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Mucosal Immunity – Reading
Immunobiology (6th Edition) Janeway, Travers, Walpert and Capra Chapter 10 (p. 432-445).
Neutra, MR et al Antigen sampling across epithelial barriers and induction of mucosal immune responses. Annu. Rev. Immunol. 14:275-300, 1996
Wright, JR. Immunoregulatory Functions of Surfactant Proteins. Nature Review Immunol. 5:58-68, 2005.
Cheroutre, H. Start at the beginning: new perspectives on the biology of mucosal T cells. Annu. Rev. Immunol. 22:217-46, 2004.
Weiner, H. Oral tolerance: immune mechanism and the generation of Th3-type TGF-beta-secreting regulatory cells. Microbes & Infection 3:947-954, 2001.
May 9, 2005
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Lymphoid System
= Mucosal surface Exposed to the environment
Challenge to protectWe have 5 mucosal surfaces
Nasopharyngeal Respiratory tract Oral Intestinal tract Urogenital tract
Specialized functions Acquiring or excreting Reproduction
Suppress Immune responses to food & commensal bacteria Gut (1014 organisms)
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Organization of Epithelial Layers
Annu. Rev. Immunol. 14:275-300, 1996
Extrinsic barrier functions•Exclude Antigens
Tight junctions >900 Da Air or fluid flow (mucus/Glycocalyx)
•Secrete factors Discourage bacterial
colonizationAntimicrobial function
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Respiratory Mucosal Surface
Wright, Jo Rae, Nature Reviews Immunol 5:58-68, 2005
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SP-A & D is Positioned to Interact with the Environment
JCI 109:707-712, 2002
Tubular Myelin = lattice networkformed by surfactant phospholipids
SP-A & D
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Ability of the SPs to Protect Mucosal Surfaces in Vivo
Group B Streptococcus
H. influenza
JI 165: 3934-3940, 2000
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Defensins
Highly conserved Plants, insects & vertebrates
Amphiphilic molecules Dominated by one structure: -helical, -pleated sheet, proline-rich
Secreted by many cell types Innate immune cells (PMNs) Paneth cells/glands (intestinal crypts) Epithelial cells (GU & Respiratory tract & skin)
Function as Broad-spectrum microbicides Act against gram – ,gram + microorganisms,
fungi, mycobacterium, spirochetes and viruses Permeabilization of outer mb
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Distribution of IgsLevels of immunoglobulins in human external secretions (g/ml)
Secretion IgA IgG IgM
Serum 1,500 10,047 1,500
Tears 80-400 Trace amounts-16
0-18
Nasal fluid 70-846 8-304 0
Whole saliva 194-206 42 64
Intestinal fluidb 166 4 8
Urine 0.1-1.0 0.06-0.56 d
Cervical fluid 3-133 1-285 5-118
Vaginal fluid 35 52 d
Fundamental Immunology (5th Edition)
Lippincott, Williams & Wilkins Chapter 31 (p.971)
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Polymeric IgR (pIgR)
Nature Immunol.
2:1004-1009, 2001
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Transcellular Transport
Fundamental Immunology (5th Edition)
Lippincott, Williams & Wilkins Chapter 31 (p.975)
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J-chain is Important for Binding SC and Mucosal Transport of pIgA
JI 157:750-754, 1996
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Antigen presentation at Mucosal Surfaces
Annu. Rev. Immunol.14:275-300, 1996
Inductive SitesEffector Sites
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A Real M Cell
Nature Immunol. 2:1004-1009, 2001
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Function of M Cells
Nature Immunol.
2:1004-1009, 2001
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Epithelial Cells Produce Chemokines in Response to Bacteria
Am J Physiol Gastrointest
Liver Physiol 280:G71217-26, 2001
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Are Immature DC Recruited to Mucosal Surfaces
Am J Physiol Gastrointest
Liver Physiol 280:G1217-26, 2001
Apical
Basolateral
Mature DCCCR7
Immature DCCCR1, CCR2CCR5,CCR6
CCL20(MIP-3)
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G-Protein Signaling
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G-Protein Signaling - Cont.
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Naïve and Memory T Cells Travel in Different Paths
Naïve (have not seen their antigen) T cells travel in the blood and lymphatics
Memory T cells (have been activated by their antigen) can also travel through tissues
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Mucosal Memory T Cells Migrate with a Different Homing Receptor
Peripherallymphnodes
Lymphaticsystem
MAdCAM-1
47: integrin
ChemokineCCL25
CCR9 (TECK):Chemokine receptor
Mucosal
HEV
ICAM-1
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Skin Memory T Cells Migrate with a Different Homing Receptor
BloodPeripherallymphnodes
Lymphaticsystem
Intestine
SkinChemokinesCCL17 / TARCCCL27 / CTACK
CD162 (PSGL-1):selectin
CCR4 & CCR10: chemokine receptors
Skin
HEVP-selectinICAM-1
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Epithelial Cells Selectively Produce Chemokines
J. Exp. Med. 4:761-8, 2000
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Activated T cells are Recruited to Certain Lymphoid Tissues by Selective Expression of Chemokines
JEM 195:135, 2002
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Oral Tolerance
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Two Mechanisms of Inducing Oral Tolerance
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Characteristics of IEL
Type A () Type B ( or )
Conventional MHC I & II Non-Conventional MHC
Memory response No memory response
Thymic dependent Mostly thymic independent
Negative & positive selection Only positive selection (autoimmune)
Both produce cytokines & chemokines
Inflammatory response Anti-inflammatory response
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T cells
T cells do not recognize Ag’ic peptides like Antibodies & TCR
o ~ TCR:1015 & Ab:1011 Ags by rearranging “V”, “D” & “J” ie junctional diversity
They bind to limited Ags due to uneven length of & chains.
Infection model finds that Ag recognition is germline encoded and not due to diversity.
TCR chains are determined by anatomic location
● Mouse spleen: V1 & V4● Mouse intesting V7
Non-classical MHC molecules● T10 & T22
Shows CDR3loop binds the T22 and not combination of peptide:MHC like CRs
CDR3loop
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Immune EffectorsKathleen Kelly [email protected]
ReadingImmunobiology (5th Edition) Janeway, Travers, Walpert and Capra
Chapter 10 (p. 381-402) and Chapter 8 (p. 295-340)
Agnello D, et al. Cytokines and transcription factors that regulate T helper cell differentiation: new players and new insights. J Clin Immunol. 23:147-161, 2003.
Mak, TM & Lohoff. Roles of Interferon Regulatory Factors in T-helper-cell Differentiation. Nature Reviews Immunol. 5:125-135, 2005.
Russell, JH & Ley, TJ. Lymphocyte-mediated cytotoxicity. Annu. Rev. Immunol. 323-370, 2002.