governing modulation of cytokine production by autophagy proteins, such as ATG16L1, remain unclear (J Cell Biol 2010;189:925–935). Overproduction of inflammatory cytokines is a hallmark of both Crohn’s disease as well as other chronic inflammatory disorders. Whereas in the mouse ATG16L1 knockout model, increased production of IL-1β gave rise to an inhibitory effect on caspase-1 activity, this was not replicated in human PBMCs carrying the 300Ala risk allele. These differences emphasize the importance of studying mechanistic responses in the human population as described in the Plantinga et al study. Most recently, monocytes isolated from Crohn’s disease patients carrying the 300Ala risk allele and infected with the Mycobacterium avium subspecies paratuberculosis (implicated as a putative causal agent of Crohn’s disease) were also observed to have increased production of cytokines IL-6 and IL-10 (World J Gastroenterol. 2011;17:2829–2837).Although it is important to study the genetic polymorphisms and affected pathways associated with Crohn’s disease, we should note that although the ATG16L1 polymorphism is present in approximately 50% of individuals, it only confers an approximately 2-fold increase in Crohn’s disease susceptibility (Nat Genet 2007;39:207–211; Gastroenterology 2007;132:1665–1671). Indeed, this is also described in the Plantinga et al study, where similar increases in IL-1β and IL-6 are observed in both healthy individuals as well as Crohn’s patients carrying the ATG16L1 Thr300Ala risk variant.This study serves to highlight the complex interactions and factors that are required for initiation and progression of Crohn’s disease, including key genetic differences. Indeed, an elegant study, continuing on from the initial observations relating to deficiency in Paneth cells, has shown that ATG16L1-deficient mice, when rederived in specific pathogen-free conditions, had Paneth cells that were indistinguishable from litter mate controls (Cell 2010;141:1135–1145). Studies have identified persistent murine norovirus as the contributing factor, along with the loss of the ATG16L1 autophagy protein, which gives rise to this deficient Paneth cell phenotype. Furthermore, after administration of the colitis- and injury-inducing agent, dextran sodium sulphate, only those mice deficient for ATG16L1, in tandem with persistent norovirus infection, experienced extensive pathologic changes reminiscent of human Crohn’s disease (Cell 2010;141:1135–1145).The study by Plantinga et al emphasizes the importance of studying and validating specific genetic polymorphisms associated with chronic inflammatory diseases, such as Crohn's disease, in the human population. Specifically, the study provides further evidence that deficiencies in autophagy pathways, because of specific polymorphisms, can lead to potentially damaging clinical outcomes. Overproduction of cytokines by immune cells coding for the 300Ala risk allele could play an important contributory role in the excessive inflammation and subsequent pathogenesis of this disease. Notably, the study also shows a direct interaction between 2 Crohn's disease risk alleles, ATG16L1 and NOD2, and further adds to the findings linking susceptibility genes in a single, but functionally different pathway to that described previously. Nonetheless, we must remember that, although autophagy does seem to contribute to Crohn's disease pathogenesis, many other cell-specific mechanisms must also occur for progression to chronic inflammation. Plantinga TS, Crisan TO, Oosting M, et al. Crohn’s disease-associated ATG16L1 polymorphism modulates pro-inflammatory cytokine responses selectively upon activation of NOD2. Gut 2011;60:1229–1235. Autophagy is a critical homeostatic cell process by which eukaryotic cells remove and degrade intracellular components including organelles, proteins, and microorganisms. Importantly, with regard to chronic inflammation, the autophagy pathway also has a central and diverse role to play in aspects of immunity. Recent genome-wide association studies (GWAS) have implicated 1 particular autophagy gene, ATG16L1, in the pathogenesis of Crohn’s disease (Nat Genet 2007;39:207–211; Nat Genet 2007;39:596–604). Building on these GWAS data, mechanistic studies have highlighted a role for the intracellular pathogen recognition receptor, NOD2, in inducing autophagy through direct interaction with ATG16L1, a major protein involved in the formation of autophagosomes (Nat Immunol 2010;11:55–62). This NOD2–ATG16L1 interaction also seems to be important in the regulation of inflammatory cytokine responses (Nature 2008;456:264–268). However, at present, the few studies examining the mechanisms associated with this