immune cells in the lung nunja c. habel-ungewitter & sabine bartel 12.11.14
TRANSCRIPT
![Page 1: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/1.jpg)
Immune cells in the lung
Nunja C. Habel-Ungewitter & Sabine Bartel12.11.14
![Page 2: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/2.jpg)
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
![Page 3: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/3.jpg)
immunity
![Page 4: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/4.jpg)
Innate vs. adaptive immunity
![Page 5: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/5.jpg)
Adaptive immune response
![Page 6: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/6.jpg)
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
![Page 7: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/7.jpg)
The immune system: overview
Antibody productionOpsonization
Antigen presentation
![Page 8: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/8.jpg)
Complement system
![Page 9: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/9.jpg)
Complement system
"Janeway's Immunobiology"
![Page 10: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/10.jpg)
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
![Page 11: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/11.jpg)
![Page 12: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/12.jpg)
Haematopoetic system
![Page 13: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/13.jpg)
Macrophages – frontline of innate immune defense
J Clin Invest. 2002;110(11):1603-1605. doi:10.1172/JCI17302
![Page 14: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/14.jpg)
• 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
![Page 15: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/15.jpg)
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
© D
r D
enni
s K
unke
l
Bliska&Casadevall Nat. Reviews
Microbiology2009
![Page 16: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/16.jpg)
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
![Page 17: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/17.jpg)
Recruitment of immune cells by macrophages
![Page 18: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/18.jpg)
Monocytes
• 5-8 %• many lysosomes• Differentiate into lung DC and Macrophages
lung M
lung DC
PBMo
![Page 19: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/19.jpg)
Recruitment of monocytes
![Page 20: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/20.jpg)
Granulocytes/polymorphonuclear leukocytes
• Cytoplasmic granules• Irregularly shaped nuclei• Short lived
![Page 21: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/21.jpg)
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
![Page 22: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/22.jpg)
Leukocyte emigration to the lung: Adhesion molecules
![Page 23: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/23.jpg)
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
![Page 24: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/24.jpg)
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
![Page 25: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/25.jpg)
Eosinophils
ww
w.la
borle
xiko
n.de
• 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
![Page 26: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/26.jpg)
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
![Page 27: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/27.jpg)
Basophils
• Less than 1% of Leukocytes
• Contain histamine and heparin
• Proteolytic enzymes
• Fast immune reaction; external antigens (asthma, hay fever)
![Page 28: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/28.jpg)
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.
![Page 29: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/29.jpg)
Mast cells - activation
Bischoff 2007
![Page 30: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/30.jpg)
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
![Page 31: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/31.jpg)
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
![Page 32: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/32.jpg)
Dendritic cells
Lambrecht & Hammad, 2003
Main function: Antigen presenting cell (APC)
![Page 33: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/33.jpg)
Dendritic cells• Secondary immune response:
Lambrecht & Hammad, 2003
![Page 34: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/34.jpg)
• 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
![Page 35: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/35.jpg)
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
![Page 36: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/36.jpg)
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
![Page 37: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/37.jpg)
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
![Page 38: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/38.jpg)
Peptide loading of MHC molecules
Postranslational modifications
Secretory pathway
Endocytic pathway
Phagocytosis
![Page 39: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/39.jpg)
Cross presentation of soluble antigen on MHC class I
Mainly in dendritic cells => activation and recruitment of CD8+ T cells
![Page 40: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/40.jpg)
Interaction of MHC- molecules with T-cell receptors
Small T-cell subpopulation: γδ-TCR => much less variable repertoire: 103 vs. 1015 (αβ)
![Page 41: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/41.jpg)
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
![Page 42: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/42.jpg)
Haematopoetic system
![Page 43: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/43.jpg)
T lymphocytes
![Page 44: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/44.jpg)
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
![Page 45: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/45.jpg)
T helper cells
![Page 46: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/46.jpg)
T helper cells
![Page 47: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/47.jpg)
T helper cell subtypes
Février et al., Viruses, 2011
Dysbalance between the subtypes => (chronic) imflammatory diseases
![Page 48: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/48.jpg)
Cytotoxic T cells
![Page 49: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/49.jpg)
Regulatory T cells
Regulatory T cellsEffector T cells
homeostasis
inflammation inflammation
Image derived from Bouma & Strober et al., Nature Reviews Immunology,
![Page 50: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/50.jpg)
Mode of action
Regulatory T cells
Valadi et al., Nature Reviews Immunology, 2008
![Page 51: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/51.jpg)
en.wikipedia.org
B lymphocytes
Establishment of a first, antibody-mediated immune response: ~ 7daysSecondary immune response: ~3 days
![Page 52: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/52.jpg)
Antibodies
![Page 53: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/53.jpg)
Antibody functions
austincc.edu
![Page 54: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/54.jpg)
Antibody classes
![Page 55: Immune cells in the lung Nunja C. Habel-Ungewitter & Sabine Bartel 12.11.14](https://reader036.vdocuments.net/reader036/viewer/2022062803/56649ce55503460f949b259a/html5/thumbnails/55.jpg)
Thank you for your attention!
„Es war einmal das Leben“, Albert Barillé, 1978-1995