Cytokines, immunology Flashcards
Type 1 Cytokines
IL-2, IFN-γ, IL-12, TNF-α
Type 2 Cytokines
IL-4, IL-5, IL-6, IL-13, IL-31
Type 17 Cytokines
IL-17, IL-21, IL-22, (IL-6, TNF-α)
Main pathogens fought by Th1
Viruses, intracellular pathogens (viruses, bacteria, protozoa, fungi)
Main pathogens fought by Th2
Multicellular Parasites, allergies, venoms
Main pathogens fought by Th17
Inflammation, extracellular pathogens (bacteria, fungi)
Activate neutrophils to throw NETosis
Cytokines to induce Th17
IL-23!!, TGF-β, IL-6
Cytokines to induce Th1
IL-12, IFN-γ
Cytokines to induce Th2
IL-4
Cytokines to induce TReg
TGF-β, IL-2
Cytokines to induce Th9
TGF-β, IL-4
IL-4 is produced by ____:
Th2 cells
Mast cells
Basophils
IL-4 induced conversion of Th0 to _____:
Th2 cells
IL-4’s role on Th1 cells
Suppression of Th1
(reduction of IL-2, IFN-γ)
IL-4’s role on Th17 cells
Suppression of Th17
IL-4’s role on B cells
Stimulates B cells to make IgG, IgE, MHC class II
IL-4’s role on macrophages
Activates macrophages
IL-4’s role on ILC2 cells
Activates ILC2 cells
Upregulates:
-IL-5
-IL-9
-IL-13
-CCL11 (eotaxin)
Main stimulator of eosinophils
IL-5
Cellular producers of IL-5
Th2 cells, mast cells, eosinophils
Cellular producers of IL-9
Th2 cells that are activated by IL-2, ILC2 cells, mucosal mast cells
Function of IL-9
-Promotes growth of helper T cells, mast cells
-Potentiates effect of IL-4 on IgE production
Cellular producers of IL-13
Th2, ILC2, Tfh13, NK, mast, DC2 cells
Functions of IL-13
Promotes Th2 response, suppresses Th1 and Th17 responses (similar to IL-4), activates eosinophils
Major cytokines produced by damaged epithelial cells or PAMPs on epithelial cells for Th2 response
-IL-25
-IL33
-TSLP
Cytokines that activate ILC2 cells
-IL-25
-IL33
-TSLP
Cytokines produced by ILC2 cells
IL-9 (mast cells, basophils)
IL-5 (eosinophil activation, recruitment)
IL-13 + IL-4 (B- cell production of Igs)
Which cytokine induces the IgM-IgG1-IgE pathway, where somatic mutation and selection occur to make high affinity IgE?
IL-13
(IL-4 alone induces IgM-IgE directly, which is lower affinity IgE)
What is present in Mast Cell granules?
- Histamine
- Serotonin
- Dopamine
- Kallikreins
- Proteases (tryptase, chymase)
- Proteoglycans (heparin, chondroitin sulfate)
- Neuropeptides
- Stored cytokines
What is synthesized by mast cells once activated?
- Leukotrienes
- Prostaglandins
- Platelet activating factor
- IL-1
- IL-3
- IL-4
- IL-5
- IL-6
- IL-9
- IL-13
- TNF-alpha
- TGF-beta
- SCF
- Chemokines
- Growth factors
- Neuropeptides
MHC for viral recognition
MHC class I
MHC expressed by infected cells
MHC class I
MHC for bacterial and allergen recognition
MHC class II
MHC expressed by dendritic cells
MHC class II
3 signals needed for naive T helper cells differentiation
1) MHC to TCR binding
2) Cell-Cell adhesion molecules (strong bond)
3) DC cytokines (ie IL-12 induces Th1)
Which cytokine is definitive for the Th1 response type?
IFN-gamma
Role of IFN gamma (type 2 interferon)
1) Activates M1, more MHC expressed on DC1s
2) Stimulates endothelial, keratinocytes, fibroblasts to secrete proinflammatory cytokines
3) Synergizes with TNF-alpha
JAK-1 dependent
Which cytokines are definitive of a Th2 response type?
