Immune cells in the lung

Nunja C. Habel-Ungewitter & Sabine Bartel12.11.14

immunity

• from immunis, Latin for "exempt“• capability of the body to resist harmful

microbes from entering it• Immunity involves both specific and non-

specific components

immunity

Innate vs. adaptive immunity

Adaptive immune response

Innate• skin/mucosal tissues• Complement System• Antimicrobial Peptides• Phagocytes (Macrophages,

PMNs, Monocytes, DCs)

• Adaptive Immune System Activation

Acquired (Adaptive)• B Lymphocytes

-Antibodies• T Lymphocytes

-Cytotoxicity -Cytokine Secretion -B cell Activation

Innate and adaptive immunity

The immune system: overview

Antibody productionOpsonization

Antigen presentation

Complement system

Complement system

"Janeway's Immunobiology"

Primary lymphatic organs: generation of lymphocytes

bone marrow, thymus

Secondary lymphatic organs: initiation of adaptive immune responses

lymphnodes, spleen;MALT

Tonsils and adenoids

Lymph nodes

Bone marrow

Appendix

Lymphatic vessels

Lymph nodes

Thymus

Peyer’s patches

Spleen

Lymphatic vessels

Lymph nodes

Lymphatic organs

Haematopoetic system

Macrophages – frontline of innate immune defense

J Clin Invest. 2002;110(11):1603-1605. doi:10.1172/JCI17302

• Named by Elie Metchnikoff : „microorganims can be engulfed and digested by phagocytic cells“

• Progenitor in the blood: monocytes– Different in the lung: self renewal, proliferation

• Resident in tissue – Alveoli alveolar macrophages– interstitium

• Relatively long-lived (ca. 40% in 1 year)

• Frontline/first line of antigen recognition and defense !

Macrophages

Macrophages - scavengers• Professional phagocytes: engulf and kill invading pathogens (microorganism, particles) cell debris and infected cells distinguish between „dangerous“ and „harmless“ antigens• Equipped with pattern recognition receptors and can rapidly produce proinflammatory cytokines and chemokines

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Bliska&Casadevall Nat. Reviews

Microbiology2009

Depletion of alveolar macrophages impairs neutrophil emigration after LPS

impaired neutrophil evasion after alveolar macrophage depletion (open bars) in response to intratracheal LPS stimulation

Maus et al., AJP Lung 2002

Recruitment of immune cells by macrophages

Monocytes

• 5-8 %• many lysosomes• Differentiate into lung DC and Macrophages

lung M

lung DC

PBMo

Recruitment of monocytes

Granulocytes/polymorphonuclear leukocytes

• Cytoplasmic granules• Irregularly shaped nuclei• Short lived

Neutrophils (PMN)

• The main effector of innate immunity (55-70%)

• Phagocytes

• Kills the pathogens mainly by ROS and enzymes (e.g., neutrophil elastase)

• 2 types of vesicles:1) lysosomal enzymes2) collagenase and lactoferrin (toxic)

• Become apoptotic after some hours to days or after phagocytosis of pathogen

Leukocyte emigration to the lung: Adhesion molecules

Neutrophils-NETosis

• Release of granule proteins and chromatin extracellular fibersbind gram-pos. and –neg. bacteria

• NETs: neutrophil extracellular traps degradation of virulence factors, kill bacteria

Neutrophil Extracellular Traps Kill Bacteria ; Brinkmann et al. Science 2004

immunopaedia.org

Neutrophils-NETosis

Young et al. PlosONE 2011

A) Inactive neutrophils B) active neutrophils E) extracellular NETs

Bacteria trapped in NETsA) Staphylococcus aureus B) Salmonella typhimurium

Eosinophils

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• 2-5% of leukocytes• Granules: enzymes & toxic proteins• Important for defense against parasites• MBP: major basic protein

• Attack surfaces that are marked with IgE (cells or parasites)

• Involved in allergic inflammatory reactions

• Also important role in attacking the mucosa and the airway epithelium in asthma

Eosinophils – Asthma bronchialeBronchus

Antigen

Knochenmark

EosinophilerGranulozyt

TH 2-Zelle

Bronchial-Schaden

Granula-ProteineLeukotriene

IL-13

Verlängertes Überleben

Interleukin-4GM-CSFInterleukin-5

Selektin

VCAM-1ICAM-1

Adhäsion

Endothelium

Blut

Diapedese

Chemokine(RANTES, Eotaxin,

MCP-1, MIP-1α )

HistaminLeukotrieneIL-4, IL-13

Mastzelle

NEJM 344, 350-362, 2001

Basophils

• Less than 1% of Leukocytes

• Contain histamine and heparin

• Proteolytic enzymes

• Fast immune reaction; external antigens (asthma, hay fever)

Mast cells

• only in tissue and mucosa • bind IgE on their surface

• degranulate among antigen contact and release histamin, leukotrienes etc. from their granulas

• main cells which confer acute allergic symptoms (swelling, bronchial obstruction) in acute asthma etc.

