免疫学与免疫系统疾病：lecture21-MucosalImmuneSystem

1、Xiao-Ping Chen 2015Specialized Immunity at Epithelial BarriersMucosal Immune SystemXiao-Ping Chen 2015Surface areas: Skin 2 m2 Lung 140 m2 Gastrointestinal (G.I.) 400 m2 (size of tennis court, half of soccer field) Contains large number of lymphocytesNormal Flora (microbiota, commensal bacteria, pro

2、biotics): Humans = 1012 to 1013 cellsFlora: skin, gut, other mucosa sites: 1013 to 1014 bacteria(1000 species)Opportunistic infections, iatrogenic infectionsYou are only 10% human!Basics on Mucosal Immune systemXiao-Ping Chen 2015In adult, the number of commensal bacterial is immense.1.1000 species,

3、 mainly bacteria, but viruses, fungi and protozoa are also present.2.majority of the intestinal bacteria are Gram-negative anaerobes.90% are obligate anaerobes, predominantly: Bacteroides(类杆菌 ), Eubacterium, Bifidobacterium（双歧杆菌属 ）, Fusobacterium, Peptostreptococcus （梭杆菌属 ）and others. Regularly pres

4、ent but in small proportion e.g. Escherichia coli, Enterobacter and Lactobacillusstomach: a few bacteria. Gram-negative spiral-shaped Helicobacter pylori duodenum and jejunum: a few bacteriaileum:massive and diverse microbial population (about 109 /ml)colon:highest numbers of bacteria displaying eno

5、rmous diversityXiao-Ping Chen 2015In germ-free animals (delivered by Cesarean)1. marked reduction of the size of all peripheral lymphoid organs 2. reduced levels of antibodies of all isotypesPresence of commensals affects development of immune organs Xiao-Ping Chen 2015Hygiene Hypothesis （卫生假说）Comme

6、nsals affects the occurrence of allergic diseases, autoimmune diseases and autoinflammatory diseases. Xiao-Ping Chen 2015Structures of mucosal immune system1. Epithelial barrier (singlegut; multipleskin)-contains lymphocytes- mediating innate immunity (barrier) and effector arm of adaptive immunity.

7、2. Underlying connective tissues (lamina propriagut; dermisskin) contains lymphocytes, M, DC mediating innate immunity and effector arm of adaptive immunity.3. Unencapsulated secondary lymphoid tissues (Peyers patchgut)-drainage of antigens and activation of nave lymphocytes 4. Encapsulated draining

8、 lymphoid tissues, usually outside mucosal tissues (mesenteric LN-gut, skin-draining LN, mediastinal LN-lung)- drainage of antigens and activation of nave lymphocytes 1+2+3-mucosa-associated lymphoid tissues (MALT)Xiao-Ping Chen 2015NALT (nasal-associated lymphoid tissue) tonsils, adenoids BALT (bro

9、nchial-associated lymphoid tissue) bronchus, lungGALT (gut-associated lymphoid tissue) gut, appendix Urogenital tractuterus, vagina, bladderCALT（cutaneous-associated lymphoid tissue)Mucosal-associated lymphoid tissues (MALT)Xiao-Ping Chen 2015Gut-associated lymphoid tissue (GALT)Epithelium enterocyt

10、es, goblet cells, Paneth cells, and enteroendocrine cells, intraepithelial lymphocytes (IEL，effector T) Lamina propria macrophages, dendritic cells (APC), lamina propria lymphocytes (LPL)(effector T, plasma cell)Peyers patchmacrophages, dendritic cells (APC), M cells (antigen transport), nave lympho

11、cytes; primary draining lymph node for GALT （ileum）Isolated lymphoid follicle： Similar to PP, primary draining lymph node for GALT （colon）Mesenteric lymph node (MLN) draining lymph nodes for gutXiao-Ping Chen 2015Cutaneous immune system Xiao-Ping Chen 2015Characteristics of T lymphocytes in IEL and