IL-4, IL-13
Where is IL-4 produced? What’s its role?
Lymphoid organs, IgE production
Where is IL-13 produced? Whats its role?
Peripheral tissues, local allergic reactions
When are Th17 strongly produced?
Chronic inflammation
What is the function of Th17?
Trigger inflammation
B cell helpers
POTENT – need to balance Th17 with Treg
What makes ILC2 different from Th2?
Same cytokines, but ILC2 is present under body surfaces, not in lymphoid organs
Which cytokine does Th1 NEED for proliferation?
IL-2
Which cytokines do Th2 use for proliferation?
IL-2 OR IL-4 OR IL-1
(Does not depend on IL-2 like Th1 does)
Which hormones induce a Th2 response?
Low dose GCs
Beta agonists (catecholamines, bronchodilators)
**Also NaCl (activates NFAT5, higher Na in atopic skin than healthy skin, NaCl affects microbiome)
Which hormones induce a Th1 response?
Testosterone
Which hormones induce low Th1 and Th2 responses?
High dose GCs, estrogen, progestin
Which type of T cell lives in the lymph nodes and helps regulate B cell antibody production (crucial for high affinity IgE production and acute anaphylaxis)?
Follicular helper T cells
Which cytokine stimulates Tfh cells to help make high affinity IgE?
IL-13
T or F: Are IgE easily destroyed by heat?
True
SCF is produced by _____:
-Fibroblasts
-Endothelial cells
Role of SCF
Activates Mast cells, Mast cell survival signal, regulates IgE production
What does SCF bind to on mast cells?
KIT surface receptor
What are the 3 types of granules in eosinophils?
1) Crystalloid granules, large/ specific
2) Primary granules, small
3) Dense vesicles, small
What is inside the crystalloid granule CORE of eosinophils?
-Major basic protein
-Eosinophil peroxidase
What is inside the crystalloid granule MATRIX of eosinophils?
-Eosinophil cationic protein
-Eosinophil-derived neurotoxin
(both are ribonucleases)
Which animals do NOT have crystalloid granule cores?
Cows, mink
What is the role of major basic protein (MBP)?
1) Disrupts plasma membranes of nearby cells
2) Stimulates histamine release from MCs, basophils
3) Activates neutrophils, platelets
4) Stimulates superoxide dismutase from macrophages
5) toxic to bacteria, helminths
What is the most common eosinophil granule protein?
Major basic protein (MBP)
Which protein is the reason for eosinophils staining pink?
Eosinophil cationic protein (ECP)
What is the role of eosinophil cationic protein?
1) Damage cell membrane
2) mast cell degranulation
3) Kills bacteria, viruses, parasites
What is the role of eosinophil-derived neurotoxin?
1) Damages myelinated nerves
2) Chemoattractant for immature DCs
What is the role of eosinophil peroxidase? (EPO)
Oxidizing agent; kills ingested bacteria (YES! Eosinophils are APCs, MHC cl II)
Differentials for chronic eosinophilia
-FAD
-CAFR
-Parasites
-Adverse drug reaction
-Bronchial asthma
-ECG
-Eosinophilic enteritis
-MCT
-Lymphomas
3 ways mast cells can be triggered to degranulate
1) IgE-mediated
2) Non-IgE mediated (LPS, PRRs, Drugs, complement peptides, IgG+antigen, neuropeptides)
3) Mas-related G-protein coupled receptor X2 (MRGPRX2) (Substance P, neurotensin, cathelicidins, beta-defensins, major basic protein, eosinophil peroxidase) –> some degranulation, limited cytokine synthesis. SLOWER AND FEWER GRANULES RELEASED
Which cell type is crucial in mast-cell late-phase responses?
Th17
True or False: basophils are phagocytic, like eosinophils
FALSE. Basophils are NOT phagocytic
(Eos are though!)
Which cell type is more common in reptiles/ turtles than mammals?
