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Review
. 2021 Dec;19(12):2469-2480.
doi: 10.1016/j.cgh.2020.09.023. Epub 2020 Sep 16.

Exploring the Early Phase of Crohn's Disease

Giorgos Bamias  1 , Fabio Cominelli  2
Affiliations
Review

Exploring the Early Phase of Crohn's Disease

Giorgos Bamias et al. Clin Gastroenterol Hepatol. 2021 Dec.

Abstract

The development of Crohn's disease (CD) is characterized by a breakdown of homeostatic immune-bacterial communication, which takes place at the intestinal mucosa when environmental triggers impact genetically predisposed individuals. Converging lines of evidence support the hypothesis that this pathogenetic model develops through sequential, although inter-related, steps that indicate failure of mucosal defense mechanisms at various stages. In this context, immunologic phenomena that mediate the initial appearance of inflammatory lesions across the intestinal tissue may differ substantially from those that mediate and perpetuate chronic inflammatory responses. A compromise in the integrity of the epithelial barrier is among the earliest events and leads to accelerated influx of intraluminal antigens and intact microorganisms within the immunologically rich lamina propria. Inadequate clearance of invading microorganisms also may occur as a result of defects in innate immunity, preventing the timely and complete resolution of acute inflammatory responses. The final step is the development of persistent adaptive responses, which also differ between early and late Crohn's disease. Current progress in our ability to delineate single-cell transcriptomics and proteomics has allowed the discovery of cellular and molecular mechanisms that participate in each sequential step of CD development. This not only will advance our understanding of CD pathogenesis, but also facilitate the design of targeted therapeutic approaches.

Keywords: Adaptive; Crohn's Disease; Cytokines; Early Disease; Epithelium; Innate; Pathogenesis.

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Conflict of interest statement

The authors report no conflict of interest

Figures

Figure 1.
Figure 1.. Early steps in the pathogenesis of Crohn’ s Disease.
Crohn’s disease develops due to sequential failure of defense mechanisms within the intestinal mucosa that requires the unfavorable combination of genetic defects, caused by one or more CD-risk modifying polymorphisms, and mucosal injury, inflicted by harmful environmental factors. The latter also intervenes with the composition and metabolic properties of the commensal flora, leading to structural or functional dysbiosis, which critically contributes to the loss of mucosal homeostasis. Breaches in the integrity of the epithelial barrier are among the earliest pathogenetic events in Crohn’s disease, which, in combination with defective repair mechanisms, allow for a constant flux of bacterial antigens from the intestinal lumen into the immunologically-rich lamina propria (epithelial model). In healthy states, such bacterial-related products are effectively removed by phagocytes of the innate arm of immunity. In contrast, patients with CD demonstrate defective “clearance” mechanisms induced by genetically-determined deficiencies that include, but are not limited to, bacterial-sensing, autophagy and unfolded protein response. These processes culminate to inadequate removal of antigenic material and relentless stimulation of inflammatory responses (innate-immunity model). A final effect of such constant inflammatory input is the unbalanced expansion of pro-inflammatory, Teff-type adaptive immunity, which is dominated by Th1 cells and cytokines, along with inefficient suppressive activity, either due to Treg defects and/or inefficient apoptosis of Teff cells (early adaptive immunity model).
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