genetic variation and disease have tended to utilize in vitro or rodent inflammation models. In the current study, the authors investigated genetic variation in the autophagy gene ATG16L1 in the human population and the consequences for inflammatory cytokine responses after stimulation of NOD2. The authors recruited 2 independent cohorts of healthy individuals (n = 46 and n = 90) and genotyped for the ATG16L1 Thr300Ala (c.898A→rs2241880) polymorphism that has previously been associated with a greater susceptibility to Crohn’s disease. They also analyzed 1 cohort of patients with Crohn’s disease (n = 74) and selected 5 patients homozygous for the 300Thr allele, 5 patients for the 300Ala allele, and 5 heterozygous patients. From these 15 patients, peripheral blood mononuclear cells (PBMCs) were isolated for subsequent cytokine assays. Initially, they assessed the role of autophagy in the induction of the proinflammatory cytokines from PBMCs isolated from individuals in both healthy cohorts. Increased production of both interleukin (IL)-1β and IL-6, but not tumor necrosis factor-α, was observed in response to stimulation with the NOD2 ligand, muramyl dipeptide (MDP) in individuals bearing the ATG16L1 genotype. However, stimulation of PBMCs with the Toll-like receptor ligands lipopolysaccharide (LPS) and Pam3Cys did not induce any significant changes between the different genotypes. These observations were also replicated in a group of Crohn’s disease patients. To determine whether these cytokine responses were mediated through autophagy, stimulation of PBMCs with MDP and an autophagy inhibitor (3-MA) was performed. Treatment with the inhibitor abrogated this difference between the ATG16L1 genotypes, indicating a specific role for autophagy in this context. In ATG16L1 300Ala variant PBMCs, addition of 3-MA alone induced secretion of IL-1β at levels higher than MDP alone. Importantly, the authors confirmed previous research, which showed that mutations in NOD2 completely abrogated MDP-induced IL-1β production. The mechanisms underlying the effect of the ATG16L1 Thr300Ala genotype on NOD2-induced IL-1β responses were assessed at transcriptional and translational levels. Increased IL-1β mRNA and elevated intracellular pro–IL-1β were observed 24 hours after MDP stimulation of PBMCs from individuals homozygous for the ATG16L1 300Ala allele when compared with individuals heterozygous or homozygous for the 300Thr allele. In contrast, when the investigators examined caspase-1 activation in PBMCs isolated from the various genotypes, they did not observe any differences in either unstimulated or MDP-stimulated cells. Finally, the authors examined mRNA expression levels of ATG16L1 from both unstimulated and stimulated (with MDP, LPS, or Pam3Cys) PBMCs isolated from the individuals with the different ATG16L1 genotypes. When the relative mRNA expression of ATG16L1 was analyzed at 24 hours, there were no differences between unstimulated or stimulated groups or genotypes. However, Western blot analysis of cell lysates indicated changes in the amount of ATG16L1 between the genotypes. Specifically, protein expression of ATG16L1 was enhanced after 3-hour MDP, LPS, or Pam3Cys stimulation in patients carrying the 300Thr allele, in contrast with those patients carrying the 300Ala allele, where ATG16L1 expression remained unchanged. Overall, there were also higher amounts of absolute ATG16L1 protein in the 300Thr genotype compared with the 300Ala genotype after stimulation. In summary, this study shows that the human ATG16L1 polymorphism, which confers an increased susceptibility to Crohn’s disease, leads to an increased production of the inflammatory cytokines, IL-1β and IL-6 in response to NOD2 stimulation. CommentComplex interactions involving gut microorganisms, host immune responses, and environmental factors play a role in the pathogenesis of Crohn’s disease. Importantly, a genetic contribution is also central to disease pathobiology, in tandem with the dysregulation of these individual components. Crohn’s disease is considered a polygenic disorder, with 10%–15% of patients having affected family members. Advances in high-throughput genetic tools have contributed enormously to our appreciation of the complex genetic associations and subsequent susceptibilities involved in Crohn’s disease. Recent GWAS studies have indicated a strong link with mutations in autophagy genes, specifically ATG16L1, with a higher susceptibility to this disease. Moreover, recent meta-analysis indicates a female gender-specific Crohn’s disease association in the ATG16L1 polymorphism, owing in large part to different allele distributions in healthy male and female control subjects (Inflamm