Mast cell-orchestrated immunity to pathogens Soman N. Abraham and Ashley L. St. John Nature Reviews...

Mast cell-orchestrated immunity to pathogens

Soman N. Abraham and Ashley L. St. JohnNature Reviews ImmunologyJune 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

Carboxypeptidase

Leuko-trienes

Prosta-glandins

Plateletactivating factor

TNF

IL-4

IL-5

IL-6

IL-3

IL-12 Histamine

SerotoninHeparin

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

InnatInnatee

AdaptiveAdaptive

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