respiratory mucosal immunity
DESCRIPTION
Respiratory mucosal immunity Presented by Jaichat Mekaroonkamol, MD October03, 2014TRANSCRIPT
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
Respiratory system
Gastrointestinal tract
2010Natureimmunology
Respiratory tractRespiratory tract
5Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
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
Respiratory tractRespiratory tract
8Middleton’s Allergy. 8tt ttttttt
• Protection against dangerous antigens and effectively eliminate
• Tolerogenic immune response against harmless environmental components
Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
Epithelial cells
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
Airway epitheliumAirway epithelium
Mucus and Lung WaterMucus and Lung Water
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Fahy JV, Dickey BE. N Engl J Med 2010;363:2233-47.
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
Mucociliary systemMucociliary system
17Stark JM, Colasurdo GN. In Kendig's Disorders of the Respiratory Tract in Children;2006:205-23.
Respiratory tract epithelial cell
Middleton’s Allergy. 8tt ttttttt
Respiratory tract epithelial cell
Component of the innate immune system
Middleton’s Allergy. 8tt ttttttt
Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
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
GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
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
GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Tight junction associated MARVEL protein: TAMP
• Barrier regulation during inflammation
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
GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Deficiency: epithelial-mesenchymal transition (EMT) airway remodeling
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
GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Growth factors• Chemoattractants
• Cytokines
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
Middleton’s Allergy. 8tt ttttttt
Tissue-resident cellsHigh phagocytic capacity
MacrophageMacrophage
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
34Middleton’s Allergy. 8tt ttttttt
MacrophageMacrophage
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
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
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)
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)
Cell-associated Pattern Recognition Receptors (PRRs)
Cell-associated Pattern Recognition Receptors (PRRs)
Cell-associated Pattern Recognition Receptors (PRRs)
Cell-associated Pattern Recognition Receptors (PRRs)
Alveolar macrophages
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)
7Abbas immunology th edition
Epithelial cells•TLRs•NLRs
•CLRs (C-type lectin)•Protease-activated receptors
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)
Integrated human immune system
Turvey SE, Broide DH. J Allergy Clin Immunol 2010;125:S24-32.
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
The Complement System
The Complement System
7Abbas immunology th edition
Functions of complement
The Complement System
The Complement System
Complement deficiencyComplement deficiency
Middleton’s Allergy. 8tt ttttttt
Early complement component deficiencies
Antimicrobial peptides
Antimicrobial peptides
• - Broad spectrum a ntimicrobial prope
rties
• Formation of pore s in the bacterial c
ell wall
7Abbas immunology th edition
Antimicrobial peptides
Antimicrobial peptides
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
Middleton’s Allergy. 8tt ttttttt
• Primary produced by epithelium• B2,3,4 defensins
Middleton’s Allergy. 8tt ttttttt
• Primary produced by invading neutrophils under inflammatory conditions
• Human neutrophils peptides: HNP-1, HNP-3
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
Middleton’s Allergy. 8tt ttttttt
Pulmonary surfactant proteins Pulmonary surfactant proteins
Middleton’s Allergy. 8tt ttttttt
• Stability• Metabolism
Pulmonary surfactant proteins Pulmonary surfactant proteins
Middleton’s Allergy. 8tt ttttttt
• Antimicrobial peptides• Mannose binding protein: 3rd C’
• Opsonin
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
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
Holt PG et al, Nat Rev Immunol 8:142 (2008)
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.
78Patrick G. Holt et al. Nature Reviews Immunology, 2008.
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
84Brandtzaeg. Frontiers in Immunology, 2013.
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Topic OutlinesTopic Outlines
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GEORAS AND REZAEE. J Allergy Clin Immunol 2014;134:509-20.
• Growth factors• Chemoattractants
• Cytokines
Protease-dependent epithelial barrier dysfunction
Hamida Hammad and Bart N. Lambrecht. Nature Reviews Immunology , 2008.
89Middleton’s Allergy. 8tt ttttttt
90Hamida Hammad and Bart N. Lambrecht. Nature Reviews Immunology , 2008.
PAR: protease-activated receptor- Enzymatically active allergens can activate
• 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
92Nature Medicine 19, 977–979 (2013)
Cytokines
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94Nature Reviews Immunology 2, 132-138, 2002
Neutrophil chemotaxis
Middleton’s Allergy. 8tt ttttttt
Growth factors
Airway remodeling
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Stephen T. Holgate and Donna E. Davies.
Immunity.2009
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.