Bowel Dis 2011; DOI: 10.1002/ibd.21781).Impairments in the integrity and function of the intestinal epithelium are major factors associated with the pathogenesis of Crohn’s disease. Initial research on the ATG16L1 mutation confirmed that ATG16L1 was indeed an autophagy protein, and, interestingly, along with another autophagy protein, ATG5, was also involved in the biology of Paneth cells. Mice deficient for ATG16L1 were defective in the generation and secretion of antimicrobial peptides, as well as other regulatory proteins from these specialized epithelial cells. Notably, when Crohn’s disease patients homozygous for the ATG16L1 risk allele were examined, these individuals also displayed similar granule pathway abnormalities (Nature 2008;456:259–263).There is increasing evidence suggesting a critical interaction between the autophagy protein ATG16L1 and NOD2 in defense and subsequent generation of immunity to intracellular/invasive bacteria. Polymorphisms in NOD2, an intracellular pathogen recognition receptor, are also associated with an increased susceptibility to Crohn’s disease (Nature 2001;411:599–603; Nature 2001;411:603–606). One particular study demonstrated that mutant NOD2 failed to recruit ATG16L1 to the plasma membrane and that engulfing of invading bacteria by autophagosomes was impaired (Nature Immunol 2010;11:55–62). It also seems that this autophagy effect requires the NOD2 signaling mediator RIPK-2 along with other autophagy proteins including PI3K, ATG5, and ATG7 (Nature Med 2010;16:90–97). Furthermore, dendritic cells isolated from Crohn’s disease patients expressing either NOD2 or ATG16L1 risk alleles were found to be defective in autophagy induction, which led to impairment in antigen processing and presentation to CD4+ T cells via MHCII (Nat Med 2010;16:90–97). Importantly for the pathogenesis of Crohn’s disease, these specific polymorphisms, in tandem with pathogenic bacterial infection, could prevent clearance, subsequently leading to persistence of the bacterium and ultimately, the generation of chronic intestinal inflammation. Moreover, deregulation of mucosal immune responses, occurring because of a breakdown in self-recognition of commensal bacteria, is a possible mechanism that can lead to the intestinal inflammation fundamental to Crohn’s disease. Future studies need to determine if these Crohn’s disease risk alleles may also play a pathogenic role after sampling of gut microbiota.Knowledge of the complex and diverse modulatory functions of autophagy in immunity and chronic inflammation continues to grow after a recent study, which demonstrated that macrophages isolated from ATG16L1 knockout mice produce elevated levels of IL-1β and IL-18 in response to stimulation by LPS (Nature 2008;456:264–268). Paneth cells from ATG16L1-deficient mice also show enhanced transcription of proinflammatory cytokines as well as adipokines (Nature 2008;456:259–263). Although this autophagy-mediated effect on inflammation occurs at the level of the inflammasome, the precise mechanisms governing modulation of cytokine production by autophagy proteins, such as ATG16L1, remain unclear (J Cell Biol 2010;189:925–935). Overproduction of inflammatory cytokines is a hallmark of both Crohn’s disease as well as other chronic inflammatory disorders. Whereas in the mouse ATG16L1 knockout model, increased production of IL-1β gave rise to an inhibitory effect on caspase-1 activity, this was not replicated in human PBMCs carrying the 300Ala risk allele. These differences emphasize the importance of studying mechanistic responses in the human population as described in the Plantinga et al study. Most recently, monocytes isolated from Crohn’s disease patients carrying the 300Ala risk allele and infected with the Mycobacterium avium subspecies paratuberculosis (implicated as a putative causal agent of Crohn’s disease) were also observed to have increased production of cytokines IL-6 and IL-10 (World J Gastroenterol. 2011;17:2829–2837).Although it is important to study the genetic polymorphisms and affected pathways associated with Crohn’s disease, we should note that although the ATG16L1 polymorphism is present in approximately 50% of individuals, it only confers an approximately 2-fold increase in Crohn’s disease susceptibility (Nat Genet 2007;39:207–211; Gastroenterology 2007;132:1665–1671). Indeed, this is also described in the Plantinga et al study, where similar increases in IL-1β and IL-6 are observed in both healthy individuals as well as Crohn’s patients carrying the ATG16L1 Thr300Ala risk variant.This study serves to highlight the complex interactions and factors that are required for initiation and progression of Crohn’s disease, including