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The Mucosal Immune System : Studies on Respiratory Defense Mechanism
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Mucosal Surfaces of the BodyComprises approx. 400 m2 (adulthood)Continuously exposed to environmental antigens, including dietary proteinsMucosal infections, e.g. respiratory and gastrointestinal, are still prevalentEquipped with an unique mucosal defence system
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Immune responses (Immunity)Natural/innate/nonspecificHumoral: type I IFN (IFN-a/b), lysozyme, Complement proteins (C)Cellular: phagocytes (neutrophils, macrophages), NK cellsAdaptive/acquired/specificHumoral: Antibodies: IgM, IgG, IgA, IgE, IgDCellular: T cells:CD4+ Th, CD8+CTL (cytolytic T lymphocytes)
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Concept of Common Mucosal Immune System (CMIS)Mucosa Associated Lymphoid Tissues (MALT)Mucosal surfaces / secretionsBALTNALTGALTOALTInductive sitesEffector sitesMigration of sensitized B - and T- cellsA framework for the development of clinically useful vaccin
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Common Mucosal Immune System (CMIS)
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Bronchus-Associated Lymphoid Tissue (BALT)Animal models(RAT, RABBIT, MICE)HumanOrganized lymphoreticular structureLess organized (mostly), with exceptional
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Respiratory infectionsViralBacterialH. influenzae (NTHI)H. parainfluenzaeMycobacteriaothersinfants : RSV (Respiratory Syncitial Virus) adults : Influenza Virus
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Immune ResponsesLocalSystemicNatural responseAdaptive response Ab - mediated : SIgA, IgE T cell - mediated: CD4+ Th, CD8+ CTLNatural responseAdaptive response Ab - mediated : IgM, IgG T cell - mediated: CD4+Th, CD8+CTL
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Mucosal IgA responses
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Respiratory Immunity after Mucosal ImmunizationHuman Rat modelVaccin candidate : killed nontypableHaemophilus influenzae (NTHI)Different routes of immunization :PO, IT, IPP, SC
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Table 1. The influence of ingested H. influenzae on acquisition of Haemophylus species in throat swabsPlacebo HI* Placebo HI* Placebo HI *Month IMonth IVMonth VII* being immunized with 10 11 killed NTHI orally (Clancy et.al., 1990)
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Animal model : Rats
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T cell responseEvidenceAdaptive transfer of T cells protectionT cell response without detectable AbAntigen - specific CD4+ T cellsThe presence of CD8+ T cells lytic action
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Action in Concert : T cells - M - neutrophilsThree stages 1. Activation of alveolar M and Tissue cellsLPSMoM TNF-IL-1IL-1CD4+TcellsIL-2CD4+TH1CD8+NK cellsIFN- MTNF-
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2. Recruitment of neutrophil leukocytesExpression of adhesion molecules(leukocytes endothelium)e.g. LPS L - selectinTNF- ICAM-1, E-selectin, CR3/Mac-1/CD11b/CD18, CR4TNF- activates neutrophilsINF- activates M : ROI secretionTNF-(TH1-cytokine) activates neutrophil3. Activation of recruited neutrophilRespiratory burstdegranulation
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Down-regulatory Role for TH2 - type cytokinesIL - 4IL - 10
IL - 5IL - 6Inhibits TH1 - type cytokines (IFN-),inhibits cell-mediated immunity Ab productionTerminal diff. of B cells Plasma cells
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ConclusionSpecific immunity of the respiratory system comprises Ab-responses and Tcell-mediated reactionsThe functional property of IgA antibodies seems to inhibit the attachment and colonization of pathogens onto mucosal surfacesT cell-mediated responses act directly to some pathogens or by inducing M as effector cells