respiratory mucosal immunity

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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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

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Respiratory tract epithelial cell

Component of the innate immune system

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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

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Tissue-resident cellsHigh phagocytic capacity

MacrophageMacrophage

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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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MacrophageMacrophage

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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

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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)

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

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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

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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

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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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• Primary produced by epithelium• B2,3,4 defensins

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• Primary produced by invading neutrophils under inflammatory conditions

• Human neutrophils peptides: HNP-1, HNP-3

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• 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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Pulmonary surfactant proteins Pulmonary surfactant proteins

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• Stability• Metabolism

Pulmonary surfactant proteins Pulmonary surfactant proteins

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• 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

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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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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.