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Gastrointestinal associated lymphoid tissue (GALT)

Gastrointestinal associated lymphoid tissue (GALT). Anatomy of immune system. primary or central lymphoid organs bone marrow B cells thymus T cells secondary or peripheral lymphoid organs lymph nodes spleen cutaneous immune system

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Gastrointestinal associated lymphoid tissue (GALT)

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  1. Gastrointestinal associated lymphoid tissue (GALT)

  2. Anatomy of immune system

  3. 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

  4. Mucosal immune system (MIS)Mucosal associated lymphoid tissue (MALT) • 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）

  5. Mucosal associated lymphoid tissue (MALT) • gastrointestinal associated lymphoid tissue • bronchopulmonary associated lymphoid tissue • genitourinary associated lymphoid tissue

  6. Component of gastrointestinal 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

  7. Immunity of gastrointestinal system

  8. 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

  9. Structure of gastrointestinal system

  10. Innate immunity in the astrointestinal tract 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

  11. chemical barrier • 转铁蛋白 • 溶菌酶 • Defensin • α-defensins(small bowel Paneth cells ) • β-defensins (colonabsorptive epithelial cells)

  12. biological barrier • 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) 

  13. Adaptive Immunity in the Gastrointestinal Tract • 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

  14. The Functional Anatomy of the Adaptive Immune System in the Gastrointestinal Tract

  15. 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

  16. 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）

  17. 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

  18. 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

  19. Humoral Immunity in the Gastrointestinal Tract • 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

  20. IgA isotype switching in B cells in GALT and mesenteric lymph nodes • T-dependent mechanisms • T-independent mechanisms

  21. Secreted IgA is transported through epithelial cells into the intestinal lumen by an IgA/IgM-specific Fc receptor called the poly-Ig receptor

  22. Transport of IgM and IgG • IgM Poly-IgR • IgG neonatal Fc receptor (FcRn) • bidirectional transport

  23. Functions of sIgA • 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

  24. T Cell–Mediated Immunity in the Gastrointestinal Tract • 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

  25. 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

  26. 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

  27. 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

  28. Regulation of Immunity in the Gastrointestinal Tract by Regulatory T Cells and Cytokines • 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.

  29. 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

  30. 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

  31. 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

  32. 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

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