respiratory mucosal immunity
DESCRIPTION
Respiratory mucosal immunity Presented by Jaichat Mekaroonkamol, MD October03, 2014TRANSCRIPT
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Jaichat Mekaroonkamol, MD
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Topic OutlinesTopic Outlines
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Regional Immunity
Specialized Immune Response i n Epithelial and Immune Privile
ged Tissues
7Abbas immunology th edition
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Respiratory system
Gastrointestinal tract
2010Natureimmunology
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Respiratory tractRespiratory tract
5Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
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Regional Immunity
Important regulatory functions to prevent unwanted responses to no pathogenic microbes and
foreign substances that are pre sent at different barriers
7Abbas immunology th edition
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Respiratory tractRespiratory tract
8Middleton’s Allergy. 8tt ttttttt
• Protection against dangerous antigens and effectively eliminate
• Tolerogenic immune response against harmless environmental components
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Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
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Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
Epithelial cells
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Intrinsic lung defenses
Intrinsic lung defenses•Aerodynamic filtering
•Humidification
•Airway reflexes Sneezing Bronchoconstriction Cough reflex
•Mucus and airway surface liquid Respiratory mucus Mucociliary clearance
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Intrinsic lung defenses
Intrinsic lung defenses•Aerodynamic filtering
•Humidification
•Airway reflexes Sneezing Bronchoconstriction Cough reflex
•Mucus and airway surface liquid Respiratory mucus Mucociliary clearance
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Middleton’s Allergy. 8tt ttttttt
Airway epitheliumAirway epithelium
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Airway epitheliumAirway epithelium
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Mucus and Lung WaterMucus and Lung Water
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Fahy JV, Dickey BE. N Engl J Med 2010;363:2233-47.
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Mucus: Important airway defense
mechanism
Mucus: Important airway defense
mechanism
16Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
• Covering sheet that entraps particulate matter and microorganisms
• Movable medium that can be propelled by cilia
• Waterproofing layer • Reduce fluid loss through the
airways• Layer present to detoxify noxious
inhaled irritants• Medium that transports essential
secreted substances• enzymes, defensins, collectins,
antiproteases, and immunoglobulins
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Mucociliary systemMucociliary system
17Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
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Respiratory tract epithelial cell
Middleton’s Allergy. 8tt ttttttt
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Respiratory tract epithelial cell
Component of the innate immune system
Middleton’s Allergy. 8tt ttttttt
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Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
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Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
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Cellular ComponentCellular Component
Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
Respiratory epitheliumInflammatory cells in the lung
• Macrophage• Dendritic cells• Mast cells• Neutrophil• Eosinophil• Natural killer cells
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Essential for normal epithelial development and barrier function
• Deficiency: transepidermal water loss (TEWL) atopic dermatitis
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Tight junction associated MARVEL protein: TAMP
• Barrier regulation during inflammation
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Junctional adhesion molecule: JAM-A• Tissue-specific role• Intestinal permeability not lung
• Coxsackie adenovirus receptor:CAR• Multiple CAR isoforms• Promote entry of viral paticles
• Coxsackie and adenovirus in respiratory tract may be not pathogens
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Deficiency: epithelial-mesenchymal transition (EMT) airway remodeling
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Lacking p120 catenin disrupted AJs and TJs
• P120 is degraded by LPS and negatively regurates TLR4 signaling
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Growth factors• Chemoattractants
• Cytokines
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Cellular ComponentCellular Component
Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
Respiratory epitheliumInflammatory cells in the lung
• Macrophage• Dendritic cells• Mast cells• Neutrophil• Eosinophil• Innate lymphoid cells
Resident cell defenses
Recruited cellular
defenses
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Middleton’s Allergy. 8tt ttttttt
Tissue-resident cellsHigh phagocytic capacity
MacrophageMacrophage
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Middleton’s Allergy. 8tt ttttttt
Tissue-resident cellsHigh phagocytic capacity
MacrophageMacrophage• AMs are he
dominating macrophage
• Localization “outside the body”
• Maintenance of steady-state mucosal homeostasis
• Sequestering antigens from other cells
• suppress the induction of adaptive immune
• NO, IL-10, and TGF-β
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34Middleton’s Allergy. 8tt ttttttt
MacrophageMacrophage
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35Middleton’s Allergy. 8tt ttttttt
MacrophageMacrophage
Macrophages may become activated in an antigen-independent•microbial compounds•cytokines
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MacrophageMacrophage
7Abbas immunology th editionInterstitial macrophages
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• Located near epithelial surfaces• An approximately 30-fold increase is
observed in chronic allergen-induced pulmonary inflammation• VCAM-1• α4β7 and α4β1 integrins
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Dendritic cell routeDendritic cell route
Middleton’s Allergy. 8tt ttttttt CD8 CD11b CD4
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Dendritic cell routeDendritic cell routeNonpathogenic
conditions
Th2
Repeated low-dose antigen
exposure
Foxp3+ Treg
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Dendritic cell routeDendritic cell routeTLR signaling
Th1Th17
High-dose antigen
exposure
Repeated low-dose antigen
exposure
Th2
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42Hamida Hammad and Bart N. Lambrecht. Nature Reviews Immunology , 2008.
