immunology, papworth hospital, cambridgear exley mucosal immune system dr andrew exley immunology...
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Immunology, Papworth Hospital, CambridgeAR Exley
Mucosal Immune System
Dr Andrew Exley
Immunology Lab & Lung Defence Unit
Papworth Hospital
Immunology, Papworth Hospital, CambridgeAR Exley
Introduction
Mucosal DefenceMucosal 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, CambridgeAR Exley
Mucosal Defence
Direct interface with exterior
First line defences
Innate immunity
Antigen load - food, inhaled antigen, microbes– Germ-free animals
Immunology, Papworth Hospital, CambridgeAR Exley
Mucosal Defence Mechanisms
Commensal bacteria Gastric Acid, Bile Mucous secretion Shedding of Epithelium Peristalsis Lactoferrin Lysozyme
Commensal bacteria?
Mucous secretion Mucociliary escalator Soluble factors
– Complement– Surfactant proteins– Defensins– Proteases
GI tract Respiratory tract
Immunology, Papworth Hospital, CambridgeAR Exley
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 / , and regulatory T cells
Immunology, Papworth Hospital, CambridgeAR Exley
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
Immunology, Papworth Hospital, CambridgeAR Exley
Intra-epithelial Lymphocytes
<20% of epithelial cells 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
T cells CD8 /– extra-thymic development
– Role in humans?
Immunology, Papworth Hospital, CambridgeAR Exley
Lamina propria Lymphocytes
T cells, B cells, macrophages, dendritic cellsCD4+ T cellsNaive CD45RA+ & memory CD45RO+ TTH2/TH3 cytokines dominant
– IL-4, IlL-5, IL-10, TGF-IgA switch factor)– Regulatory T cells!
TH1 cytokines non-dominant – IFN-, IL-2, IL-12, TNF-
Immunology, Papworth Hospital, CambridgeAR Exley
Controlling the Immune Response in the GI tract
FoodProtection
Infection Pathogenic immunity
Bacteria driven Inflammatory Bowel disease– Adoptive transfer studies– Colitis : CD4+ CD45RBhigh
– Protection : CD4+ CD45RBlow CD25+ subset
Immunology, Papworth Hospital, CambridgeAR Exley
CD4+ CD45RBlow CD25+ T cells
Naturally activated~10% of CD4+ T cellsUnresponsive in vitroInhibit wide range of immune responses
– To self– To pathogens Maloy 2003
Transcription factor Foxp3Effector function present in thymus
Immunology, Papworth Hospital, CambridgeAR Exley
Regulatory T cells - natural
T cells from thymus / peripheral bloodClassical transfer experimentsCD4+ CD25+ T cells in mice inhibit
– autoimmune diabetes– inflammatory bowel disease– anti-tumour immunity– expansion of other T cells in vitro– Promote tolerance to skin allografts
Immunology, Papworth Hospital, CambridgeAR Exley
Regulatory T cells - induced
Foxp3 transcription factor positive– Physiological inducers?– Trl IL10 producers– Tr3 TGF producers
» Inducible with TGF 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
Immunology, Papworth Hospital, CambridgeAR Exley
Oral Tolerance – Clinical Use?
Good data in autoimmune disease models – Prophylaxis prevents / attenuates disease
– Treatment suppresses disease
– Dose dependent effects
Poor 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, CambridgeAR Exley
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 OKT31 (Ala-Ala) within 6 weeks of diagnosis» Insulin production stable / better
» Metabolic control stable / better
» IL-10 increased, IFN- decreased Herold 2003
Immunology, Papworth Hospital, CambridgeAR Exley
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
Immunology, Papworth Hospital, CambridgeAR Exley
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
Immunology, Papworth Hospital, CambridgeAR Exley
Secretory IgA Transepithelial Transport
Epithelial IgA Interstitial IgA/IgG Polymeric IgR / Secretory componentCrypts / Villous epithelium
Polymeric IgReceptor Deficient Mice Johansen 1999
Immunology, Papworth Hospital, CambridgeAR Exley
Polymeric IgR Deficient Mice
Immunology, Papworth Hospital, CambridgeAR Exley
Secretory IgA - Function
Specificity– 2 – 5% reacts with specific Ag after immunisation– Commensal flora? Dietary antigens?
Resists proteolysisInhibits microbial adherence Neutralisation of viruses, toxins (cholera)Activates complement (alternative pathway)
Immunology, Papworth Hospital, CambridgeAR Exley
Selective IgA Deficiency
1 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– Pentameric IgM (J chain, polyclonal IgR transport)
Recurrent infections associated with additional antibody deficiencies – Poor antibody response to vaccines!
Immunology, Papworth Hospital, CambridgeAR Exley
Pathogens Targeting the Mucosal Immune System
M cellsPolio
HIV
SalmonellaS.typhiS.typhimurium
Immunology, Papworth Hospital, CambridgeAR Exley
Mucosal Immunity
– sIgA at mucosal surfaces, IgM + IgG in blood Live attenuated microbes
– oral Polio (Sabin) – rotavirus (rhesus/human virus with VP-7 Ag)
Killed microbes + potent adjuvants– Vibrio cholera + cholera toxin B (CTB)– ~85% protective, and cross-protection vs
enterotoxigenic E.coli (ETEC)
Immunology, Papworth Hospital, CambridgeAR Exley
Conclusion
Mucosal 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, CambridgeAR Exley
References 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):1875-1886.
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, hOKT31(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- and FOXP3. J.Clin.Invest. 2004; 114 (1):28-38.