Neutrophils
What cytokine is the main basophil activator (promotes basophil fate, survival)?
IL-3
What are the 2 pathways to degranulation in basophils?
1) IgE-mediated
2) TSLP-mediated
What products are released by basophils in IgE-mediated degranulation?
-IL-4
-Histamine
-PAF
-Leukotrienes
-Prostaglandins
-Proteases
-Substance P
What products are released by basophils in TSLP-mediated degranulation?
-IL-4
-IL-6
-IL13
-Histamine
-Chemokines
-Proteases
-Substance P
What are effects of H1R binding?
1) Increased NO –> vasodilation
2) Increased prostaglandins, leaky vessels –> edema, hives, nasal discharge, ocular tears
3) Itch/pain
What are the effects of H2R binding?
1) Increased gastric acid
2) Increased vasodilation –> hypotension
3) Increased TLR expression on sentinel cells with H2Rs
What are the effects of H3R binding?
1) Appetite regulation
2) Cognition
3) Sleep
What are the effects of H4R binding?
1) Hypersensitivity
2) Chemotaxin, cytokine production by MC, Eos, DC, T cells
3) Modulates inflammation and pruritus in allergic disease
Role of Serotonin
1) Vasoconstriction –> hypertension
2) Important for acute inflammation in RODENTS
Little effect on vascular permeability
Role of Dopamine
1) Decreased lymphocyte proliferation
2) Decreased neutrophil, MC, NK function
3) MAJOR MEDIATOR OF ANAPHYLAXIS IN COWS
Role of GABA
Important for allergic asthma
Anaphylotoxins
C3a, C5a
Role of C3a, C5a
1) Proinflammatory
2) Chemoattractants
3) Vascular dilation, permeability
4) Kill bacteria
5) Smooth muscle contraction
6) Wheal and flare on intradermal rxns
7) Activate platelets, macs, neuts, eos
8) Bind receptors on MC –> degranulation
9) Release IL-6, TNF-alpha from B cells, monocytes
10) Regulate tissue fibrosis
Role of Kinins
1) Increased vascular permeability
2) Smooth muscle contraction
3) Pain receptors
4) Activates kallikreins
Ie bradykinin
Role of Bradykinin
Edema, itch, anaphylaxis
Enzyme that turns arachadonic acid to leukotrienes
Lipooxygenase
Enzyme that turns arachadonic acid to prostaglandins
Cyclooxygenases (COX1, COX2)
Enzyme that turns cell-membrane phospholipids to arachidonic acid
Phospholipase A2
What is the rate limiting step in steroidogenesis?
Conversion of cholesterol to pregnenolone by P450scc (CYP11A1)
What is the rate limiting step in eicosinoid synthesis?
Phospholipid release to arachidonic acid via Phospholipase A2
What is the role of leukotriene B4 (LTB4)?
-Neutrophil attractant and activator
-Eosinophil chemotaxis
Which cell is the primary producer of leukotriene B4?
Mast cells
Which cell is the primary producer of leukotrienes C4, D4, E4?
Basophils
What is the role of leukotrienes C4, D4, E4?
-Increased vascular permeability
-Smooth muscle contraction
Release of slow reacting substance of anaphylaxis (SRS-A)
Which eicosinoid is a major stimulant of IL-13? Leading to a major inflammation feedback loop
LTD4
What is the role of slow reacting substance of anaphylaxis (SRS-A)?
More potent than histamine, but lower contraction with longer duration
What is the most abundant prostaglandin?
PGE2
What is the role of PGE2?
Regulates immune response, blood pressure, GI
What is the role of PGD2?
-Receptor in airway epithelium
-Bronchoconstriction
-Coronary + pulmonary vasoconstrictor
-Peripheral vasodilator
What is the role of TXA2?
Platelet adhesion, made by platelets
What is the role of lipoxins?
Anti-inflammatory
-slows neutrophil migration
What is the role platelet activating factor (PAF)?
