Transcript Common Variable Immunodeficiency

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
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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
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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
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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
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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
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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
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– 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
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Live attenuated microbes
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oral Polio (Sabin)
rotavirus (rhesus/human virus with VP-7 Ag)
Killed microbes + potent adjuvants
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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
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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
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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