Transcript Mast cell-orchestrated immunity to pathogens

Mast cell-orchestrated immunity
to pathogens
Soman N. Abraham and Ashley L. St. John
Nature Reviews Immunology
June 2010
Sentinels of host defence
• Host-environment interface
Blood vessels
Neurons
Sentinels of host defence
• Host-environment interface
Lymphatic vessels
Dendritic cells
Mast cell mediators
Carboxy
peptidase
Leukotrienes
Prostaglandins
Chymase
Platelet
activating
factor
Lipid
derived
Proteases
Tryptase
TNF
IL-5
Chemokines
IL-12
Bactericidals
VEGF
Histamine
IL-6
Cytokines
IL-4
IL-3
Heparin
Serotonin
Mast cell heterogeneity
• Different types – mucosal and connective tissue
• Different granule composition - proteases
• Different stimuli- IL4, Il10
• Different receptors (C5aR)
• Different response to stimuli – cytokine,
phenotype
Recognition of pathogens
• Recognize PAMPs by PRR – TLR , Fc receptors, others
• TLR heterogeneity
• Direct and indirect recognition
• Pathogen associated substance – mastoparan, vector borne
• Endogenous inflammatory factors – neurotensin, substance P,
endothelin 1, complement; feedback mechanism
• IgG and IgE, cross linking, superantigens
Two waves of mediator release
Nature, duration, specificity
• 1) Degranulation – temporal
advantage
• Some soluble, most insoluble
• Insoluble: slow, prolonged release
• Long distance delivery
• 2) De novo synthesis
Cytokines
Mediator functions
• Protease: Neutrophil recruitment
• Leukotrienes: rolling and extravasation through
chemotaxis
• Prostaglandins: Vascular permeability, mucus,
nerve cells
• Cytokines: chemotaxis, bactericidal killing,
feedback
Effector functions in immunity
Innate
• Vascular permeability, oedema
• Immune cell recruitment
• Bactericidals: cathelicidins,
reactive O2
• Impede colonization, physical
expulsion
Adaptive
• Activation and Ag presentation
of DCs
• Cell trafficking to draining
lymph nodes
• Lymph node hypertrophy TNF
• Antigen presentation
• Sensitization to Ag –
immunological memory
1. Parasites
• First study – helminths.
Mast cell proliferation
• Immune cell recruitment,
gut permeability, parasite
expulsion
• Primary vs. secondary
challenge
• Leishmaniasis: T cell
function, lesion size
2. Bacteria
• Mouse model, peritonitis
• Bacterial containment, prevention of dissemination
• E. coli from peritoneum, bladder; K. pneumoniae from lungs; P.
aeruginosa lesions
• Cell trafficking, lymphocyte retention
3. Viruses
• Less clear
• Poly I:C: chemokines
• CD8+ T cells, NK cells
• Induced cytokine release
• Cell mediated clearance
Mast cells in vaccines
• Enhancing adaptive immune response
• Adjuvant activity
• Mast cell activator (48/80) – humoral immunity
• IgA production, mucosal immunity
• Cellular mobilization, communication with
draining lymph nodes
Conclusions
• Adaptive and innate immunity against pathogens
• Kinetic advantage
• Immunological memory
• Functional outcome of heterogeneity
• Long distance communication strategy
• Vaccine design