4 Inflammation and Its Mediators Flashcards
Responsible for elimination of pathogens in subsequent phases of infection
Adaptive immune system
Responsible for maintenance of immunological tolerance
Adaptive immune system
T/F Adaptive immunity exists only in vertebrates
T
Cells that recognize altered self
NK cells
Neutrophilic granules that contain lysozyme, elastase, and collagenase
Specific granules
Lysosomes that contain enzymes and microbicidal substances found in the cytoplasm of neutrophils
Azurophilic granules
Most prevalent cell type in the early phases of antimicrobial response
Neutrophils
Dominant effector cells in the later stages of inflammation
Recruited monocytes-macrophages
Within ___ days, neutrophils are almost completely replaced by monocytes-macrophages
1-2
T/F PAMPs are essential for microbial survival
T
PRR: Characterized by extracellular leucine-rich repeat (LRR) domain and intracellular Toll IL-1 receptor (T1R) domain
TLR
Number of TLRs identified in humans
13
TLR: Expressed at the cell surface and mainly recognize bacterial products unique to bacteria
TLR 1,2,4,5,6,10
TLR: Located almost exclusively in intracellular compartments, including endosomes and lysosomes
TLR 3,7,8,9,11,12,13
PAMP-origin-PRR-main effector function: LPS
G-bacteria; TLR4, CD14; macrophage activation
PAMP-origin-PRR-main effector function: Unmethylated CpG nucleotides
Bacterial DNA; TLR9; macrophage, B-cell, plasmacytoid cell activation
PAMP-origin-PRR-main effector function: Terminal mannose residues
Microbial glycoprotein and glycolipids;
1) Macrophage mannose receptor; phagocytosis
2) Plasma MBL; complement activation opsonization
PAMP-origin-PRR-main effector function: LPS, dsRNA
Bacteria, viruses; Macrophage scavenger receptor; Phagocytosis
PAMP-origin-PRR-main effector function: Zymosan
Fungi; TLR2, Dectin-1; Macrophage activation
PAMP-origin-PRR-main effector function: dsRNA
Viral; TLR3, RIG-I; IFN Type I production
PAMP-origin-PRR-main effector function: ssRNA
Viral; TLR7/8, MDA5; IFN Type I production
PAMP-origin-PRR-main effector function: N-formylmethionine residues
Bacteria; Chemokine receptors; Neutrophil and macrophage activation and migration
PAMP-origin-PRR-main effector function: MDP
G+ and G- bacteria; NOD2, NALP1; Macrophage activation
TLR located in both cell surface and endolysosomal compartment
TLR4
TLR-Ligand: TLR1
Lipopeptides
TLR-Ligand: TLR2
Zymosan, peptidoglycans, lipoteichoic acids, lipoarabinomannan, porins, envelope glycoproteins
TLR-Ligand: TLR3
dsRNA
TLR-Ligand: TLR4
LPS, lipoprotein, HSP60 (chlaymida), fusion protein (RSV)
TLR-Ligand: TLR5
Flagellin
TLR-Ligand: TLR6
Diacyl lipopeptides (mycoplasma), lipoteichoic acid (G+ bacteria)
TLR-Ligand: TLR7&8
ssRNA and short dsRNA
TLR-Ligand: TLR9
Unmethylated CpG DNA
TLR-Ligand: TLR10
Unknown
TLR-Ligand: TLR11
Profilin and flagellin (apicomplexan parasites)
TLR-Ligand: TLR12
Profilin (apicomplexan parasites)
TLR-Ligand: TLR13
Bacterial 23S rRNA (G- bacteria)
Key cell types expressing TLRs
APCs (including macrophages, DCs, and B lymphocytes)
Cytosolic receptors that function in pattern recognition of viral and bacterial pathogens
1) NLRs (NOD-like receptors)
2) RLRs (RIG-I-like receptors)
NLRs consists of
N-terminal effector region
Centrally located NOD (or NACHT)
C-terminal LRR that sense PAMPs
Makes up the N-terminal effector region of NLRs
CARD or Pyrin domain or Acidic domain or BIRs
NLRs containing a pyrin domain
NLRPs
Most well-characterized among NLRs
1) NOD family
2) NLRPs
NODs that are involved in sensing bacterial molecules derived from synthesis and degradation of peptidoglycan
NOD1 and NOD2
NOD that recognizes diaminopimelic acid produced primarily by G- bacteria
NOD1
NOD that recognizes muramyl dipeptide (MDP), a component of both G+ and G- bacteria
NOD2
T/F DAMPs also activate PRRs
T
Receptors on macrophage surface
1) PRR
2) CD40
3) Fc and complement receptors
DAMPs released during necrotic or inflammatory based cell death
Alarmins
Calcium-binding proteins expressed in the cytoplasm of phagocytes and secreted by activated monocytes and neutrophils
Calgranulins (S100A8, S100A9, and S100A12)
3 major downstream signaling pathways responsible for mediating TLR-induced responses
1) NF-κB
2) MAPKs
3) IRFs