12、LPL in GALT S: small intestines; c: colon; IEL: intraepithelial lymphocyte; LPL: lamina propria lymphocytes 1. sIEL are mainly CD8, whereas the ratio of CD4 and CD8 in the spleen and lymph node is 2:1.2. Restricted TCR usage3. Lots of these T cells are effector lymphocytes even in the absence of app

13、arent infections.4. IEL: 10-20 IEL/100 epithelial cellsConventional T: TCR, CD4 or CD8IEL T: TCR/CD4-CD8-, TCR /CD8, TCR/CD8Xiao-Ping Chen 2015Challenges1.Appropriately mount protective immunity against pathogenic organisms (usually invasive).2.Tolerance to commensal bacteria (Not mounting harmful i

14、mmune responses by micobiota) .3.Oral tolerance to food.1 needs activation of immune responses; 2 and 3 need inhibition or tolerize immune responses. How to build and maintain the fine balance?Xiao-Ping Chen 2015Mechanisms of tolerance to commensal bacteriaMaintenance of GI homeostasisXiao-Ping Chen

15、 2015Physical barrier: tight junctions between epithelial cells (zonula occudens 1 and claudins).Chemical barrier:mucous barrier: mucins (GI tract: by goblet cells;O-linked glycoproteins; respiratory tract: mucus and cilia);molecular barrier: defensins: GI tract (paneth cells, epithelia cells; skin:

16、 keratinocytes)surfactant A and D (SP-1, SP-D): respiratory tract. I. Mucosal barrier Xiao-Ping Chen 2015Intestinal epithelial cells express TLR2 (peptidoglycans), 4 (lipopolysaccaride), 5(flagellin), 6 (MDP), 7(ssRNA); and 9 (CpG DNA).Ligation of surface TLRs results increased strength of the tight

17、 junctions between epithelial cells, and increased motility of GI tract. Compartmentalized expression of some PRRs excludes the possibility that microbiota induces inflammation via activation of them, and ensures that only invasive pathogenic bacteria can initiate inflammation.II. Engagement of PRRs

18、 with ligands does not lead to inflammation Xiao-Ping Chen 2015III. Large amount of dimeric secretory IgA present in GI tract blocks the interaction of microbial PAMP with PRRs on epithelial cells, blocks the entry of invasive microbes, and blocks the colonization. A 70kg people secretes 2g of IgA p

19、erday, about 60-70% of total antibody production.Mainly produced by large numbers of Ig A-producing plasma cells in lamina propria.Produced IgA are mostly secreted into mucosal lumen, thus it only represents a minor component in blood.Xiao-Ping Chen 2015IV. Regulatory T cells and Th17 are abundant i

20、n GALT.FoxP3+ CD4+ Treg is 2-fold greater in LP than in other peripheral lymphoid tissues. IL-10 and TGF- generted from Treg are important in maintaining homeostasis.IL-17 and IL-22 from Th17 cells are able to promote the production of mucin and defensins. Xiao-Ping Chen 2015V. IL-10, TGF- and IL-2

21、are important in maintaining homeostasis in the gut immune system. IL-10Immunity 25:941-952, 2006T cells in the GALT are easy to be induced to produce IL-10.Xiao-Ping Chen 2015Mechanisms on activation of lymphocytes in mucosal immune systemXiao-Ping Chen 2015Antigen uptake, processing and presentati

22、on in GALTVia M-DCVia DCPPXiao-Ping Chen 2015Homing of naive lymphocytes to the MLN and PP is mediated by CD62L (crossing HEV) and CCR7 (T-cell zone)Addressins on HEV (MLN) or HEV-like (PP) L-selectin on nave Lymphocytes Homing to GlyCAM-1 (MLN) CD62L MLN MAdCAM-1 (PP) CD62L Peyers patchXiao-Ping Ch

23、en 2015Recirculation of naive lymphocytes in GALT. If it is not activated, it will also drain to MLN then recirculate to next PP.Xiao-Ping Chen 2015Specific homing of activated lymphocytes (effector T and plasma cells) back to GALT (IEL, LPL) is mediated by 47 and CCR9, imprinted by metabolism of vi

