최신연구결과(해외)

Review articleGastric immune homeostasis imbalance: An important factor in the development of gastric mucosal diseases

관리자
2023-09-13
조회수 857

Biomed Pharmacother. 2023 May;161:114338. doi: 10.1016/j.biopha.2023.114338. 


1. Introduction

* Gastric mucosal immune system: gastric epithelial cells, immune cells, signaling molecules

 - Congenital immune cells: Congenital lymphocytes (ILCs), Macrophages, Dendritic cells, NK cells

 - Gastric adaptive immunity: T-cell immunity, B-cell immunity

* Gastric epithelial cells에서 innate immune cells (such as macrophages and dendritic cells (DCs))이 activation 되면, T-cell 과 B-cell의 proliferation 및 differentiation이 진행되고, series of proinflammatory a& anti-inflammatory cytokines의 분비와 함께 gastric mucosa infection을 억제하고 mucosal reapir를 증가시키기 위한 local immune response가 이루어지게 됩니다.

* 이러한 mucosal immune cells의 regulation이 mucosal diseases 의 진행과 밀접한 연관성이 있으며, microbial infection이나 gastric mucosal epithelial cells의 손상이 일어나게 되면, mucosal homeostasis의 balance가 깨지게 되어 질환이 발생하게 됩니다. 

* This review summarizes the importance of maintaining gastric mucosal immune homeostasis and the relevant mechanisms of gastric mucosal diseases to provide new insights into gastric mucosal diseases (Fig. 1).  

Fig. 1. Diagram of gastric immune homeostasis imbalance leads to multiple gastric mucosal immune diseases. Composition and function of gastric mucosal immunity and three types of gastric mucosal diseases, including AIG related diseases, H. pylori-induced diseases and various types of GC. AIG: autoimmune gastritis; H. pylori: Helicobacter pylori; GC: gastric cancer. 


2. Gastric mucosal immunity: composition and function 

* Microorganisms과 gastric mucosal host cells의 interaction은 엄격하게 조절되고 있으며, autoimmune tolerance와 immune regulation mechanisms을 통해 gastric immune system의 internal environment를 유지해 가게 됩니다. 

* Integrin α4β7 은 intestinal 및 mucosa-associated lymphoid tissues (MALT)와 memory lymphocytes와의 매게 과정에 중요한 물질로, 면역세포를 장내 세포로 이동 시키는데 중요한 역할을 하는 세포 표면 단백질 입니다.

* Gastric tissue에는 gut-associated lymphoid tissue (GALT) 가 없는 대신, gastric mucosa에 Integrin α4β7의 역할과 일치하는, α4β7hi CD4+ T cells 이 풍부하게 존재하고 있어서 이러한 specific T-cell subsets의 부분적인 aggregation이 immune cells을 gastric mucosa로 guide하는 역할을 수행합니다. 

(GALT: Peyer’s patches (PPs), Mesentery lymph nodes (MLNs), Isolated lymphoid follicles (ILFs) 같은 mucosal immune system (MIS)의 induction site)

* Gastric tissue 3개의 layers: epithelial layer, lamina propria & muscularis mucosa

* 이 중에서도 mucosal epithelial layer는 physical barrier이면서 innate immunity를 통한 host defense에 중요한 역할을 수행 합니다. 

* Intestinal epithelium의 Paneth cells은 antimicrobial peptides (AMPs)나 α-defensins를 분비하여 직접적으로 micro-organisms를 없애지만, gastric epithelium에는 존재하지 않습니다. 

* Gastric epithelial cells은 mucus를 분비하여 physical barrier를 형성하고, major class II histocompatibility complexes (MHC-II) as antigen-presenting cells 을 발현하여 immune defense에 관여하게 됩니다. 그리고, inflammation과 tissue damage 동안 IL-6, IL-8, tumor necrosis factor α (TNF-α), IL-1β, IL-1α, granulocyte macrophage colony stimulating factor (GM-CSF), monocyte chemoattractant protein-1 (MCP-1), TGF-β  와 같은 다양한 cytokines을 분비하여 immune response에 관여하게 됩니다. 


