• Overwhelming majority of initial antigen encountersoccur at mucosal surfaces• Surface bathed by a heterogeneous population ofmicroorganisms• Confronted by a large number of antigenic stimuli which must be deciphered for pathologic potential• For the majority, a response characterized by eitherignorance or active suppression is appropriate • For a few, a robust immune response is in orderIntroductionHarvard-MIT Division of Health Sciences and Technology HST.121: Gastroenterology, Fall 2005Instructors: Dr. Richard S. Blumberg• Gut associated lymphoid tissue (GALT) is characterizedby a regulated state of physiologic inflammation• GALT is poised for, but actively restrained from, full action and noteable for a tendency to suppress responses, called oral tolerance• Certain microorganisms and food antigens elicit vigorousimmune responses• The rules which govern these immunologic decisisonsare beginning to be clear and are important to the development of vaccines and the treatment of inflammatory bowel diseaseIntroduction (II)MUCOSAL BARRIER FUNCTIONIllustration by MIT OCW.Adapted from illustrations by Per Brandtzaeg at Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), University of Oslo.See Brandtzaeg, P., et al. Immunol. Rev. 171 (l999): 45-87.INNATE HUMORAL FACTORSLactoferrin, Lysozyme, Peroxidase, ITF, Complement, DefensinsTLR Ligands and their ReceptorsFigure removed due to copyright reasons. Please see: Figure 1 in Akira, Shizuo. "Mammalian Toll-like receptors." Curr Opin Immunol 15 (2003): 6.Commensal Bacteria Regulate Mucosal Gene ExpressionFigure removed due to copyright reasons. Please see: Figure 1 and Figure 2 in Hooper, Lora V., et al. "Molecular Analysis of Commensal Host-Microbial Relationships in the Intestine." Science 291 (2001): 881-84.INNATE HUMORALFACTORS: DEFENSINS**** Secreted by Paneth Cells, AEC(Cryptdins)Luminal Factors:Specific Extrinsic or Immunologic BarriersSecretory ImmunoglobulinsIsotype Distribution of Ig ProductionBy Mucosal Plasma CellsIgA 69%IgA 73%IgA 77%IgA 86%IgM 6%IgM 6%IgM 8%IgM 10%IgM 7%IgG 17%IgM 13%IgM 8%IgG 14%IgG 12%IgG 6%IgG 5%IgG 4%IgG 10%IgD 8%IgD 10%IgD 3%IgD 2%IgD 1%IgA 86%IgA 79%IgM 18%IgM 11%IgM 6%IgA80%IgA 79%IgA 84%IgA 90%IgG 3%IgG 5%IgG 4%Gastric Body Gastric AntrumDuodenum-JejunumIleum Large BowelNasal GlandsLacrimal GlandParotid GlandSubmandibular Gland Mammary GlandIsotype Distribution of Ig Production By Mucosal Plasma CellsIllustration by MIT OCW. Adapted from illustrations by Per Brandtzaeg at Laboratory for Immunohistochemistry and Immunopathology (LIIPAT)University of Oslo. See Brandtzaeg, P., et al. Immunol. Rev. 171 (l999): 45-87.17 µg/min34 µg/min162 µg/minColonic fluid207104313Duodenal fluid50-34040-168470-1632Milk0.1133Broncho-alveolar fluid08-30470-846Nasal SecretionsIgMIgGIgAFluidLevels (µg/ml) of Immunoglobulins in Human Secretions Ogra, Pearay L., et al, eds. Mucosal Immunology. San Diego, CA: Academic Press, 1999. ISBN: 0125247257.IgA2 is Enriched in Mucosal Secretions Relative to Peripheral BloodSpleen, Peripheral LymphNodes, Palatine TonsilsNasal MucosaLacrimal glands Salivary glandsMammary glandsIgA1 93%IgA1 83%IgA2 17%IgA2 7%IgA2 7% IgA2 20% IgA2 36% IgA2 40%IgA2 23% IgA2 40% IgA2 64% IgA2 57%IgA1 77%IgA1 93% IgA1 80% IgA1 64% IgA1 60%IgA1 60% IgA1 36% IgA1 43%Gastric MucosaDuodenum-JejunumIleum Colon RectumIllustration by MIT OCW. Adapted from illustrations by Per Brandtzaeg at Laboratory for Immunohistochemistry and Immunopathology (LIIPAT)University of Oslo. See Brandtzaeg, P., et al. Immunol. Rev. 171 (l999): 45-87.