Mediator of severe anaphylaxis
More potent than histamine
(Bronchoconstrictor, more neutrophil adhesion, aggregates platelets, vascular permeability)
Cells that make PAF
neutrophils, mast cells, basophils, eosinophils, platelets, endothelial cells
3 initiating cytokines, released by innate immune system upon PAMP or PRR activation
TNF-alpha
IL-1
IL-6
3 cytokines released from epithelial cell damage
IL-25
IL-33
TSLP
Cells that make TNF-alpha
1) Macrophages
2) Monocytes
3) T cells
4) Mast cells
Cells activated by TNF-alpha
Mast cells
Vascular endothelium
Macrophages
Lymphocytes
Neutrophils
Fibroblasts
Toxic effects of TNF-alpha
Kills tumor cells
Septic shock
Sickness behavior
Altered lipid metabolism
Cytokines promoted by TNF-alpha secretion
IL-1
IL-6
IL-8
Results of TNF-alpha induced inflammation
-Activates adhesion molecules
-Activates procoagulants
-Induces acute phase proteins
-Increased granuloma formation
-Increased leukocyte migration
Cells that make IL-1
Macrophages > others
If virus is present, which 2 cytokines are released by sentinel cells at the beginning of inflammation?
IFN-alpha - from leukocytes, macrophages
IFN-beta- from fibroblasts
Role of IL-1
-Fibroblast activity, collagen synthesis
-Th2 cytokine production
-Eosinophil, basophil degranulation
-Sickness feeling (fever, hyporexia)
-Cell growth (fibroblasts, keratinocytes, etc)
-Metabolism changes (mobilizes amino acids, acute phase protein synthesis, mucus production)
Which cytokine promotes both inflammation and IL-10 production, and a switch from neutrophilic to macrophagic inflammation?
IL-6
Which cytokine is induced by bacterial endotoxins, IL-1, TNF-alpha?
IL-6
Which cytokine is the most potent promoter of Th2 responses?
IL-33
What is the role of TSLP
Th2 inflammation at mucosal barriers
Binds to nerves to stimulate itch
Which cells are activated by IL-33
-B cells (IgE)
-Th2 cells (IL-4, IL-5, IL-13)
-Eosinophils (IL-8, degranulation, activation)
-Basophils (IL-3, IL-4, IL-6, IL-13, histamine, GM-CSF)
-Mast cells (IL-6, IL-13, Maturation, survival)
-Neurons (itch)
-ILC2 cells (activation, Th2 cytokines, IL-2, IFN gamma, TNF alpha)
DOWNREGULATES filaggrin synthesis
Which cells are activated by TSLP
LC + DC!!
-Basophils (production, activation)
-Th9 cells (IL-9)
-Mast cells (Th2 cytokines, Th2 cell activation)
-ILC2 cells (Th2 cytokines, Th2 cell activation)
-Th0 cells (differentiate to Th2 or Th17)
-Neurons (itch)
-DC (Th2 cytokines, Th2 cell activation)
(IL-4, IL-5, IL-13 production)
Which of the master cytokines released from epithelial cells is responsible for eosinophils recruitment, DC2 and ILC2 activation?
IL-25
Which cells are activated by IL-25?
-Eosinophils
-Th9 cells (IL-9, IL-17)
-Tuft cells (GI hyperplasia)
-ILC2 (Th2 cytokines, cell activation)
-Endothelial cells (angiogenesis)
-Th2 cells (cytokines)
-Epithelial cells (Th2 cytokines, cell activation)
Which cell produces IL-9?
Th2, Th9 cells
What disease is IL-9 associated with?
Asthma (AD, contact dermatitis, CAFR)
Which cytokine family does TSLP belong to?
IL-2
Which cytokine family does IL-33 belong to?
IL-1
Which cytokine family does IL-25 belong to?
IL-17
What is the purpose of tuft cells?
Sense/detect worms in GI
Which cytokine is produced by Tuft cells?
IL-25 (eos recruitment, DC2/ILC2 activation)
What cytokine family does IL-31 belong to?
IL-6
What is the role of IL-31
Itch inducer
Induce Th2 migration and inflammation
What is the role of CXCL8?