3. Molecular mechanism of gastric mucosal immune recognition 

* Activation and recognition of pathogenic microorganisms by gastric epithelial cells

- Recognition mechanism: immune cells에서 발현된 sensors 또는 pattern recognition receptors (PRRSs)와 host cells의 다양한 부위에 분포되어 있는 pathogen molecules나 pathogen-related molecular patterns (PAMPs)에서 시작됩니다.  

- PAMPs: lipopolysaccharide, peptidoglycan, flagellin, lipoprotein, DNA, RNA and metabolites 등을 포함하고 있습니다. 

- PRRS family: Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), DNA sensors and their PAMPs 

- 이 중에서, TLRs (TLR1, TLR2, TLR3, TLR4, TLR5 and TLR9)와 NLRs (NOD1, NOD2, NLRP3, NLRP12 and NLRX1) 중요한 역할을 수행한다. 

- TLR signaling pathway의 activation은 inflammatory cytokines, chemokines, costimulatory molecules, antigen-presenting molecule 들의 합성을 trigger 하게 됩니다. 

- PRRS는 PAMPs를 인식하여 gastric mucosa에서 Th1 & Th2 immune responses를 유도하게 되고, gastric epithelial repair와 gastric mucosal immune homeostasis 에 중요한 역할을 수행하게 됩니다. 


4. Gastric mucosal immune response 

4.1. Immune cells migrate to gastric tissue with the help of chemokines 

* Gastric mucosa에는 mucosal immune system에서 중요한 역할을 하는 mucosa-associated lymphoid tissue (MALT)가 없고, α4β7 receptor CD4+ T cells이 풍부하게 존재하고 있습니다. 

* Immune cells이 gastric lamina propria로 migration 하게 되는데, 일부 연구에서는 DCs의 retinoic acid (RA) 가 homing 을 유도한다고 합니다. 이러한 과정에서는 chemokines이 중요한 역할을 하게 됩니다. 

- Chemokines (4 subfamilies)

: CXC-, CC-, C, CX3C chemokines 의 4가지 subfamilies가 있고, 그 중 CXCL1 (GRO)-α, CXCL8 (IL-8), CCL5 (RANTES), CXCL10 (IP-10), CXCL11 (MIG), CCL20 (MIP-3) α-chemokines (such as LARC) 등이 gastric mucosal immune cells의 recruitment 와 concentration에 중요한 역할을 하게 됩니다. 

* Migration process

: microorganisms 에 의해 gastric mucosa가 infection되면 immune cells와 activation된 endothelial cells 간의 interaction으로 immune cells의 flow rate가 줄어들고, vascular wall의 endothelium을 따라 rolling 하다가 chemokine receptor를 통해 fixed 되어 있는 cheomokines에 붙게 되고, immune cells에 있는 integrin과 endothelial cells의 cell adhesion molecule (CAM) 이 서로 binding 함으로써 immune cells이 더 단단하게 붙게 되어 vascular endothelium으로 부터 stomach으로 immune cells이 들어 오게 됩니다. 

4.2. Effect of immune cells 

* Gastric mucosal immunity: Humoral immunity & Cellular immunity (main role)

* Cellular immunity

: TLR-expressing antigen-presenting cells (macrophages & DCs)

: DCs

- Cytokines 분비 (IL-12, IL-10, IL-23) 

- Upregulation of MHC-II, CD80, CD83, CD86 costimulatory molecules

- CD4+ T cells의 helper T-cell subsets로의 분화를 유도

(hepler T-cell subsets: Th1 (interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α)), Th2 (IL-4, IL-5, and IL-13), Th17 (IL-17A), NK cells)

: CD8+ T-cells의 수 증가 (주로, activated cytotoxic CD8+ T lymphocytes)

: CD4+ T cells와 CD8+ T cells의 activation <- expressing major histocompatibility complex II (MHCII) and serving as antigen-presenting cells 

* CD4+ T cells & CD8+ T cells이 acquired immunity에서 주요 역할을 하고 있으며, 이중에서 immune homeostasis에 중요한 것은 CD4+ T-cell immunity 입니다. 


5. Gastric autoimmune dysfunction leads to the occurrence of gastric mucosal diseases 

Mucosal immnity의 imbalance가 발생하면 여러 다른 immune mucosal diseases, 즉 autoimmune gastritis (AIG)-related diseases, H. pylori-induced diseases, 그리고 various types of GC 가 발생하게 됩니다. 그래서, gastric immune homeostasis를 유지하는 것이 매우 중요합니다.

