Immune cells in the lung - Lungeninformationsdienst

Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14

immunity • from immunis, Latin for "exempt“ • capability of the body to resist harmful microbes from entering it • Immunity involves both specific and nonspecific components

immunity

Innate vs. adaptive immunity Innate immune system

Adaptive immune system

non-specific response

pathogen and antigen specific response

highly conserved pattern recognition receptors (PRRs) immediate maximal response (hours)

highly specialized, variable receptors lag time between exposure and maximal response (days)

cell-mediated and humoral components no immunological memory

cell-mediated and humoral components

found in nearly all forms of life

found only in jawed vertebrates

immunological memory

Adaptive immune response

Innate and adaptive immunity 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

The immune system: overview

Antigen presentation

Complement system

Complement system

"Janeway's Immunobiology"

Lymphatic organs Tonsils and adenoids Lymph nodes Lymphatic vessels Thymus Lymph nodes Spleen Peyer’s patches Appendix Lymph nodes Bone marrow

Primary lymphatic organs:

Lymphatic vessels

generation of lymphocytes bone marrow, thymus

Secondary lymphatic organs:

initiation of adaptive immune responses lymphnodes, spleen;MALT

Haematopoetic system

Macrophages – frontline of innate immune defense

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

Macrophages • 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 - scavengers

© Dr Dennis Kunkel

• 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

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

PBMo

lung DC

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 enzymes 2) 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 fibers bind 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

A) Inactive neutrophils

B) active neutrophils

E) extracellular NETs

Bacteria trapped in NETs A) Staphylococcus aureus B) Salmonella typhimurium Young et al. PlosONE 2011

• 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

www.laborlexikon.de

Eosinophils

Eosinophils – Asthma bronchiale Bronchus Knochenmark Antigen

Mastzelle

Eosinophiler Granulozyt

TH 2-Zelle BronchialSchaden

Interleukin-4 GM-CSF Interleukin-5

Histamin Leukotriene IL-4, IL-13

Granula-Proteine Leukotriene Verlängertes Überleben IL-13

Chemokine (RANTES, Eotaxin, MCP-1, MIP-1α )

Selektin VCAM-1 ICAM-1

Diapedese Adhäsion Endothelium

Blut 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) • 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

Lambrecht & Hammad, 2003

Dendritic cells Main function: Antigen presenting cell (APC)

Lambrecht & Hammad, 2003

Dendritic cells • Secondary immune response:

Lambrecht & Hammad, 2003

Dendritic cells

• 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 (DC) pattern recognition receptors (TLR 2,4,7,9...)

integrins (CD11b, CD11c)

MHC class II

maturation

antigen presentation MHC class II  co-stimulatory CD80/CD86  phagocytosis capacity  T cell stimulation  antigen uptake

immature DC

mature DC

Antigen presentation via MHC-molecules MHC= major histocompatibility complex; repertoire differs between individuals MHC Class II MHC Class I

CD8+

CD4+

Killing

Activation

Endogenous Antigens

MHC I: ubiquitous expr.

Exogenous Antigens

MHC II: professional APC

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

Phagocytosis

Endocytic pathway

Postranslational modifications

Secretory pathway

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

T lymphocytes Helper T cell (Th-CD4+)

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

Cytotoxic T cell (Tc-CD8+)

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

T helper cells

T helper cells

T helper cell subtypes

Dysbalance between the subtypes => (chronic) imflammatory diseases Février et al., Viruses, 2011

Cytotoxic T cells

Regulatory T cells Regulatory T cells

Effector T cells

homeostasis

inflammation

inflammation

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

Regulatory T cells Mode of action

Valadi et al., Nature Reviews Immunology, 2008

B lymphocytes

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

en.wikipedia.org

Antibodies

Antibody functions

austincc.edu

Antibody classes

Thank you for your attention!

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