Intro to Immunology Flashcards
Cathelicidins
Cathelicidins (CATionic HELIcal bacteriCIDal proteIN) are α-helical peptides
Human cathelicidin LL37 is highly expressed by PMNs and numerous mucosal and epithelial cell types.
Defensins
Defensins are β-strand peptides connected by disulfide bonds
cathelicidins and defensins - how they work
Most are short peptides (
HSC –> myeloid requires what signals
IL-3, GM-CSF
HSC –> lymphoid requires what signals
IL-7
what are cytokines
Cytokines are soluble secreted molecules involved in cell-to-cell signaling. All cytokines are proteins / glycoproteins.
what are chemokines
Chemokines are a large family of cytokines that can attract cells into inflamed tissues and play a role in leukocyte homing and recruit cells of the innate and adaptive immune response to fight off an infection
Major cytokine categories
Interferons Interleukins Colony stimulating factors chemokine tumor necrosis factors transforming growth factors
interferons
In general, these are cytokines that are important in limiting the spread of viral infections.
interleukins
Large group of cytokines produced mainly by T cells (also macrophages, dendritic cells, and epithelial cells, etc.). Variety of functions including causing neighboring cells to divide and differentiate.
CSFs
Primarily involved in directing the division and differentiation of bone marrow stem cells and precursors of blood leukocytes. Controls how many and what kind of leukocyte is to be produced
Chemokine
Chemotactic cytokine used to direct the movement of leukocytes around the body.
TNFs
Particularly important in mediating inflammation and cytotoxic reactions.
TGFs
Important in regulating cell division and tissue repair.
PLC pathway (example T cell)
TCR – PLC gamma 1 –> split PIP2 –> DAG and IP3– IP3 stimulates Ca release from ER – activate calmodulin – calcineurin –NFAT –>
IL-2 (T cell proliferation)
In B-cells, its a BCR and then PLC gamma 2
Ras/MAP Pathway
TCR mediated signals –> Ras/ Dag –> MAP kinase cascade –> gene activation (AP-1)
PKC pathway (example T cell activation)
TCR/CD3 –> DAG/PKCo –> signal… –> NF-kB pathway –> gene activation
PKC in general associated with
proinflammatory and activation events rather than regulatory processes
interleukin 1 family
IL-1alpha/beta/Ra/18/33
Proinflammatory mediators
Secreted early in immune response from presence of foreign antigen
Hematopoietin (Class I cytokine) family
IL-2, 3, 4, 5,6,7,12,13,15,21,23,
GM-CSF, G-CSF, GH, prolactin, erythropoeitin/hematopoietin
Sequence and functional diversity (similar 3D shape)
Interferon (class II cytokine) family
IFN- alpha/beta/gamma
IL-10, 19, 20, 22, 24
Antiviral (IFN) and modulators of immune responses
Tumor necrosis factor family
TNF-alpha, beta CD40L, Fas (CD95), BAFF, APRIL, LTB soluble or membrane bound immune system development, effector functions and homeostasis (signal development, cell survival, death) function as trimers
Interleukin 17 family
IL-17 a, B, C, D, F
Promote neutrophil accumulation and activation
Proinflammatory
Chemokines
IL-8, CCL19, CCL21, RANTES, CCL2 (MCP-1), CCL3 (MIP-1a)
Chemoattractant
Hematopoietin receptors
Receptors generally include two types of protein domains – an immunoglobulin domain and a fibronectin-like domain.
The fibronectin-like domain is referred to as the cytokine-binding homology region (CHR).
CHR is common to cytokine receptors from several families.
Three subfamilies of receptors.
gamma, beta, gp130
gp130 hematopoietin receptor
KO in mice is lethal
cytokine members include IL-6 and IL-12
Specificity comes from ligand-specific chains in dimers or trimers coupled with gp130
two major types of interferon
Type I = IFN alpha, beta
Type II = IFN gamma
Signal transduction of Class I and II cytokines
Cytokine binds - dimerization of receptor – activation of JAK family tyrosine kinases - phosphorylated – tyrosine phosphorylation of STAT by JAK kinase - dimerization of STAT – into nucleus – specific gene transcription
TNF alpha
proinflammatory cytokine. Produced primarily by activated macrophages, but
also by other cell types
in response to infection, inflammation, and environmental stressors
Binds TNF-R1 or TNF-R2
TNF beta
produced by activated lymphocytes and can deliver a variety of signals.