5.1. Gastric immune imbalance and autoimmune gastritis (AIG)-related diseases 

5.1.1. Autoimmune disorder is related to the occurrence of autoimmune gastritis (AIG)  

* H+/K+-ATPase and intrinsic factor (IF) on parietal cells may be the target antigens of Th1 cytotoxic T-cell attack.

(H+/K+-ATPase에 있는 peptide에 T-cell receptor (TCR)가 specific하게 작용함)

* Development of AIG (Two stages)

(1) Inflammatory reaction stage (non-atrophic stage)

 - Increased infiltration of CD3+ intraepithelial lymphocytes (IELs) in the deep acid-secreting mucosa 

 - In the early stage, the main inflammatory cell infiltration includes lymphocytes, B cells, plasma cells, basophils, mast cells and other inflammatory cells infiltrating the submucosa, lamina propria and gastric glands.

- resulting in the loss of parietal cells, main cells and P/D1 cells that produce gastrin, whereby the main cells and P/D1 cells are destroyed because they are adjacent cells to the parietal cells.

- PCA, IFA가 AIG에서 중요한 marker 이긴 하지만, 모든 환자에서 양성으로 나오는 것은 아니기 때문에 parietal cell apoptosis의 main factors는 아닌 것으로 보입니다.

(2) Atrophic stage 

- Atrophic change에 있어서 두 개의 main immune cells: auto-reactive T helper 1 (Th1) cells와 cytotoxic T cells

- CD4+ T cells (Th1 cell, IFN-γ)

: H+-K+-ATPase와 TNF-α (B cell에서 Ig 생성과 AIG의 progression을 촉진 시킴)에 의해 stimulation

: IFN-γ는 gastric parietal cell에서 Fas와 MHCII molecules의 발현을 증가 시켜, Fas protein과 CD4+ T cells의 결합을 촉진시켜 perforin과 fas/fasl signaling pathways 을 통한 parietal cell의 손상과 소실을 일으키게 됩니다. 

- 과거 연구에서는 Th1 cell immunity가 중요한 역할을 한다고 하였지만, 최근 연구에서는 AIG 환자 위점막의 intrinsic mononuclear cells (LPMC)에서 분비되는 IL-19, IL-17A 및 IL-17F가 중요하다고 알려져 있습니다. 

- K+/H+-ATPase가 활성화되면, IL-17A, IL-17F, IL-21, IL-17E이 증가됩니다. 

- IL-17은 gastric cancer 에 대한 potent risk factor 입니다.

- IL-19는 vitamin B12 치료를 받는 AIG 환자의 anemia에 대한 monitor에 이용될 수도 있습니다. 

- IL-27은 gastric mucosal atrophy와 metaplasia의 prevention, treatment에 관여 합니다. 

* 결국, AIG는 K+/H+-ATPase에 대한 CD4+ T cells의 attack과 관련되어 있고, IL-17이 pathogenesis에 중요한 역할을 하는 것 같습니다.


5.1.2. Type I gastric neuroendocrine tumors originate from the AIG

Gastric neuroendocrine tumors (g-NETs, Type 1)

* Hypergastrinemia increases the expression of metalloproteinases in the stomach, including MMP1, MMP7, MMP9, and PAPPA2

- PAPPA2 are mainly ECL cells expressing cholecystokinin digitalis receptor (CCK2R) 

- MMP increases the bioavailability of IGF by binding to insulin-like growth factor-binding protein 5 (IGFBP-5) released by subepithelial cells

- PAPPA2 increases the bioavailability of IGF by cleaving IGFBP-3, promoting cell migration and tissue remodeling, cell proliferation and eventual development of g-NETs 

- Gastrin/CCK2R antagonists (netaxeltide (YF476)): g-NET regression을 유도

* miR-202–3p was upregulated in type 1 gNET lesion (DUSP1 was its target gene)

- DUSP1 is a tumor suppressor gene that is closely related to gastric tumors, but its molecular mechanism is still unclear and needs to be further explored.

- Sonic hedgehog (Shh) is an endocrine factor secreted by parietal cells and an important factor affecting gastric organogenesis and gland differentiation.