Neutrophil chemoattractant
Which cell makes CXCL2?
Macrophages
Which cells do CXCL2 act on?
Neutrophils
Which cell does CCL4 attract?
CD4 T cells
Which cell does CCL2 attract?
Monocytes (respiratory burst)
Which cells make CCL2?
T cells, fibroblasts, keratinocytes, endothelial cells
Which cells do CCL3 attract?
B cells, eosinophils, CD8 T cells
Which cells do CCL5 attract?
Eosinophils + histamine release from basophils
What transcription facto binds to aromatic hydrocarbons (diet, environment, microbiotia) to stimulate IL-23 and a Th17 response?
Aryl hydrocarbon receptor (AhR)
Also assocaited with more IL-33, TSLP, artemin binding and allodynia
Which type of T-cell response is protective against AD?
Th17, protects against overresponse of Th2
What is role of Th17
-Protect against bacteria at epithelial surface
-Responsible for neutrophilic inflammation in AD dogs
Which cytokine is present in chronic AD lesions, and regulates production of antimicorbial peptides?
IL-22
Which cytokines are elevated in intrinsic AD?
IL-33, IL-25, TSLP
LOW LEVELS IL-4, IL-5, IL-13– not IgE mediated
Where are gamma delta T cells in the skin?
Epidermis
Where are alpha beta T cells in the skin?
Dermis
Role of IFN-alpha, IFN-beta (type 1 inteferons)
antiviral state, increased MHC class I expression
NK cell activation
IL-6 Role
Synthesis of acute phase proteins by liver
Proliferation of plasma cells (Ig)
Elevated in dogs with coccidiomycosis
Th9 role
Reprogrammed Th2?
Important for FOOD ALLERGY
Produce IL-9, IL-10
Perpetuates chronic inflammation in allergy
Th22 role
Epidermal immunity
Infiltrate epidermis in inflammatory diseases (ie contribute to epidermal hyperplasia in chronic AD dogs, limit staph growth)
What cytokines do Tfh2 cells make?
IL-4, IL-6, IL-22 to increase IgE
Role of DC1
-Anti-tumor responses
-Present endogenous antigens from tumors via MHC class I to CD8 T cells
-Activate Th1
DC1 produce which cytokines
IL-12
IL-1 alpha
IL-1 beta
IL-6
IL-23
Role of DC2
Activate Th2 cells
Cytokines produced by DC2
IL-4
IL-5
IL-10
Chemokine that moves Langerhans cells to the LN?
CCR-7
Cytokines/chemokines made by Langerhans cells when stimulated by TSLP
Th2, Th22 responses
IL-16
IL-8
MCP/CCL2
TARC/CCL1
(Geared for antigen presentation)
Role of IL-8
Chemotaxis of neutrophils
Binds to CCR1, CCR2
Endothelial cells, macrophages, mast cells can also respond
Role of TARC (thymus and activation regulated chemokine)/CCL17
-Biomarker for AD
-Attracts Th2 cells by binding CCR4
Role of MDC/CCL22 (monocyte-derived chemokine)
Attracts Th2 cells by binding CCR4
Induced by IL-4, IL-13
Role of IL-16
Chemotactic for CD4+ T cells, activates them
Chemokines made by langerhans cells
TARC (Th2)
MDC/CCL22 (Th2)
IL-8 (neutrophils)
IL-16 (CD4+)
Which cytokines utilize JAK-1?
TSLP
IL-25
IFN gamma
IL-10
IL-4
IL-13
Which cell makes the most cytokines?
Macrophages
Which cells makes the second most cytokines?
Keratinocytes
Which cytokine is critical in equine allergy? Vaccine against ____ helps with IBH pruritus. Per Fadock
IL-5
Role of IL-1
Broad proinflammatory activity
Major cause of malaise, fever, lethargy, sleep, anorexia
Difference between IL-1 alpha and IL-1 beta
IL-1 alpha has strong intracrine activity
Which cells make IL-1? Which cells is affected by IL-1?
