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