key genetic differences. Indeed, an elegant study, continuing on from the initial observations relating to deficiency in Paneth cells, has shown that ATG16L1-deficient mice, when rederived in specific pathogen-free conditions, had Paneth cells that were indistinguishable from litter mate controls (Cell 2010;141:1135–1145). Studies have identified persistent murine norovirus as the contributing factor, along with the loss of the ATG16L1 autophagy protein, which gives rise to this deficient Paneth cell phenotype. Furthermore, after administration of the colitis- and injury-inducing agent, dextran sodium sulphate, only those mice deficient for ATG16L1, in tandem with persistent norovirus infection, experienced extensive pathologic changes reminiscent of human Crohn’s disease (Cell 2010;141:1135–1145).The study by Plantinga et al emphasizes the importance of studying and validating specific genetic polymorphisms associated with chronic inflammatory diseases, such as Crohn's disease, in the human population. Specifically, the study provides further evidence that deficiencies in autophagy pathways, because of specific polymorphisms, can lead to potentially damaging clinical outcomes. Overproduction of cytokines by immune cells coding for the 300Ala risk allele could play an important contributory role in the excessive inflammation and subsequent pathogenesis of this disease. Notably, the study also shows a direct interaction between 2 Crohn's disease risk alleles, ATG16L1 and NOD2, and further adds to the findings linking susceptibility genes in a single, but functionally different pathway to that described previously. Nonetheless, we must remember that, although autophagy does seem to contribute to Crohn's disease pathogenesis, many other cell-specific mechanisms must also occur for progression to chronic inflammation. Complex interactions involving gut microorganisms, host immune responses, and environmental factors play a role in the pathogenesis of Crohn’s disease. Importantly, a genetic contribution is also central to disease pathobiology, in tandem with the dysregulation of these individual components. Crohn’s disease is considered a polygenic disorder, with 10%–15% of patients having affected family members. Advances in high-throughput genetic tools have contributed enormously to our appreciation of the complex genetic associations and subsequent susceptibilities involved in Crohn’s disease. Recent GWAS studies have indicated a strong link with mutations in autophagy genes, specifically ATG16L1, with a higher susceptibility to this disease. Moreover, recent meta-analysis indicates a female gender-specific Crohn’s disease association in the ATG16L1 polymorphism, owing in large part to different allele distributions in healthy male and female control subjects (Inflamm Bowel Dis 2011; DOI: 10.1002/ibd.21781). Impairments in the integrity and function of the intestinal epithelium are major factors associated with the pathogenesis of Crohn’s disease. Initial research on the ATG16L1 mutation confirmed that ATG16L1 was indeed an autophagy protein, and, interestingly, along with another autophagy protein, ATG5, was also involved in the biology of Paneth cells. Mice deficient for ATG16L1 were defective in the generation and secretion of antimicrobial peptides, as well as other regulatory proteins from these specialized epithelial cells. Notably, when Crohn’s disease patients homozygous for the ATG16L1 risk allele were examined, these individuals also displayed similar granule pathway abnormalities (Nature 2008;456:259–263). There is increasing evidence suggesting a critical interaction between the autophagy protein ATG16L1 and NOD2 in defense and subsequent generation of immunity to intracellular/invasive bacteria. Polymorphisms in NOD2, an intracellular pathogen recognition receptor, are also associated with an increased susceptibility to Crohn’s disease (Nature 2001;411:599–603; Nature 2001;411:603–606). One particular study demonstrated that mutant NOD2 failed to recruit ATG16L1 to the plasma membrane and that engulfing of invading bacteria by autophagosomes was impaired (Nature Immunol 2010;11:55–62). It also seems that this autophagy effect requires the NOD2 signaling mediator RIPK-2 along with other autophagy proteins including PI3K, ATG5, and ATG7 (Nature Med 2010;16:90–97). Furthermore, dendritic cells isolated from Crohn’s disease patients expressing either NOD2 or ATG16L1 risk alleles were found to be defective in autophagy induction, which led to impairment in antigen processing and presentation to CD4+ T cells via MHCII (Nat Med 2010;16:90–97). Importantly for the pathogenesis of Crohn’s disease, these specific polymorphisms, in tandem with