24、tamine A into retinoid acid by gut DC.Retinal dehydrogenases (RALDH), largely expressed by gut DC.Xiao-Ping Chen 2015Specific homing of activated lymphocytes back to skin is mediated by CLA and CCR4, CCR8 and CCR10, imprinted by making of vitamine D3 by skin-associated DC after UVBXiao-Ping Chen 201

25、5IgA class switching can be accomplished in the gut via both T-dependent and T-independent mechanisms.Xiao-Ping Chen 2015Transport of dimer IgA across epithelial cells is mediated by poly-Ig receptor via transcytosisProtects IgA from proteolysisGI, bile, milk, saliva, and sweat.Xiao-Ping Chen 2015Tr

26、ansport of IgG across epithelial cells is mediated by neonatal FcR (FcRn).Recall: Transport of IgG across placenta, mother milk to infant blood is mediated by neonatal FcR (FcRn).Xiao-Ping Chen 2015Neonatal IgG receptor FcRn present in endothelial cells contributes to long half-life of IgG. For this

27、 reason XX-Fc (-cept) fusion proteins are generated and used clinically to prolong half-life of effective molecules XX.Xiao-Ping Chen 2015Diseases related to immune responses in the gut and skinXiao-Ping Chen 2015Inflammatory bowel disease (IBD)Chronic granulomatous inflammation and thickness of bow

28、el wall of GI tract (Crohns disease, especially terminal ileum) or of colon (ulcerative colitis).Defects in innate immunity to gut commensals.Abnormal Th17 and Th1 (high)Defective TregAutoinflammtory disease, treated by various anti-inflammatory drugs, corticosteroids, mesalamine, TNF antagonists, a

29、nd antimetabolites (methotrexate, mecaptapurine)./wiki/Inflammatory_bowel_diseaseXiao-Ping Chen 2015Celiac diseaseGluten-sensitive enteropathy, non-tropical sprue (乳糜泻）Inflammatory disease of the small bowel caused by immune responses (type IV, T-cell mediated) against ingested

30、 gluten protein present in wheat./wiki/Coeliac_diseaseblunting of villi, crypt hyperplasia, and lymphocyte infiltration of crypts TreatmentpathogenesisdiagnosisXiao-Ping Chen 2015Food allergyFailure of adaptive immune tolerance to food antigens. Type I hypersensitivityIgEB cell

31、IL-4Th2Nave T cellDendritic cellfood? Mast cells(IgE-FcreRI association)IL-4Positive feedbackPredisposing population Xiao-Ping Chen 2015MALT lymphomas/wiki/MALT_lymphomaMALT lymphoma (MALToma) is a form of B cell lymphoma, frequently involving the stomach, but virtually any muc

32、osal site can be afflicted. It is a cancer originating from B cells in the marginal zone of the MALT. Highly associated with H. pylori infection in stomach. Good example that cancer can be caused by chronic infection and chronic inflammation.Early stage: eradication of Helicobacter pylori by antibio

33、tics.Late stage: anti-CD20 mAb (Rituximab ) CD3CD20HEDOI: 10.4103/0301-4738.81993 Xiao-Ping Chen 2015PsoriasisChronic inflammatory disorder of skin.doi:10.1038/492S52a /wiki/PsoriasisImmunosuppressive drugsAnti-TNFAnti-IL-12, IL-23, IL-17Anti-T cell (LFA-1)Xiao-Ping Chen 2015At

34、opic dermatitisChronic allergic type I inflammatory disease of skin.Xiao-Ping Chen 2015Summary on shared features of mucosal immune system1. Relatively impermeable mucus- and defensin-secreting epithelial barriers;2. Localized collections of lymphoid tissues just beneath the epithelium;3. Constant sampling of antigens located outside barriers by immune cells (M cells, or DC) within the barrier;4. Constant integration of pro