Elucidating the Role of Innate and Adaptive Immune Responses in the Pathogenesis of Canine Chronic Inflammatory Enteropathy-A Search for Potential Biomarkers

Abstract

Canine chronic inflammatory enteropathy (CIE) is one of the most common chronic gastrointestinal diseases affecting dogs worldwide. Genetic and environmental factors, as well as intestinal microbiota and dysregulated host immune responses, participate in this multifactorial disease. Despite advances explaining the immunological and molecular mechanisms involved in CIE development, the exact pathogenesis is still unknown. This review compiles the latest reports and advances that describe the main molecular and cellular mechanisms of both the innate and adaptive immune responses involved in canine CIE pathogenesis. Future studies should focus research on the characterization of the immunopathogenesis of canine CIE in order to advance the establishment of biomarkers and molecular targets of diagnostic, prognostic, or therapeutic utility.

Keywords: adaptive immune response; canine chronic inflammatory enteropathy; inflammatory bowel disease; innate immune response; microbiota.

Figure 1

Cross-talk in the immune responses and their possible role in the pathogenesis of chronic inflammatory enteropathy (CIE) in dogs. (A) In CIE, barrier integrity breakdown leads to pathological inflammation and loss of immunological tolerance. A decrease in bacteria forming part of the physiologic microbiota such as Faecalibacterium spp. and Fusobacterium phyla has been identified. (B) Goblet-cell-derived peptide and glycoprotein expression from enterocytes is up- or down-regulated. (C) During intestinal inflammation, IL-8 contributes to neutrophil recruitment and secretion of IL-1α, IL-1β, and TNF-α. (D) Phagocytic cells, including antigen-presenting cells (APCs) such as dendritic cells (DCs) and macrophages phagocyte microorganisms and differentiate to a pro-inflammatory phenotype, secreting IL-12, TNF-α, IL-1β, and IL-6. Additionally, (E) the number and degranulation of eosinophils and (F) the number and granules of mast cells are increased. (G) When the barrier is disrupted, mucosal permeability facilitates microbiota influx and phagocytosis. The microbiota influx also promotes microbiota–mast-cell interaction and releasing of immunomodulatory molecules. (H) APCs phagocyte pathogens and migrate to mesenteric lymph nodes to present antigens and activate different subpopulations of CD4+ T lymphocytes. (I) Th1 is stimulated by IL-12 released by APC and secretes mainly IL-2, IL-12, INF-γ, and TNF-α, while (J) Th2 is stimulated by IL-4 released by APC to produce IL-6, IL-4, IL-5, IL-9, and IL-13. (K) There is an increase in B lymphocytes and in IgG, IgG3, and IgG4 levels but a decrease in IgA in the intestinal mucosa. (L) When activated, APCs secrete IL-6 and TGF-β, and a Th17 subpopulation is activated. This population secretes IL-17A, IL-17F, and IL-22, which participate in neutrophil recruitment. Finally, (M) Treg subpopulations secrete IL-10 and TGF-β, contributing to control of the immune response. However, in dogs, a Th predominant immune profile for CIE has not been completely determined. In addition, (N) an increase in intestinal intraepithelial lymphocytes has been identified in dogs with CIE.