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Dendritic cell routeDendritic cell route
Middleton’s Allergy. 8tt ttttttt NO! CD11b CD4
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Alveolar Dendritic cellAlveolar Dendritic cell
CD11- CD4- CD8+/-
Produce IL-10• development of
peripheral tolerance• prevention of
inflammatory processes
Middleton’s Allergy. 8tt ttttttt
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45Hamida Hammad and Bart N. Lambrecht. Nature Reviews Immunology , 2008.
Activation of DCs, macrophages, and
epithelial cells largely
depends on signals provided by pattern
recognition receptors(PRRs)
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7Abbas immunology th edition
Recognition of MicrobesRecognition of Microbes
Innate immune system recognizes molecular structures that are characteristic of microbial pathogens but not mammalian cells.
Pathogen-associated molecular patterns (PAMPS)
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Cell-associated Pattern Recognition Receptors (PRRs)
Cell-associated Pattern Recognition Receptors (PRRs)
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Cell-associated Pattern Recognition Receptors (PRRs)
Cell-associated Pattern Recognition Receptors (PRRs)
Alveolar macrophages
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Cell-associated Pattern Recognition Receptors (PRRs)
Cell-associated Pattern Recognition Receptors (PRRs)
Alveolar dendritic cell
Type I Interferons : Antiviral immunity
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Cell-associated Pattern Recognition Receptors (PRRs)
Cell-associated Pattern Recognition Receptors (PRRs)
Holt PG et al, Nat Rev Immunol 8:142 (2008)
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7Abbas immunology th edition
Epithelial cells•TLRs•NLRs
•CLRs (C-type lectin)•Protease-activated receptors
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Cellular ComponentCellular Component
Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
Respiratory epitheliumInflammatory cells in the lung
• Macrophage• Dendritic cells• Mast cells• Neutrophil• Eosinophil• Innate lymphoid cells
Resident cell defenses
Recruited cellular
defenses
Invading pathogens
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Adhesion proteinAdhesion protein
• Adhesion and migration of circulating inflammatory cells Integral to cell recruitment and
activation response to injury
• Three major families : Immunoglobulin superfamily Integrins Selectins
Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
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Adhesion proteinAdhesion protein
7Abbas immunology th edition
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Traffcking of lymphoid cells mediated by specific adhesion molecules and chemokine receptors
Holt PG et al, Nat Rev Immunol 8:142 (2008)
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Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
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Innate Immunity Innate Immunity• Cellular components
• Respiratory epithelium• Phagocyte• Dendritic cells• Mast cells• Eosinophils• Natural killer cells
• Recognition of microbes
• Soluble recognition and effector molecules• Complement system• Antimicrobial peptides
• Pulmonary surfactant
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The Complement System
The Complement System
7Abbas immunology th edition
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Functions of complement
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The Complement System
The Complement System
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Complement deficiencyComplement deficiency
Middleton’s Allergy. 8tt ttttttt
Early complement component deficiencies
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Antimicrobial peptides
Antimicrobial peptides
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• - Broad spectrum a ntimicrobial prope
rties
• Formation of pore s in the bacterial c
ell wall
7Abbas immunology th edition
Antimicrobial peptides
Antimicrobial peptides
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Antimicrobial peptides
Antimicrobial peptides
Middleton’s Allergy. 8tt ttttttt
The major function of all these peptides = direct antimicrobial activity against gram-positive and gram-negative bacteria, fungi, and viruses
• Interfere with the membranes of the pathogens• Leading to membrane permeabilization and pathogen
killing• Neutralize microbial toxins such as LPS • Aggregation of pathogens promotes their elimination
from the respiratory tract• Chemoattractants for innate (e.g., monocytes,
neutrophils, immature dendritic cells [DCs]) and adaptive (e.g., memory T cells) immune cells
• Involved in epithelial cell proliferation and repair processes
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Middleton’s Allergy. 8tt ttttttt
• Primary produced by epithelium• B2,3,4 defensins
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Middleton’s Allergy. 8tt ttttttt
• Primary produced by invading neutrophils under inflammatory conditions
