Mucosal immune system markers

Nucleotide oligomerization domain (NOD2), also known as CARD-15 or IBD1, is an intracellular pattern-recognition receptor involved in gastrointestinal immunity and expressed in monocytes and macrophages. Mutations in the NOD2 gene are associated with Crohn’s disease.

Autophagy related 16 like 1 (ATG16L1) is an intracellular protein that plays a critical role in the autophagy pathway. Several single-nucleotide polymorphisms (SNPs) in the ATG16L1 gene have been linked to an increased risk of Crohn’s disease.

Interleukin-23 receptor (IL23R) is strongly expressed on the cell membrane of memory T cells and other immune cells, including monocytes, dendritic cells and natural killer cells. IL23R interacts with the cytokine IL23, which regulates immune cell activity and is essential in the inflammatory response. Several IL23R variants are associated with Crohn’s disease.

Defensins are small antimicrobial peptides produced by epithelial cells and innate immune system cells. Altered defensin production has been implicated in IBD pathogenesis.

Regenerating islet-derived protein 3 (REG3) is a member of the REG family – a group of small secretory proteins involved in intestinal homeostasis. REG3 is abundantly expressed in the small intestine and modulates the host defense mechanism in the gut via bactericidal activity. However, the precise roles of REG proteins in IBD have not yet been defined.

​Cathelicidins are small antimicrobial peptides that play a crucial role in the innate and adaptive immune systems by acting as “natural antibiotics”­. Human cathelicidin, LL-37, has been suggested to play an essential role in the development and progression of IBD. Thus, cathelicidin expression is increased in the intestinal mucosa of patients with ulcerative colitis.

Toll-like receptors (TLRs) are a family of pattern recognition receptors that constitute the first line of the antimicrobial defense system and are critical for maintaining intestinal homeostasis. TLRs act as key immune sensors of gut microbiota, recognizing abnormal microbes and inducing an immune response. Overactivation of TLRs can ultimately disrupt immune homeostasis, increasing the risk for inflammatory diseases and autoimmune disorders. Both TLRs and TLR-activated signaling pathways have been implicated in the pathogenesis of IBD.

Tumor necrosis factor (TNF) is a major factor produced by various immune and stromal cell types during the onset of IBD and is therefore widely used in clinics.

Interleukin 10 (IL-10) is an anti-inflammatory cytokine that plays an essential role in maintaining mucosal homeostasis and preventing pro-inflammatory responses. Loss-of-function mutations in genes encoding IL-10 cytokine and IL-10 receptor have been linked to very early-onset IBD.

Transforming growth factor-β (TGF-β) is an immune-suppressive cytokine produced by many cell types, including immune cells. TGF-β signaling regulates mucosal immune system reactions and is shown to be impaired in the intestines of patients with IBD.

Chemokines play a key role in the pathogenesis of Crohn’s disease and ulcerative colitis, triggering multiple inflammatory response actions, including leukocyte activation and chemoattraction. Several chemokines have been investigated in the IBD setting, with the receptors CCR9 and CXCR3 and their respective ligands CCL25 and CXCL10 being the principal targets for anti-chemokine therapy in IBD.

Inflammasomes are cytosolic protein complexes of the innate immune system that induce inflammatory responses. Inflammasome activation results in the release of pro-inflammatory cytokines IL-1β and IL-18 and cleavage of Gasdermin D (GSDMD), subsequently inducing pyroptotic cell death.

The NLRP3 inflammasome has been linked to the pathogenesis of several inflammatory disorders, including Alzheimer’s disease and diabetes, but its detailed role in IBD is still being investigated.

Thymic stromal lymphopoietin (TSLP) is a cytokine strongly expressed in lung and skin-derived epithelial cells. TSLP is involved in the initiation of allergic inflammatory responses. Furthermore, recent human and mouse studies have linked TSLP to the development and progression of allergic diseases, including asthma and allergic rhinitis.

IL-25 belongs to the IL-17 cytokine family, which are mostly produced by epithelial cells and innate immune cells and are critical in host defense responses and inflammatory diseases. Multiplex human and animal studies implicate IL-25 in the pathogenesis of some endotypes of asthma.

IL-33 is a cytokine involved in type-2 innate immunity via activation of allergic inflammation-related immune cells, including eosinophils, basophils, mast cells, and macrophages.

IL-4 and IL-13 are related cytokines regulating multiple aspects of allergic inflammation, including responses of lymphocytes, myeloid and non-hematopoietic cells. These two cytokines are produced by Th2 and ILC2 cells in the early stage of the allergic reaction (sensitization) to induce IgE -producing plasma cells and allergen-specific memory B cells.

IL-5 is a pro-inflammatory cytokine responsible for eosinophil maturation, proliferation, activation, survival, and recruitment to airways. IL-5 plays a central role in the pathogenesis of eosinophilic asthma and represents a valuable target for anti-asthma biological therapies.

IL-9 is a cytokine, produced by multiples immune and epithelial cells, which contributes to various immunopathological processes via activation of different cells (eg, Tregs, Th17 cells, NK cells, mast cells, etc). IL-9 is involved in allergic inflammation and promotes activation and recruitment of inflammatory cells.