(IgA-secreting cells, no. per 105lymphocytes)<10ConventionalLTα-/-1,600 ± 860Germ-freeC57BL/6<1SPFaly/aly9,500 ± 540SPFTNFR-1-/-9,100 ± 930ConventionalCD4-/-2,800 ± 1,700SPFC57BL/6 nu/nu3,900 ± 1,600SPFTCRβ-/-δ-/-11,600 ± 1,500SPFC57BL/6Intestinal lamina propriaHousing conditionsMouse strainT Cell Independent IgA Secretion in the IntestineEnrichment of dimeric (d)IgA inMucosal Secretions Relative to SerumWhich contains monomeric IgA85% IgA1Serum100%50% IgA250% IgA1Secretions100%Monomeric IgADimeric IgA15% IgA 2ssssssssssssssssssIllustration by MIT OCW. Adapted from illustrations by Per Brandtzaeg at Laboratory for Immunohistochemistry and Immunopathology (LIIPAT)University of Oslo. See Brandtzaeg, P., et al. Immunol. Rev. 171 (l999): 45-87.Secretory dIgA is formed by AssociationWith J Chain and proteolytic fragmentof pIgR or SCIllustration by MIT OCW. Adapted from illustrations by Per Brandtzaeg at Laboratory for Immunohistochemistry and Immunopathology (LIIPAT)University of Oslo. See Brandtzaeg, P., et al. Immunol. Rev. 171 (l999): 45-87.STRUCTURE OF POLYMERIC IgRECEPTOR (pIgR)12 3456PIg-bindingsiteDisulfidebridge to IgAPossiblecleavagesitesBasolateraltargeting&CalmodulinbindingAvoiddegradationRapidendocytosisSignal fortranscytosisExtracellular Transmembrane CytoplasmicserPsers ss ssss ss ssssss sCOOHH2NIllustration by MIT OCW. Adapted from illustrations by Per Brandtzaeg at Laboratory for Immunohistochemistry and Immunopathology (LIIPAT)University of Oslo. See Brandtzaeg, P., et al. Immunol. Rev. 171 (l999): 45-87.Intracellular Transport of pIgA via pIgRIllustration by MIT OCW. Adapted from illustrations by Per Brandtzaeg at Laboratory for Immunohistochemistry and Immunopathology (LIIPAT)University of Oslo. See Brandtzaeg, P., et al. Immunol. Rev. 171 (l999): 45-87.Quantification of IgA ProductionIn Mucosal SecretionsImage removed due to copyright reasons.IgA is a Component of Bile via Expression of pIgR in hepatocytes (rat)or bile duct epithelium (human)Image removed due to copyright reasons.IgA has complex effects in Mucosal TissuesThrough interaction with Fcα-receptorsImage removed due to copyright reasons.• MHC I-like structure/β2m associated• Closed cleft/no defined role in antigen presentation• Binds overlapping region of IgG as Protein A• Binds IgG with a 2:1 stoichiometry• Binds IgG at pH 6.0 (Kd= 10 nM) but negligibly at physiologic pH 7.4The Neonatal Fc Receptor for IgG, FcRnFigure removed due to copyright reasons. Please see:Burmeister, W. P., et al. "Crystal structure at 2.2 A resolution of the MHC-related neonatal Fc receptor." Nature 372 (1994): 336-43.Polymeric IgR-mediatedIgA TransportFcRn-mediated IgGTransport IECDCapicalbasalIgGCD4 +T cellsB cell or Plasma cellsIgApIgR FcRnFcRnFcRn Plays a Role in the Uptakeof Lumenal AntigensIntrinsic Barrier Function of EpitheliumTJDesmosomeBMIELAssociation of Dendritic