Mast cells - activation

Bischoff 2007

Asthma bronchiale

cross-linking of membrane-bound IgE by allergenes

Activation

Release of:

histamine, leukotrienes, proteoglycans

cytokines (IL-1,2,3,4,5, TNF-α, GMCSF)

early response

bronchial spasm

oedema

bronchial obstruction

late response

mucosal inflammation

bronchial obstruction

bronchial hyperreactivity

development of matrix

Dendritic cells (DC)

Lambrecht & Hammad, 2003

• Myeloid and lymphoid progenitors (small subpopulation); lat. dendriticus = branched (verzweigt)

• Key cells: link innate with adaptive immunity• Immature DCs: phagocytic - enter tissue & mature after pathogen encountering

Dendritic cells

Lambrecht & Hammad, 2003

Main function: Antigen presenting cell (APC)

Dendritic cells• Secondary immune response:

Lambrecht & Hammad, 2003

• Mature DCs shape t-cell response (Hammad & Lambrecht, J Allergy Clin Immunol 2006) :

• Which type of t-cells is activated?• Different Ils or different

concentrations• Defines tolerance vs. Immunity• Immature DCs cannot activate

naive T cells.

Dendritic cells

Dendritic Cells (DC)

integrins(CD11b, CD11c)

pattern recognition receptors

(TLR 2,4,7,9...)

antigen uptake

immature DC

maturation

antigen presentationMHC class II

co-stimulatory CD80/CD86 phagocytosis capacity

T cell stimulation

mature DC

MHC class II

MHC Class I

MHC Class II

CD4+ CD8+

Endogenous Antigens Exogenous Antigens

MHC I: ubiquitous expr. MHC II: professional APC

MHC= major histocompatibility complex; repertoire differs between individuals

Killing Activation

Antigen presentation via MHC-molecules

Antigen presenting cells

MHCII expression :Constitutive on all professional APCs costimulatory molecules

– present to CD4+ helper T-cells– HLA-DR, DP, DQ

MHC I expresion:Constitutive on all nucleated cells

– present to CD8+ cytotoxic T-cells– HLA (Human Leukocyte

Antigen)A, B, C

Peptide loading of MHC molecules

Postranslational modifications

Secretory pathway

Endocytic pathway

Phagocytosis

Cross presentation of soluble antigen on MHC class I

Mainly in dendritic cells => activation and recruitment of CD8+ T cells

Interaction of MHC- molecules with T-cell receptors

Small T-cell subpopulation: γδ-TCR => much less variable repertoire: 103 vs. 1015 (αβ)

Interaction of MHC- molecules with T-cell receptors

Signals required for activation:

1.Antigen-specific binding TCR-MHC

2.Co-stimulatory molecules (e.g. CD28 interaction with CD80/CD86 (B7) or ICOS with ICOS-L)

3.Cytokines (IL-4, -15, -12 or TGF-ß)

Gutcher et al., JCI, 2007

Haematopoetic system

T lymphocytes

Helper T cell (Th-CD4+) Cytotoxic T cell (Tc-CD8+)

Activated helper T cell– “The Bureaucrat”– Directs other cells– Uses cytokines as its “memos”

Activated killer cell– “The Hitman”– Kills on contact– Also produces cytokines (IFN-,

TNF-

T lymphocytes

T helper cells

T helper cells

T helper cell subtypes

Février et al., Viruses, 2011

Dysbalance between the subtypes => (chronic) imflammatory diseases

Cytotoxic T cells

Regulatory T cells

Regulatory T cellsEffector T cells

homeostasis

inflammation inflammation

Image derived from Bouma & Strober et al., Nature Reviews Immunology,

Mode of action

Regulatory T cells

Valadi et al., Nature Reviews Immunology, 2008

en.wikipedia.org

B lymphocytes

Establishment of a first, antibody-mediated immune response: ~ 7daysSecondary immune response: ~3 days

Antibodies

Antibody functions

austincc.edu

Antibody classes

Thank you for your attention!

„Es war einmal das Leben“, Albert Barillé, 1978-1995