On binding to neutrophils, endothelial cells, and osteoclasts (bone cells), TNF-beta delivers activation signals.
In other cells, binding of TNF-beta can lead to increased expression of MHC and adhesion molecules.
TLRs are technically ——–
PRRs
TLRs respond to
pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs)
PAMPs include
LPS, peptidoglycan, lipopeptides, flagellin, bacterial DNA and viral dsRNA
DAMPs include
intracellular proteins and protein fragments from the extracellular matrix
Stimulation of TLRs by PAMPs and DAMPs initiates
signaling cascades that lead to the activation of AP-1, NF-kB and interferon regulatory factors –> production of IFNs, pro-inflammatory cytokines, and effector cytokines that direct adaptive immune response
Mother of all immune system transcription factors
NF-kB
TLR signaling consists of at least three distinct pathways:
a MyD88-dependent pathway that leads to the production of inflammatory cytokines and one that leads to the production of IFN-α, and a MyD88-independent pathway associated with the stimulation of IFN-β and the maturation of dendritic cells.
cellular responses to TLR signaling
activation of NF-kB –> expression of pro-inflammatory genes (PGs, LTs, interleukins and cytokines), increased phagocytosis and synthesis of ROS/RNS, increased efficiency of antigen presentation
two major phagocyte lineages
monocytes polymorphonuclear granulocytes (neutrophils, basophils, eosinophils)
Colony forming units that can give rise to granulocytes, erythrocytes, monocytes, and megakaryocytes
CFU-GEMMs
CFU-GEMMs –> 1 of 5 pathways
IL-3 and granulocyte-macrophage colony stimulating factor (GM-CSF) = CFU-GM, CFU-B or CFU-Eo
CFU-GM –> further differentiation
IL-3 and GM-CSF further differentiation of granulocytes and monocytes
Eosinophil differentiation
CFU-Eo –> Eo with IL-5
development of mononuclear phagocytes
Myeloid progenitors in the bone marrow differentiate into pro-monocytes and then into circulating monocytes, which migrate through the blood vessel walls into organs to become macrophages.
morphology monocyte
large, horseshoe shaped nucleus, azurophilic (blue) granules
Monocyte expresses
CD14 (binds LPS)
MHC class II
CD11a and b (adhesion molecules)
CD64 and CD32 –> Fc receptors (bind antibodies)
neutrophils attracted to what chemotactic agents
Protein fragments released when complement is activated (C5a)
Factors derived from the fibrinolytic and kinin systems
Products of other leukocytes and platelets
Products of certain bacteria
primary granules of neutrophils carry
are lysosomes containing acid hydrolases, myeloperoxidase, and muramidase (lysozyme); they also contain the antimicrobial proteins including defensins, seprocidins, cathelicidins, and bacterial permeability inducing (BPI) protein
secondary granules of neutrophils carry
lactoferrin and lysozyme
neutrophils express
CD11a, b, and c –> associated with CD18β2 chains (adhesion molecules)
CD64, CD32, and CD16 –> Fc receptors (bind antibodies)
basophils and mast cells both bind
Fc epsilon
IL-4 on B cell
activation, proliferation, differentiation
IL-4 on T cell
Proliferation and differentiations
IL-4 on Mast cell
Proliferation
TLR 4/4
Gram negative bacteria and viral proteins
TLR 2/1
bacteria, parasites
TLR 2/6
Gram +, fungi
TLR 5/5
Flagellated bacteria
TLR 3/3
Viral dsRNA
TLR 7/7
viral ssRNA
TLR 8/8
viral ssRNA
TLR 9/9
bacterial/viral DNA
TLR signaling, 3 distinct pathways
MyD88 dependent to inflammatory cytokines, MyD88 dependent to INF a, MyD88 independent to IFNb
MyD88 pathway common to all TLR except
TLR3
NF-kB activation causes
Expression of pro-inflammatory genes
- Production of prostaglandins and other leukotrienes
- Production of interleukins and other cytokines
Increased phagocytosis and synthesis of reactive oxygen and nitrogen molecules in macrophages and neutrophils
Increased efficiency of antigen presentation