Almost all cells make it; almost all cells are affected by IL-1
Which cytokine is elevated in dogs with coccidiomycosis
IL-6, TNF alpha
What are the 3 major proinflammatory cytokines per Fadock?
IL-1, IL-6, TNF alpha
Which cells make TNF alpha? Which cells respond to TNF alpha?
Almost all make it, almost all respond to it
Role of IL-17
Activation of neutrophils
Control of extracellular pathogens
Important in autoimmune/inflammatory diseases
Cytokine associated with periodontal disease
IL-17
Cytokine associated with canine Leishmaniasis
IL-17
Cytokine associated with atopic dermatitis in humans and possibly dogs per Fadock
IL-17
Cytokine associated with IMHA in dogs (poor prognosis if persistently elevated)
IL-17
Cytokine associated with canine steroid-responsive meningitis-arteritis
IL-17
Cytokine associated with equine arthritis, laminitis, +/- asthma
IL-17
Role of IL-12
Development of Th1
Anti-tumor activity
IL-17E ‘s other name
IL-25, alarmin in epidermis
Interface dermatitis may occur due to _____:
Type I interferons (antiviral)
IL-28, IL-29 (type 3 interferon) role
Anti-viral
Adjuvants to increase production of IFN-gamma
IFN alpha, beta for which viruses in Vet Derm?
Feline herpes virus
Canine papillomatosis
Name 2 anti-inflammatory cytokines
TGF beta
IL-10
Which cytokines can sometimes be pro-inflammatory and sometimes anti-inflammatory, depending on context?
IL-4
IL-6
IL-11
IL-13
Role of TGF beta
Antiinflammatory or profibrotic; context
Important for immunotherapy
Role of IL-10
Treg, debby downer
Involved with Th2 repertoire
May be involved in mechanism of allergy
Which cytokine may be responsible for the lack of effective responses to Leishmania?
IL-4
Which cytokine can inhibit Th1 and Th17 responses
IL-4
IL-4 is synergistic with _____ to promote IgE production
IL-13
IFN gamma is synergistic with _____ to promote macrophage killing
TNF alpha
IL-1, IL-6, and _____ are synergistic to promote inflammation
TNF alpha
IFN gamma antagonizes ______’s ability to induce Th2
IL-4
IL-4 antagonisizes IFN gamma and _____’s ability to induce Th1
IL-12
_____ antagonizes the proinflammatory activities of TNFalpha
TGF beta, IL-10
_____ is a natural antagonist for IL-1; It can bind the IL-1 receptor but does not activate it. This prevents IL-1 signaling
IL-1ra
Which interferons can be used to treat cAD?
IFN gamma, IFN omega
How does high levels of IL-4 in Th2 (atopic) dogs relate to cancer?
IL-4 suppresses Th1, which is important for anti-tumor activity
What is the impact of high Th2 cytokines on the skin barrier?
IL-4, IL-6 decrease lipid synthesis, filaggrin
IL22 increases desmosome maturation
*If these cytokines are blocked, you will repair the skin barrier (in human med, IL-4 and IL-13 mABs)
Where is the glucocorticoid receptor?
Cytosolic
GC passes through cell membrane into cytoplasm
GC receptor dimerizes, goes into nucleus, alters gene production
Why does Cyclosporine take weeks to work?
It works by decreasing production of cytokines, which takes a long time
Which JAK does Apoquel preferentially bind?
JAK-1 > JAK-3 > JAK-2, Tyk2
Function of JAK2
Myelopoiesis, erythropoiesis, platelet function, growth
Function of JAK1
Inflammation, allergy, pruritus
When Apoquel is bound, what happens to JAK1?
It dimerizes, but cannot be phosphorylated, so STAT never binds –> no upregulation of allergic cytokines
Where does Cytopoint bind IL-31
extracellularly, does not need receptor
Which TLRs are bound by LPS (endotoxin) in post frooming furunculosis?
TLR4
Which TLR binds to chitin, for demodex recognition?
TLR2