pathogenic bacterial infection, could prevent clearance, subsequently leading to persistence of the bacterium and ultimately, the generation of chronic intestinal inflammation. Moreover, deregulation of mucosal immune responses, occurring because of a breakdown in self-recognition of commensal bacteria, is a possible mechanism that can lead to the intestinal inflammation fundamental to Crohn’s disease. Future studies need to determine if these Crohn’s disease risk alleles may also play a pathogenic role after sampling of gut microbiota. Knowledge of the complex and diverse modulatory functions of autophagy in immunity and chronic inflammation continues to grow after a recent study, which demonstrated that macrophages isolated from ATG16L1 knockout mice produce elevated levels of IL-1β and IL-18 in response to stimulation by LPS (Nature 2008;456:264–268). Paneth cells from ATG16L1-deficient mice also show enhanced transcription of proinflammatory cytokines as well as adipokines (Nature 2008;456:259–263). Although this autophagy-mediated effect on inflammation occurs at the level of the inflammasome, the precise mechanisms governing modulation of cytokine production by autophagy proteins, such as ATG16L1, remain unclear (J Cell Biol 2010;189:925–935). Overproduction of inflammatory cytokines is a hallmark of both Crohn’s disease as well as other chronic inflammatory disorders. Whereas in the mouse ATG16L1 knockout model, increased production of IL-1β gave rise to an inhibitory effect on caspase-1 activity, this was not replicated in human PBMCs carrying the 300Ala risk allele. These differences emphasize the importance of studying mechanistic responses in the human population as described in the Plantinga et al study. Most recently, monocytes isolated from Crohn’s disease patients carrying the 300Ala risk allele and infected with the Mycobacterium avium subspecies paratuberculosis (implicated as a putative causal agent of Crohn’s disease) were also observed to have increased production of cytokines IL-6 and IL-10 (World J Gastroenterol. 2011;17:2829–2837). Although it is important to study the genetic polymorphisms and affected pathways associated with Crohn’s disease, we should note that although the ATG16L1 polymorphism is present in approximately 50% of individuals, it only confers an approximately 2-fold increase in Crohn’s disease susceptibility (Nat Genet 2007;39:207–211; Gastroenterology 2007;132:1665–1671). Indeed, this is also described in the Plantinga et al study, where similar increases in IL-1β and IL-6 are observed in both healthy individuals as well as Crohn’s patients carrying the ATG16L1 Thr300Ala risk variant. This study serves to highlight the complex interactions and factors that are required for initiation and progression of Crohn’s disease, including key genetic differences. Indeed, an elegant study, continuing on from the initial observations relating to deficiency in Paneth cells, has shown that ATG16L1-deficient mice, when rederived in specific pathogen-free conditions, had Paneth cells that were indistinguishable from litter mate controls (Cell 2010;141:1135–1145). Studies have identified persistent murine norovirus as the contributing factor, along with the loss of the ATG16L1 autophagy protein, which gives rise to this deficient Paneth cell phenotype. Furthermore, after administration of the colitis- and injury-inducing agent, dextran sodium sulphate, only those mice deficient for ATG16L1, in tandem with persistent norovirus infection, experienced extensive pathologic changes reminiscent of human Crohn’s disease (Cell 2010;141:1135–1145). The study by Plantinga et al emphasizes the importance of studying and validating specific genetic polymorphisms associated with chronic inflammatory diseases, such as Crohn's disease, in the human population. Specifically, the study provides further evidence that deficiencies in autophagy pathways, because of specific polymorphisms, can lead to potentially damaging clinical outcomes. Overproduction of cytokines by immune cells coding for the 300Ala risk allele could play an important contributory role in the excessive inflammation and subsequent pathogenesis of this disease. Notably, the study also shows a direct interaction between 2 Crohn's disease risk alleles, ATG16L1 and NOD2, and further adds to the findings linking susceptibility genes in a single, but functionally different pathway to that described previously. Nonetheless, we must remember that, although autophagy does seem to contribute to Crohn's disease pathogenesis, many other cell-specific mechanisms must also occur for progression to chronic inflammation." @default.
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