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 Proteases Lipid derived Cytokines Chymase Tryptase Carboxy peptidase Leuko- trienes Prosta- glandins Platelet activating factor TNF IL-4 IL-5 IL-6 IL-3 IL-12 Histamine Serotonin Heparin VEGF Chemokines Bactericidals

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 2 ) De novo synthesis Cytokines 1) Degranulation – temporal advantage Some soluble, most insoluble Insoluble: slow, prolonged release Long distance delivery Nature, duration, specificity

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 Vascular permeability, oedema Immune cell recruitment Bactericidals: cathelicidins, reactive O2 Impede colonization, physical expulsion Activation and Ag presentation of DCs Cell trafficking to draining lymph nodes Lymph node hypertrophy - TNF Antigen presentation Sensitization to Ag – immunological memory Innate Adaptive

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