Immunology sentinel cells, PRRs, PAMPS, DAMPs, and intracellular signaling

sentinel cells

continuously monitor tissues for infection and damage, serving as the first line of immune detection

pattern recognition receptors (PRRs)

germ-line encoded receptors that recognize conserved microbial structures (PAMPs) and endogenous danger signals (DAMPs)

PAMPS

conserved aspects of microbial molecules such as LPS, flagellin, dsRNA, and umethylated CpG DNA

DAMPs

include host-derived molecules that signal sterile cellular damage (apotosis>necrosis)

PRR engagement initiates

intracellular signaling cascades involving adaptor proteins like MyD88, TRIF, MAVS

key transcriptional factors activated by PRR signaling include

NF-k8

IRF-3/7

Ap-1

which regulate expression of inflammatory cytokines, interferons, and antimicrobial peptides

jak/stat signaling

main downstream pathway of many cytokine receptors activated during PRR signaling, and is targeted therapeutically in chronic inflammatory diseases

sentinel cell activation results in

cytokine and chemokine release

upregulation of costimulatory molecules used in adaptive immunity

recruitment of leukocytes and antigen presentation cells

dysregulated PRR signaling contributes to disease states

autoimmunity

autoinflammatory syndromes

sepsis

chronic inflammatory conditions

therapeutic exploitation of PRR pathways

vaccine adjuvants (TLR agonists)

immunotherapies

anti-inflammatory agents

when sentinel cell activated it initiates

1. cytokine and chemokine production

2. upregulation of costimulatory molecules and adaptive immune cell molecules (T cells)

3. type I IFN responses

   1. phagocytosis and ROS/nitric oxide production

macrophages

phagocytic cells derived from monocytes

resides in tissues where they ingest pathogens, present antigens, and release pro-inflammatory cytokines

dendritic cells

specialized antigen-presenting cells that link innate and adaptive immunity

upon sensing PAMPs, they migrate to lymph nodes and activate naive T cells

mast cells

found in mucosal and connective tissues

key in allergic responses

release histamine, proteases, and cytokines upon activation

innate lymphoid cells (ILC)

3 subsets

produce cytokines in response to infection and help shape adaptive immunity

skin sentinel cell

langerhans and macrophages

early antigen capture and inflammation

lung sentinel cells

alveolar macrophages and epithelial cells

antiviral responses and homeostasis

gut sentinel cells

dendritic cells, epithelial cells

tolerance vs immunity balance

CNS sentinel cell

microglia

neuroimmune surveillance

liver sentinel cells

Kupffer

blood filtration, endotoxin sensing