primary or central lymphoid organs bone marrow B cells thymus T cells

secondary or peripheral lymphoid organs lymph nodes spleen cutaneous immune system mucosal immune system

主要包括呼吸道、消化道及泌尿生殖道黏膜固有层和上皮

细胞下散在的无被膜淋巴组织，以及某些带有生发中心、 器官化的（有被膜的）淋巴组织（如扁桃体、小肠的集合

淋巴结、阑尾等）

gastrointestinal associated lymphoid tissue

bronchopulmonary associated lymphoid tissue

genitourinary associated lymphoid tissue

Secondary lymphoid tissue in gut wall Peyer’s patch isolated follicles (colon Appendix) Mesenteric lymph node Diffusely distributed immune cells Lamina propria lymphocyte, LPL intraepithelial lymphocyte, IEL

two remarkable properties of gastrointestinal tract

the combined mucosa of the small and large bowel has a total surface area of more than 200 m2

It is estimated that more than 500 different species of bacteria, amounting to approximately 1014 cells, live in the mammalian gut

commensal organisms noncommensal pathogenic organisms

physical barrier epithelial cells barrier mucous barrier secreted mucins 300 to 700 μm membrane-bound mucins  30 to 500 nm 其主要功能： 阻挡微生物接近上皮细胞 为共生菌提供栖息地和营养 捕获并排除病原体 作为分泌型 IgA 的储存库

转铁蛋白 溶菌酶 Defensin α-defensins(small bowel Paneth cells ) β-defensins (colonabsorptive epithelial cells)

commensal organisms 作用：阻止病原体在肠道的定居 与病原体竞争空间和营养 产生抗菌物质（如蛋白样毒素）

TLRs and NLRs 的表达对黏膜固有免疫的影响

DCs and macrophages in the lamina propria of the gut inhibit inflammation

IL-10 transforming growth factor-β (TGF-β) 

features of gastrointestinal adaptiveimmunity

The major form of adaptive immunity in the gut is humoral immunity 

The dominant protective cell-mediated immune response consists of TH17 effector cells

The adaptive immune system in the gut must continuously suppress potential immune responses to food antigens and commensal microbial antigens

Peyer’s patches and isolated follicles

lymphoid follicles, with germinal centers containing B lymphocytes, follicular helper T cells, follicular dendritic cells (FDCs), and macrophages

M cells （ microfold cell ） The main function of M cells is transcellular transport of

various substances from the lumen of the intestine across the epithelial barrier to underlying antigen-presenting cells

Antigen-sampling DCs they extend dendrites through the junctions between

adjacent epithelial cells ， these DCs are capable of processing and presenting protein antigens to T cells within the GALT

Fc receptor–mediated pathways neonatal Fcγ receptor (FcRn ）

Mesenteric lymph nodes （肠系膜淋巴结） 100 to 150 differentiation of B cells into dimeric IgA–secreting

plasma cells and the development of effector T cells as well as regulatory T cells

The cells that differentiate in the mesenteric lymph nodes in response to bowel wall invasion by pathogens or commensals often home to the lamina propria

gut-homing of IgA-producing cells and effector T cells 

Effector lymphocytes that are generated in the GALT and mesenteric lymph nodes are imprinted with selective integrin- and chemokine receptor–dependent gut-homing properties, and they circulate from the blood back into the lamina propria of the gut

production of secretory IgA in the GALT secretory immunity ： Within the lumen,

IgA, IgG, and IgM antibodies bind to microbes and toxins and neutralize them by preventing their binding to receptors on host cells.

IgA is produced in larger amounts than any other antibody isotype

2 g of IgA per day

T-dependent mechanisms

T-independent mechanisms

Transport of IgM and IgG IgM Poly-IgR

IgG neonatal Fc receptor (FcRn) bidirectional transport

阻断微生物黏附于黏膜，使多数共生菌滞留于肠腔而不侵入人体，维持机体和共生菌之间的生态平衡

与 IgG 协同，抵御穿越肠道上皮组织的致病菌，控制感染蔓延

中和作用

T cells are found within the gut epithelial layer, scattered throughout the lamina propria and submucosa, and within Peyer’s patches and other organized collections of follicles

most of the intraepithelial T cells are CD8+ cells

Lamina propria T cells are mostly CD4+, and most have the phenotype of activated effector or memory T cells

T cells within Peyer’s patches and in other follicles adjacent to the intestinal epithelium include CD4+ helper T cells and regulatory T cells

DCs of gastrointestinal immune system

effector DCs CD11b+CX3CR1+ induce T cells into IFN-γ– or IL-17–producing effector

cells regulatory DCs CD103+CX3CR1− induce the differentiation of naive T cells into

FoxP3+ regulatory T cells

TH17 cells TH17 cells produce IL-17 and IL-22 which induce the

expression of proteins important for barrier function, such as mucins and β-defensins  

TH2 responses which are effective in eliminating the worms in intestinal

helminthic infections because the TH2 cytokines IL-4 and IL-13 cooperate in enhancing fluid and mucus secretions and inducing smooth muscle contraction and bowel motility

FoxP3+ Treg Treg are thought to suppress immune responses by

several mechanisms. Of these, the dominant mechanism in the gut seems to be production of the immunosuppressive cytokine IL-10.

cytokines maintaining homeostasis in the gut immune system

TGF-β, IL-10, and IL-2 The uncontrolled inflammation observed in the gut in the

absence of these cytokines or their receptors is most likely caused by innate and adaptive immune responses to commensal gut flora

Oral Tolerance

Oral tolerance is systemic adaptive immune tolerance to antigens that are ingested or otherwise administered orally and is a potential way of treating diseases in which unwanted immune responses occur, such as autoimmunity

The physiologic role of oral tolerance is speculated to be the prevention of potentially harmful immune responses to food proteins and commensal bacteria

其可能的机制： 口服高剂量抗原导致特异性 T细胞凋亡或失能，巨噬细胞在吞噬凋亡细胞过程中产生 TGF-β ，诱导 Treg产生

口服低剂量抗原诱导调节性 T细胞

肠系膜淋巴结是诱导口服耐受的主要部位，该部位 DC 共刺激分子表达减少，而共抑制分子表达增加