Downstream signaling pathways: Play central roles in induction of a proinflammatory response
1) NF-κB
2) MAPKs
Downstream signaling pathways: Essential for stimulation of IFN production
IRFs
MAPK-activated pathways
p38, JNK, ERK
TLR signaling pathway that induces the early-phase NF-κB and MAPK activation that controls the induction of proinflammatory cytokines
MyD88-dependent signaling pathway
TLR signaling pathway that activates IRF3, which is required for induction of IFN-β and IFN-inducible genes
MyD88-independent signaling pathway
TLR signaling pathway that mediates the late-phase NF-κB and MAPK activation
MyD88-independent signaling pathway
Th1- vs Th2-related cytokines: IFN-γ
Th1
Th1- vs Th2-related cytokines: Polarize macrophages to an M1 phenotype
Th1
Th1- vs Th2-related cytokines: IL-4
Th2
Th1- vs Th2-related cytokines: IL-13
Th2
Th1- vs Th2-related cytokines: Polarize macrophages to an M2 phenotype
Th2
M1 vs M2 macrophages: Dampen inflammation
M2
M1 vs M2 macrophages: Promote tissue remodeling and repair
M2
M1 vs M2 macrophages: Help in parasite clearance
M2
M1 vs M2 macrophages: Suppress tumor immunosurveillance
M2
T/F A single macrophage can change between M1 and M2 phenotype function in response to changes in the local environment
T
Interferons are a treatable target using
1) Monoclonal Ab that blocks either the cyokine or receptor
2) JAKi that blocks IFNAR (Type 1 IFN receptor) signaling
Protein complex responsible for production of biologically active IL-1 (i.e. secretion of mature IL-1β and IL-18)
Inflammasome
NLR that has been ascribed a role in recognition of uric acid crystals
NLRP3
Components of inflammasome
1) Adaptor ASC
2) Procaspase-1
3) An NLR
Mutations in the NLRP3 and NLRC4 genes in humans are associated with disease characterized by excessive production of IL-1β and IL-18, which are called
Autoinflammatory diseases
Activated vs inactive pyrin: Phosphorylated form
Inactive or blocked form
Distinct subtype of DCs that display unique capacity to secrete large amounts of type I IFN (α/β) in response to certain viruses and other stimuli
pDCs aka plasmacytoid interferon producing cells
Trigger TLR7&9 expressed by pDCs, leading to type I IFN production
Viral nucleic acids
Self-nucleoproteins internalized in the form of immune complexes
Diseases with increased Type I IFN signaling, hence pDCs have been implicated in their pathophysiology
SLE, JDM
First signals for gene expression and synthesis of inactive IL-1β and IL-18 precursors in the canonical activation of inflammasome
TLR ligands
Second signals for gene expression and synthesis of inactive IL-1β and IL-18 precursors in the canonical activation of inflammasome
Exogenous ATP OR mitochondrial ROS
Protein mutated in FMF (gain of function mutation) that is able to form with ASC and caspase 1 its own inflammasome
Pyrin (aka MEFV)
Activates the serine-threonine kinases PKN1 and PKN2 that phsophorylate and block pyrin
GTPase RhoA
Pyrin inflammasome activation inactivates ___ resulting in dephosphorylation of pyrin
GTPase RhoA
2 major subsets of NK cells are identified according to
Level of expression of CD56: CD56dim and CD56bright
CD56dim vs CD56bright: 90% of NK cells in peripheral blood
CD56dim
CD56dim and CD56bright: Immature
CD56bright
CD56dim and CD56bright: Plays a major role in cytokine production
CD56bright
CD56dim and CD56bright: Better able to leave the circulation
CD56bright
CD56dim and CD56bright: Constitutes majority of NK cells in lymphoid organs
CD56bright
Binds with inhibitory receptor on NK cell
MHC I
Leads to loss of MHC I expression of cell, thereby lack of ligand for inhibitory receptor of NK cell leading to killing of the affected cell
Viral infection
Receptors on NK cell
Activating receptor
Inhibitory receptor
Fc receptor (FcγRIIIa)
Potent inducer of NK cell IFN-γ secretion and cytolytic activity
IL-12 produced by macrophages
Cytokine secreted by NK cell that further activates macrophages to kill phagocytosed microbes
IFN-γ
Lymphoid derived cells with effector functions that parallel that of T cells but do not bear a T cell receptor and instead respond to stimuli in an innate-like fashion
Innate lymphoid cells (ILCs)
Innate lymphoid cells (ILCs): Produce cytokines typically associated with Th1 T-cell responses
