**2. IBD and immunity system**

Epithelial layer integration permits the gastrointestinal bacteria to communicate with the immune system [18]. The mucosal layer is the first physical barrier on the mucosal surface and is produced by the polymerization of gel-forming mucins secreted by Goblet cells. The second defense barrier against bacterial attack is the intestinal epithelium, which makes up of enterocytes and particular epithelial cells called Goblet and Paneth cells [19]. Intestinal epithelial cells prevent the influx of antigens and the attack of pathogens and commensal microbes [18]. Intestinal epithelial cells (IECs) also express toll-like receptors (TLRs) and nucleotide oligomerization domain receptors (NODs), which are pathogen-sensitive innate immune receptors. IECs then make chemokines and cytokines to engage immune cells [18]. TLR signaling pathways helps the epithelial barrier to remain intact and produce 12 and interleukin 6 [18, 20]. The epithelial barrier impairment causes intestinal permeability to increase, which has been shown in CD and also in UC, and this might be a main pathogenetic mechanism in IBD [19]. TLR acts as pro/ anti-inflammatory gene activation inducer and controls the adaptive immune responses [21, 22].

Intestinal immune cells including innate immune cells and adaptive immune cells significantly involve in immune responses in IBD [23]. Macrophages, TLRs, and NOD-like receptors (NLRs) are essential for developing tolerance to certain pathogens and promoting wound treatment. Binding to pathogene receptors leads to the activation of different signaling pathways and the production of proinflammatory cytokines, chemokines, and antimicrobial peptides. The antigen-presenting cells (APCs) link innate immunity and adaptive immunity by secreting cytokines and presenting antigens to the T cells [24]. Fine gut-resident macrophages, described by a lack of CD14 expression, manifest decreased response, proliferation, and chemotactic activity. The gut-resident macrophages have increased phagocytic activity and secretion of cytokines in IBD patients, causing dramatic inflammation [25]. After microorganisms' invasion, innate immunity activates after a few hours [26]. Macrophage cells kill specific pathogens, such as peptides and lipopolysaccharides. In IBD acute phase, the number of macrophages in the intestinal mucosa increases dramatically, and a large number of T cells and costimulatory molecules such as CD40, CD80, and CD86 are involved in the inflammatory process and intolerance of commensal microbes and immune activity [27].

Malfunction in TLR signaling can induce an intestinal inflammatory response with various clinical phenotypes, including the IBD. A considerable target of the TLR signaling is the activation of the transcription factor NF-kB, which regulates the expression of a variety of genes responsible for controlling the innate response, such as IL-1, IL-2, IL-6, IL-12, and TNF- [28, 29]. **Table 1** shows the cytokines and cellular sources involved in immune response in IBD. Both IL-1 and TNF- share numerous pro-inflammatory properties responsible for the development of IBD [30]. Dendritic cells are professional antigen-presenting cells that activate T cells and induce adaptive immune responses, describing key players in the cross talk between innate and adaptive immunity [38].

The other IBD risk variants in other genes are involved in IL-12 and *CCR6*, chemokine receptors preferentially expressed on IL-17 producing cells [19]. IL-23/IL- 17 axis has a key role in this cross talk and the *IL23R* gene encodes a specific subunit of the IL23 receptor that has been identified and largely replicated in independent cohorts of patients with both CD and UC [45]. Other clinical studies have found that the intestinal mucosa and lamina propria of IBD patients contain much higher levels of Th17 cells, IL-17, and IL-23 compared with the healthy controls [24].

Appositive of the innate immune response, the adaptive immune system is very specific, it presents long-lasting immunity. Key players of the adaptive immune response are T cells. Th0 cells can become activated and either differentiate into Th1 or Th2 or Th17 cells [19, 38]. However, a dysregulated T cell response with abnormal development of activated T cell subsets causes inflammation because of an excess release of cytokines and chemokines, which have multiple pathogenic impacts on components of the immune system. **Figure 2** shows the immune response in IBD. The levels of T-cell-derived cytokines detected in IBD mucosa, different studies have associated CD and UC with different subtypes of proinflammatory immune responses. Therefore, the innate immune response is as important as the adaptive immune system in inducing gut inflammation in these patients [19, 24, 38].

Genome-wide association studies and immunological studies have mentioned that IBD pathogenesis is related to mucosal innate immune responses, including classical Th1 response in CD patients and Th2 type-like response in UC patients [45, 46].

In mouse model studies, induction of CD caused increase of IFN- expression in their spleen and local intestinal mucosa [43]. CD evolution is generally mediated


*Abbreviations: Mϕ: Macrophage, IECS: Intestinal epithelial cells, DCs: dendritic cells, STAT-3: signal transducer and activator of transcription, NF-κB: nuclear factor kappa B.*

#### **Table 1.**

*The pro-inflammatory agents' contribution in immune response in IBD.*

by CD4+ Th1 and Th17 cells, and IFN- is a major cytokine declared in this disease [47]. Deficiencies of IL17-A and IL17-B in experimental models showed both proinflammatory and tissue-protective effects against colitis depending on the model used [19, 48]. However in mucosa of IBD patients, IL-17A cells regulate and induce a number of pro-inflammatory molecules [38].

Regulatory T cells (Treg) produce the anti-inflammatory cytokines (IL-10, TGF) and exert an effective anti-inflammatory action in experimental colitis. Treg are reduced in peripheral blood of patients with active IBD in comparison with quiescent IBD patients and control subjects [49, 50]. In contrast, Treg are increased

**Figure 2.** *The role of immune response on progress IBD.*

in the intestinal mucosa of IBD patients, and their function is normal. An intact TGF signaling, which is impaired in inflamed IBD mucosa because of upregulation of the inhibitory molecule Smad7, is needed for Treg function [19]. Treg cells, expressing the transcription factor forkhead box P3 (FOXP3), have a negative immunomodulatory character in immune tolerance and a crucial role in the pathogenesis of IBD [24, 51, 52].
