Anti-TNF Antibodies and Autophagy: A Hidden Nexus for a Successful Therapeutic Response?

Crohn's disease [CD] and ulcerative colitis [UC] are the two major forms of inflammatory bowel disease [IBD]. First-line therapies are based on neutralisation of the immune system by corticosteroids, or on blockage of pro-inflammatory cytokines such as tumour necrosis factor-α [TNF-α]. 1 It is now becoming clear that these treatments required a personalized benefit versus risk assessment; therapy will be based on individual clinical patient profiles, determined through available biomarkers and tissue signatures. 2 Therefore, it is necessary to improve our current understanding of IBD pathogenesis, with the ultimate goal of personalising therapeutic intervention. IBDs are characterised by chronic intestinal inflammation and an excessive recruitment of leukocytes into the intestinal mucosa. A current hypothesis is that alterations of the gut microbiota have a pivotal role in the initiation and maintenance of inflammation, in genetically predisposed individuals. 3 The research for genetic determinants of disease onset and progression has recently culminated in the Immunochip project, which has identified more than 160 loci containing IBD susceptibility genes. 4 The relevance of genome-wide association studies [GWAS] initially was confirmed by the identification of a nucleotide-binding oligomerization domain containing two [NOD2] variants, which remain the strongest determinants of susceptibility to CD, after more than one decade from its discovery. 5 NOD2 is an intracel-lular sensor of bacterial infections, which drives the production of pro-inflammatory cytokines in macrophages 6 and antimicrobial peptides such as α-defensin in Paneth cells, 7 confirming the relevance of innate immune responses to gut microbiota and priming of adaptive immunity. Moreover, performing GWAS allowed uncovering novel disease-associated pathways, such as autophagy. Autophagy was initially implicated in the pathogenesis of CD by the discovery of the Thr300Ala [T300A] variant in the autophagy related 16-like 1 [ATG16L1] gene in a non-synonymous single nucleotide pol-ymorphism [SNP] association study. 8 Soon afterward, the immunity-related GTPase family M [IRGM] gene variants were associated with an increased risk of developing both CD and UC, 9 confirming the relevance of autophagy in the control of intestinal inflammation. However, the mechanisms through which IRGM regulates autophagy were poorly understood, and only recently has been elucidated the involvement of IRGM in the recruitment of the autophagy machinery in order to actively conduct antimicrobial defense. 10 In contrast, ATG16L1 activities have been deeply investigated in mice, healthy individuals, and patients with CD. 11,12,13 Using Atg16L1-deficient and hypomorphic mice, it has been clarified that ATG16L1 is able to control both canonical and …