Group 1 ILCs
Innate lymphoid cells (ILCs): Share many of the effector functions of CD4+ Th2 cells
Group 2 ILCs
Innate lymphoid cells (ILCs): Have cytotoxic functions like CD8+ T cells
Group 1 ILCs
Innate lymphoid cells (ILCs): Predominate in the intestinal mucosa and may contribute to IBD
Group 3 ILCs
Innate lymphoid cells (ILCs): NK cells are a major component of this group
Group 1 ILCs
Innate lymphoid cells (ILCs): Thought to be important in antihelminthic responses
Group 2 ILCs
Innate lymphoid cells (ILCs): Express the transcription factor RORγT
Group 3 ILCs
Innate lymphoid cells (ILCs): Make IL-17 and IL-22 much like Th17 cells
Group 3 ILCs
Innate lymphoid cells (ILCs): Found in synovial fluid of children with JIA
Group 3 ILCs
Pathway of complement activation: Activated by direct binding of C3b to microbial cells
Alternative pathway
Pathway of complement activation: Activated by binding of C1 to CH2 domains of IgG or CH3 domains of IgM that have bound antigen
Classical pathway
Pathway of complement activation: Activated by direct recognition of carbohydrate or acetylated PAMPs by MBL and ficolins
Lectin pathway
3 pathways of complement activation converge upon this central protein
C3
Type 1 vs type 2 complement receptor: CR1
Type 1
Type 1 vs type 2 complement receptor: CD35
Type 1
Type 1 vs type 2 complement receptor: CR2
Type 2
Type 1 vs type 2 complement receptor: CD21
Type 2
Type 1 vs type 2 complement receptor: Expressed by almost all blood cells
Type 1
Type 1 vs type 2 complement receptor: Present on B lymphocytes and follicular DCs of LN germinal centers
Type 2
Type 1 vs type 2 complement receptor: Mainly functions as co-receptor for B cell activation by antigen
Type 2
Type 1 vs type 2 complement receptor: Promotes phagocytosis of C3b coated microbes
Type 1
Type 1 vs type 2 complement receptor: Mainly functions to stimulate trapping of antigen-antibody complexes in germinal centers
Type 2
Complement receptor expressed on RBCs that bind to immune complexes with attached C3b thereby transporting these complexes to the liver and spleen where they are removed from the erythrocyte surface and cleared
CR1
Complement receptors that are members of the integrin family and are expressed by innate immune system cells
Type 3 and 4 complement receptors
Complement receptors that promotes activation of innate cells resulting in phagocytosis of microbes opsonized with C3b
CR3 and CR4
Complement receptor: Clearance of immune complexes
CR1 (CD35)
Complement receptor: Receptor for EBV
CR2 (CD21)
Complement receptor: Adhesion to endothelium via ICAM
CR3 (CD11b/CD18)
Deficiency of this complement component is associated with serious pyogenic infections
C3
Defects of this complement component is associated with increased risk of disseminated Neisseria infections
Terminal complement components C5-C9
Deficiency of this protein, which functions to regulate the proteolytic activity of C1, the initiator of the classical pathway, causes hereditary angioedema
C1 inhibitor
Characterized by excess alternative pathway activation leading to C3 consumption and glomerulonephritis
Deficiency of factor H
Adhesion molecules constitutively expressed on circulating leukocytes that ensures firm adherence of leukocytes to endothelial cells
Integrins
Weak adhesion of leukocytes to the endothelium
Rolling
Adhesion molecule-cell distribution-ligand-main function: P-selectin
Activated endothelium; sialyl lewis x; initiate leukocyte-endothelium interaction
Adhesion molecule-cell distribution-ligand-main function: E-selectin
Platelets; PSGL-1; -
Adhesion molecule-cell distribution-ligand-main function: L-selectin
Activated endothelium & leukocytes; GlyCAM-1, CD34, MADCAM-1; -
Adhesion molecule-cell distribution-ligand-main function: VLA4-5
Leukocytes; JAM-B; homing to inflamed tissue
Adhesion molecule-cell distribution-ligand-main function: LFA-1
Leukocytes; ICAM-1/3, JAM-A; Leukocyte adhesion to endothelium
Adhesion molecule-cell distribution-ligand-main function: VE-cadherin
Endothelium lateral junctions; VE-cadherin; cell to cell adhesion
Adhesion molecule-cell distribution-ligand-main function: VLA-4
Leukocytes; VCAM-1; leukocyte adhesion to endothelium
Cytokines are classified in these 5 main categories
1) Interleukins
2) Interferons
