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Mucosal Immune System Dr Andrew Exley Immunology Lab & Lung Defence Unit Papworth Hospital AR Exley Immunology, Papworth Hospital, Cambridge Introduction Mucosal Defence Mucosal Immune system – – – – – – AR Exley Antigen - induced expansion of lymphoid tissue Lymphocyte homing Functional and phenotypic diversity Regulatory T cells Immunoglobulin IgA Immunity thru’ Vaccination Immunology, Papworth Hospital, Cambridge Mucosal Defence Direct interface with exterior First line defences Innate immunity Antigen load - food, inhaled antigen, microbes – Germ-free animals AR Exley Immunology, Papworth Hospital, Cambridge Mucosal Defence Mechanisms GI tract Commensal Respiratory tract bacteria Gastric Acid, Bile Mucous secretion Shedding of Epithelium Peristalsis Lactoferrin Lysozyme AR Exley Commensal bacteria? Mucous secretion Mucociliary escalator Soluble factors – – – – Complement Surfactant proteins Defensins Proteases Immunology, Papworth Hospital, Cambridge Mucosal Immune System Immune response – Induction & Expression within same system Mucosal Lymphocytes – Remain within the mucosal immune system – Lymphocyte migration / homing / retention Special T cells – CD8 a/a, gd , and regulatory T cells AR Exley Immunology, Papworth Hospital, Cambridge Gut-associated Lymphoid Tisssue Functional and phenotypical division Secondary lymphoid tissue – Peyer’s patches, lymphoid follicles in gut wall » ~lymph nodes, for Ag uptake and presentation – Draining lymph nodes » Mesenteric LNs Non-lymphoid tissue – Lamina propria lymphocytes – Intra-epithelial lymphocytes AR Exley Immunology, Papworth Hospital, Cambridge Intra-epithelial Lymphocytes <20% of epithelial cells gd T cells – – – – Groh 1998 NK receptor NKG2D versus MHC class I non-classical MHC class I MIC-A, MIC-B MIC-A/B upregulated by stress Deletion of damaged, aged, disordered epithelial cells ab T cells CD8 a/a – extra-thymic development – Role in humans? AR Exley Immunology, Papworth Hospital, Cambridge Lamina propria Lymphocytes T cells, B cells, macrophages, dendritic cells CD4+ T cells Naive CD45RA+ & memory CD45RO+ T TH2/TH3 cytokines dominant – IL-4, IlL-5, IL-10, TGF-b (IgA switch factor) – Regulatory T cells! TH1 cytokines non-dominant – IFN-g, IL-2, IL-12, TNF-a AR Exley Immunology, Papworth Hospital, Cambridge Controlling the Immune Response in the GI tract Food Protection Infection Pathogenic immunity Bacteria driven Inflammatory Bowel disease – Adoptive transfer studies – Colitis : CD4+ CD45RBhigh – Protection : CD4+ CD45RBlow CD25+ subset AR Exley Immunology, Papworth Hospital, Cambridge CD4+ low CD45RB CD25+ T cells Naturally activated ~10% of CD4+ T cells Unresponsive in vitro Inhibit wide range of immune responses – To self – To pathogens Transcription Maloy 2003 factor Foxp3 Effector function present in thymus AR Exley Immunology, Papworth Hospital, Cambridge Regulatory T cells - natural T cells from thymus / peripheral blood Classical transfer experiments CD4+ CD25+ T cells in mice inhibit – – – – – AR Exley autoimmune diabetes inflammatory bowel disease anti-tumour immunity expansion of other T cells in vitro Promote tolerance to skin allografts Immunology, Papworth Hospital, Cambridge Regulatory T cells - induced Foxp3 transcription factor positive – Physiological inducers? – Trl IL10 producers – Tr3 TGFb producers » Inducible with TGFb Chen 2003 – Inhibit Th1, Th2 responses in vivo Classical – Ag delivered at mucosal sites induces peripheral + mucosal unresponsiveness Ostroukhova 2004 – Soluble Peptide induced tolerance » oral, nasal, peritoneal, subcutaneous, intradermal route » Peptides must be ~ naturally occurring epitopes AR Exley Immunology, Papworth Hospital, Cambridge Oral Tolerance – Clinical Use? Good data in autoimmune disease models – Prophylaxis prevents / attenuates disease – Treatment suppresses disease – Dose dependent effects Poor – – – – AR Exley results to date from studies of Clinical diseases Monitor state & mode of oral