• Human neutrophils peptides: HNP-1, HNP-3
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Middleton’s Allergy. 8tt ttttttt
• Primary produced by myeloid and epithelial cells
• Secreted as proform after inflammatory stimuli serine proteases
• Antiapoptotic of PMN• Chemoattractrant• Stimulates angiogenesis
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Middleton’s Allergy. 8tt ttttttt
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Pulmonary surfactant proteins Pulmonary surfactant proteins
Middleton’s Allergy. 8tt ttttttt
• Stability• Metabolism
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Pulmonary surfactant proteins Pulmonary surfactant proteins
Middleton’s Allergy. 8tt ttttttt
• Antimicrobial peptides• Mannose binding protein: 3rd C’
• Opsonin
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Pulmonary surfactant proteins A and D (SP-A and SP-D)
• Collectins family• Mainly synthesized by alveolar type II cells. • Bind to polysaccharides, phospholipids, and
glycolipid ligands
• Organisms• Gram-negative and gram-positive bacteria• Fungi: A fumigatus, C neoformans, C
albicans• Other: P carinii, M tuberculosis• Viruses: RSV, influenza A virus, CMV
Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
Pulmonary surfactant proteins Pulmonary surfactant proteins
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Pulmonary surfactant proteins Pulmonary surfactant proteins
Am J Physiol Lung Cell Mol Physiol 291: L847–L850, 2006
Receptors: SPR-210,on type II cells and alveolar macrophages
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Holt PG et al, Nat Rev Immunol 8:142 (2008)
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Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
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Dendritic cell routeDendritic cell route
Patrick G. Holt et al. Nature Reviews Immunology, 2008.
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78Patrick G. Holt et al. Nature Reviews Immunology, 2008.
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DCs in pulmonary immune regulation
DCs in pulmonary immune regulation
• Antigen capture and presentation
• T cell activation and differentiation– Induce differentiation toward Th2, regulatory T (Treg)
cell, not Th1 or Th17 phenotypes
• IgA class switching
79Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
TGF-B
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Structure of human IgAStructure of human IgAIgA1IgA1 IgA2IgA2
IgA2 is more resistant than IgA1 to degradation by bacterial proteases
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secretory IgAsecretory IgA
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Functional of Mucosal sIgAFunctional of Mucosal sIgA
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84Brandtzaeg. Frontiers in Immunology, 2013.
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Topic OutlinesTopic Outlines
86
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Growth factors• Chemoattractants
• Cytokines
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Protease-dependent epithelial barrier dysfunction
Hamida Hammad and Bart N. Lambrecht. Nature Reviews Immunology , 2008.
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89Middleton’s Allergy. 8tt ttttttt
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90Hamida Hammad and Bart N. Lambrecht. Nature Reviews Immunology , 2008.
PAR: protease-activated receptor- Enzymatically active allergens can activate
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• Der p 2 shares functional homology with the LPS-binding adaptor protein MD-2 (i.e., TLR4 coreceptor)
• Directly facilitate TLR4 signaling. • This property seems to be specific to
the lipid-binding receptors of many aeroallergens
91Middleton’s Allergy. 8tt ttttttt
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92Nature Medicine 19, 977–979 (2013)
Cytokines
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94Nature Reviews Immunology 2, 132-138, 2002
Neutrophil chemotaxis
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Middleton’s Allergy. 8tt ttttttt
Growth factors
Airway remodeling
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Stephen T. Holgate and Donna E. Davies.
Immunity.2009
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97Clare M. Lloyd and Catherine M. Hawrylowicz. Immunity, 2009.
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Conclusion • Respiratory mucosal immunology is action of epithelial, innate,
and adaptive immune mechanisms, which consist of cellular and humoral components.
• The respiratory tract mucosa is continuously exposed to many environmental components, most of which are harmless.
• The default pathway of mucosal immunity is development of tolerance, which is an active process that starts early in life and includes all major components of mucosal immunity.
• Disturbances in the epithelial barrier function and in epithelial and innate immune activation may break immunologic tolerance and prompt an allergic mucosal immune response.