3) Pro- and anti-inflammatory cytokines
4) Chemokines
5) Growth factors
Interleukins
IL-2,4,5,7,12,13,15,18,23
Proinflammatory cytokines
IL-1α, IL-1β, TNF-α
IL-6,17,22
Antiinflamatory cytokines
IL-10, TGF-β
Interferons
Type I IFNs: IFNα, IFNβ
IFNγ
T/F Cytokines typically act locally in autocrine or paracrine fashion
T
Endocrine functions of TNF
1) Stimulate the hypothalamus to induce fever
2) Stimulate hepatocytes to produce acute phase reactants
3) Promote metabolic changes leading to cachexia
Proinflammatory cytokine which plays a major role in septic shock
TNF
Major source of TNF
Activated macrophages
Major source of IL-1
Activated macrophages
Interleukins, main biological effect: Synthesis of IFN-γ by T cells and NK cells
IL-12 and IL-18
Interleukins, main biological effect: Differentiation of Th17 cells
IL-23
Interleukins, main cell source: Il-12
Th2 cells, B cells, DC, macrophages
Interleukins, main cell source: IL-23
DC
Proinflammatory cytokines, main biological effect: Fever
IL-1, IL-6, TNF-α
Proinflammatory cytokines, main biological effect: Acute phase reactants
IL-1, IL-6, TNF-α
Proinflammatory cytokines, main biological effect: Cachexia
TNF-α
Proinflammatory cytokines, main biological effect: Activation of endothelial cells
IL-1, TNF-α, IL-17
Proinflammatory cytokines, main biological effect: B cell proliferation
IL-6
Antiinflammatory cytokines, main biological function: Suppression of macrophage function
IL-10
Antiinflammatory cytokines, main biological function: Inhibition of T and B cells
TGF-β
Interferons, main biological function: Antiviral response
Type I IFN
Interferons, main biological function: Activation of NK cells
IFN-α,β,γ
Interferons, main biological function: Induction of MHC-I on somatic cells and MHC-II on APCs
IFN-γ
Chemokine, main function: Angiogenesis
CXCL7
Chemokine, main function: HIV coreceptor
CCL4
Chemokine, main function: Allergy
CCL11
Chemokine, main function: Lymphocyte homing to lymphoid organs
CXCL13
Chemokine, main function: T cell migration to skin
CCL25 and 27
Chemokine, main function: Brain inflammation
CX3CL1
Chemokine, main function: Lymphocyte trafficking and development
XCL1
IL-1 receptor: Constitutively expressed on many cell types
Type I
IL-1 receptor: Mediates intracellular signal transmission through IRAK, leading to NF-κB and AP-1 transcription factors
Type I
IL-1 receptor: Expressed only after cell activation
Type II
IL-1 receptor: Binding with IL-1 does not result in intracellular signal transmission
Type II
IL-1 receptor: Down-modulate biological action of IL-1 by acting as decoy receptor
Type II
2 strategies for IL-1 down-modulation
1) Binding to Type II receptor
2) Binding of IL-Ra (IL-1 receptor antagonist) to IL-1 receptors but is biologically inactive
IL closely related to IL-1β and is particularly associated with NLRC4 inflammasome
IL-18
A soluble factor that binds to IL-18 and prevents its ability to ligate and activate IL-18 receptor
IL-18BP
Stimulates synthesis of APRs by the liver and production and release of neutrophils from bone marrow
IL-6
Cytokine that plays a pivotal role in sJIA
IL-6
Chemokines produced by leukocytes and resident tissues in response to proinflammatory stimuli
Inflammatory chemokines
Chemokines constitutively expressed by in the microenvironment of lymphoid tissues, skin, and mucosa involved in continuous leukocyte trafficking between circulation and lymphoid structures
Homing chemokines
Responsible for the production of prostaglandins both in physiological and pathological conditions
COX
COX that is constitutively expressed in most tissues
COX-1
COX that is normally undetectable in normal tissues but can be rapidly induced in particular cell types
COX-2
Cell types where COX-2 can be induced upon proinflammatory stimulation
Fibroblasts, monocytes, endothelial cells
Most abundant COX-2 product
PGE2 and mast cell-derived PGD2
Prostaglandin that plays a crucial role in the induction of fever after stimulation of specialized endothelial cells in hypothalamic tissue by endogenous pyrogens
PGE2
Endogenous pyrogens
TNF and IL-6
Derived from the combined actions of 5-LOX and FLAP with initial formation of 5-HPETE
Leukotrienes
Main function of matrix metalloproteinases
Remodeling of ECM during tissue resorption