- deletion of parietal cells leads to the downregulation of the Shh/Ptch signaling pathway, the proliferation of neuroendocrine cells or the metaplasia of pancreatic acinar epithelium, accompanied by the upregulation of the expression of the neuroendocrine cell proliferation markers PDX1 and CagA, ultimately leading to the progression from AIG to type I g-NETs.


5.1.3. Spasmolytic polypeptide-expressing metaplasia (SPEM) arising from AIG

* Spasmolytic polypeptide-expressing metaplasia (SPEM) is the metaplasia of antral gland cells, which originates from the mature main cells at the base of the gland.

* SPEM은 acute mucosal injury에 대한 repair process이면서, intestinal metaplasia, atypical hyperplasia, gastric adenocarcinoma와 직접적인 관계가 있습니다.

* 하지만, 아직까지 pathogenesis of SPEMintestinal-type gastric cancer이 어떻게 영향을 주고 발생하는 지는 여전히 불분명합니다.

*  Parietal cells의 손상과 소실 (atrophy)로 인한 Immune dysregulation은 SPEM의 전제 조건 입니다. 

* Parietal cell은 epidermal growth factor receptor ligands TFF2 & Shh (dual regulatory proteins)과 HB-EGF의 주요 source입니다.

* Parietal cell의 deletion은 Shh와 EGF의 downregulation을 가져오게 되고, IL-33을 activation 시킵니다.

* IL-33은 IL-1 family of cytokines 중 하나이며, ST2 (il1rl1)와 IL-1 receptor helper protein IL1RAP의 결합으로 IL-33 receptor complex (ST2)를 형성하게 됩니다. 

* 이러한 receptor complex는 group 2 congenital lymphocytes (ILC2s)를 발현 시키고 여기에는 transcription factors RORα와 GATA3이 관여하게 됩니다.

* ILC2s는 tissue remodeling, myxometaplasia, eosinophilia, activation of replacement macrophages를 유발합니다.

* IL-33/ST2 signaling은 NF-κB와 MAP kinases에 의해 활성화 되고, upregulation of Th2 cytokines (mainly IL-13)과 macrophage differentiation (mainly M2) by regulating mitochondrial metabolism 를 가져오게 됩니다. 

* IL-33은 mucosal organs (GI tract, respiratory tract) 에서 eosinophils을 유도하고 활성화시키며, SPEM 형성을 유도하는데 참여하도록 하는 중요한 역할을 수행합니다. 

* 이러한 과정은 SPEM marker인 mucin 6 (MUC6)와 trefoil factor 2 (TFF2)의 upregulation을 시키게 됩니다. 

* Infiltration of Th2 cells & M2 macrophages, Upregulation of IL-33 and IL-13, Activation of the NF-κB and IL-33/ST2 inflammatory pathways in the immune microenvironment during AIG-induced SPEM development 

--> suggest that IL-33 and its related signaling pathways are therapeutic targets for reversing SPEM

* Wnt/β-catenin signaling pathway, upregulation of CDX2, & increased expression of active KRAS -> intestinal metaplasia

* It is necessary to further explore in future studies whether related pathway antagonists block or delay this process, which is of great significance for gastric mucosal diseases (Fig. 2).

Fig. 2. Gastric immune disorder induced AIG-related diseases. The imbalance of gastric mucosal immunity leads to AIG, which can induce Type I g-NETs and SPEM. SPEM further converts into IM, ultimately promoting the development of GC. (Up arrows indicate upregulation or activation of immune factors/pathways, and downward arrows indicate downregulation or inhibition of immune factors/pathways). g-NETs: neuroendocrine tumors; SPEM: Spasmolytic polypeptide-expressing metaplasia; IM: intestinal metaplasia.


5.2. Gastric immune imbalance and H. pylori induce diseases 

5.2.1. Immune disorders are related to H. pylori-associated gastritis

* H. pylori는 Type 4 secretion system (T4SS)를 통해 virulence factors (cytotoxin related protein (CagA), vacuolar toxin protein (VacA), Urease, heat shock proteins (Hsps)) 등을 epithelial cell 내로 injecting 하면서 inflammatory pathways를 activation 함으로써 H. pylori-related gastritis 를 일으키게 됩니다. 

