The Mucosal Immune System : Studies on Respiratory Defense Mechanism
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
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)
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
Common Mucosal Immune System (CMIS)
Bronchus-Associated Lymphoid Tissue (BALT)Animal models(RAT, RABBIT, MICE)HumanOrganized lymphoreticular structureLess organized (mostly), with exceptional
Respiratory infectionsViralBacterialH. influenzae (NTHI)H. parainfluenzaeMycobacteriaothersinfants : RSV (Respiratory Syncitial Virus) adults : Influenza Virus
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
Mucosal IgA responses
Respiratory Immunity after Mucosal ImmunizationHuman Rat modelVaccin candidate : killed nontypableHaemophilus influenzae (NTHI)Different routes of immunization :PO, IT, IPP, SC
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)
Animal model : Rats
T cell responseEvidenceAdaptive transfer of T cells protectionT cell response without detectable AbAntigen - specific CD4+ T cellsThe presence of CD8+ T cells lytic action
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-
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
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
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