tolerance induced Phase III: Oral MBP analogue in Multiple sclerosis NIH study: oral insulin in juvenile diabetes mellitus Myasthenia gravis : anti-ACHreceptor responses Immunology, Papworth Hospital, Cambridge Anti-CD3 mAb induced regulatory T cells? Intervention in Type 1 Diabetes mellitus – 1st degree relatives » GAD / ICA512 Ab +ve … ~75% develop type 1 diabetes – Islet cell transplantation – Diagnosis : residual islet cell function » Prolong insulin secretion to reduce cardiac/renal disease – Human OKT3g1 (Ala-Ala) within 6 weeks of diagnosis » Insulin production stable / better » Metabolic control stable / better » IL-10 increased, IFN-g decreased AR Exley Immunology, Papworth Hospital, Cambridge Herold 2003 Oral Antigen Induces IgA Ingestion of killed Streptococcus mutans IgA antibody producing cells – Peripheral blood by day 7, peak day 10 – 12 Secretory IgA antibodies – Saliva & Tears by 2 weeks, peak 3 weeks Czerkinsky C 1987 AR Exley Immunology, Papworth Hospital, Cambridge Secretory IgA - Production IgA in blood is monomeric, >90% IgA1 Secretory IgA – polymeric, IgA1 upper respiratory & GI tract IgA2 in colon & rectum – Induction by antigen in Peyer’s patches – Production by IgA plasma cells in lamina propria – J chain polymerisation of IgA – Binds polymeric Ig-receptor for trans-epithelial transport, cleaved to release secretory IgA AR Exley Immunology, Papworth Hospital, Cambridge Secretory IgA Transepithelial Transport Polymeric IgReceptor Deficient Mice Johansen 1999 Epithelial IgA AR Exley Interstitial IgA/IgG Polymeric IgR / Secretory component Crypts / Villous epithelium Immunology, Papworth Hospital, Cambridge Polymeric IgR Deficient Mice AR Exley Immunology, Papworth Hospital, Cambridge Secretory IgA - Function Specificity – 2 – 5% reacts with specific Ag after immunisation – Commensal flora? Dietary antigens? Resists proteolysis Inhibits microbial adherence Neutralisation of viruses, toxins (cholera) Activates complement (alternative pathway) AR Exley Immunology, Papworth Hospital, Cambridge Selective IgA Deficiency in 500 – 700 Caucasians, most are healthy! IgA-producing cells in GI tract ~absent Normal numbers of Ig-producing cells! Increased IgM (65 – 75%) & IgG (20 – 35%) producing cells compensate 1 – Pentameric IgM (J chain, polyclonal IgR transport) Recurrent infections associated with additional antibody deficiencies – Poor antibody response to vaccines! AR Exley Immunology, Papworth Hospital, Cambridge Pathogens Targeting the Mucosal Immune System M cells Polio HIV Salmonella S.typhi S.typhimurium AR Exley Immunology, Papworth Hospital, Cambridge Mucosal Immunity – Live attenuated microbes – – oral Polio (Sabin) rotavirus (rhesus/human virus with VP-7 Ag) Killed microbes + potent adjuvants – – AR Exley sIgA at mucosal surfaces, IgM + IgG in blood Vibrio cholera + cholera toxin B (CTB) ~85% protective, and cross-protection vs enterotoxigenic E.coli (ETEC) Immunology, Papworth Hospital, Cambridge Conclusion Mucosal – – – – – – AR Exley Immune system Antigen - induced expansion of lymphoid tissue Lymphocyte homing Functional and phenotypic diversity Regulatory T cells Immunoglobulin IgA Immunity thru’ Vaccination Immunology, Papworth Hospital, Cambridge References AR Exley Chen W et al. Conversion of Peripheral CD4+CD25- Naive T Cells to CD4+CD25+ Regulatory T Cells by TGF-beta. Induction of Transcription Factor Foxp3. J Exp Med 2003; 198 (12):18751886. Groh V et al. Recognition of stress-induced MHC molecules by intestinal epithelial gammadelta T cells. Science 1998; 279 (5357):1737-1740. Herold et al. Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3g1(Ala-Ala). J.Clin.Invest. 2003; 111 (3):409-418. Maloy et al. CD4+CD25+ TR Cells Suppress Innate Immune Pathology Through Cytokine-dependent Mechanisms. J Exp Med 2003; 197 (1):111-119. Ostroukhova O et al. Tolerance induced by inhaled antigen involves CD4+ T cells expressing membrane-bound TGF-b and FOXP3. J.Clin.Invest. 2004; 114 (1):28-38. Immunology, Papworth Hospital, Cambridge