* H. pylori-related gastritis는 CagA, urease, UreB, HSP60과 같은 H. pylori에서 분비되는 virulent factors에 의해 NF-κB를 activation시켜 IL-8 , IL-17A, IL-6, TNF-α와 같은 inflammatory cytokines을 분비하게 함으로써 gastritis를 유도하게 됩니다.  

* 이와 동시에, external inflammatory protein A (OipA)PI3K-AKT pathway (gastritis의 progression을 활성화 시키는 IL-6 생성을 촉진시키기 위한 p38의 activation과 STAT1 phosphorylation과 IRF-1 signal transduction을 자극시켜 CXCL8의 activation)를 통해 IL-8의 생성을 증가시키게 됩니다. 

* Urease와 UreA subunits는 MKN-45 cells에서 IL-6와 TNF-α 의 production을 증가시킵니다.

* 결국, NF-κB activation은 gastritis 발생에 중요한 요소입니다. 가장 최근 연구에서는, lymphotoxin β receptor (LTβR)가 gastric epithelial cells에서 NF-κB를 대체하여 trigger 하기도 합니다. 

* 또한, H. pylori infection은 composition of gastric microorganisms (including Bacteroides, Proteus, Actinomyces and Clostridium)의 변화를 가져오게 됩니다. 실험실적으로, 상대적으로 abundance of Proteus 감소 및 number of Streptococcus 증가가 나타납니다. 또한, treatment of mice with antibiotics의 위 점막에서 Clostridium cluster IV and XIVa의 증가 및 recruitment of CD4+ T cells, INF-γ mRNA expression의 감소를 유발하게 됩니다. 즉, gastric microbiota와 H. pylori 사이의 interactiongastric immune response 조절에 중요한 역할을 수행하는 것으로 보입니다. 


5.2.2. Immune disorders are related to H. pylori-related gastric cancer


5.2.3. Immune disorders are related to H. pylori-induced gastric MALT lymphoma


Fig. 3. Gastric immune imbalance and H. pylori-induced diseases. H. pylori infection leads to the imbalance of gastric mucosal immunity, which promotes the occurrence of H. pylori-related gastritis, H. pylori-related GC and gastric MALT lymphoma. (Up arrows indicate upregulation or activation of immune factors/ pathways, and downward arrows indicate downregulation or inhibition of immune factors/pathways).


5.3. Immune dysregulation results in various types of gastric cancer 

5.3.1. Immune disorder and intestinal-type gastric cancer 

5.3.2. Immune disorders are related to diffuse-type gastric cancer 

5.3.3. Immune disorders are associated with Epstein–Barr virus-associated gastric cancer 

Fig. 4. Gastric immune disorders are related to various types of GC. Gastric mucosal immune imbalance induces different types of GC, including intestinal type of GC, diffuse-type GC and EB virus GC. (Up arrows indicate upregulation or activation of immune factors/pathways, and downward arrows indicate downregulation or inhibition of immune factors/pathways). EB: Epstein–Barr.


6. Conclusion

Previous studies have revealed the role of gastric mucosal immunity in the occurrence and development of gastric mucosal diseases, including chemokines that promote migration, immune cell infiltration, the activation of cytokines and related inflammatory pathways. These findings provide guidance for the clinical treatment of gastric mucosal immune diseases and the research and development of immunosuppressants. This paper provides a basic and systematic summary of the research in this field intended to attract researchers’ attention to the gastric mucosal immune mechanism and the occurrence and development of gastric mucosal immune diseases and to provide new perspectives for the prevention and treatment of gastric mucosal diseases (Table 1)

Table 1. The change of immune cells and cytokines after gastric immune imbalance.


ABSTRACT 

The gastric mucosal immune system is a unique immune organ independent of systemic immunity that not only maintains nutrient absorption but also plays a role in resisting the external environment. Gastric mucosal immune disorder leads to a series of gastric mucosal diseases, including autoimmune gastritis (AIG)-related diseases, Helicobacter pylori (H. pylori)-induced diseases, and various types of gastric cancer (GC). Therefore, understanding the role of gastric mucosal immune homeostasis in gastric mucosal protection and the relationship between mucosal immunity and gastric mucosal diseases is very important. This review focuses on the protective effect of gastric mucosal immune homeostasis on the gastric mucosa, as well as multiple gastric mucosal diseases caused by gastric immune disorders. We hope to offer new prospects for the prevention and treatment of gastric mucosal diseases.

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