Cytokines Flashcards
3 ways to categorize Immune signals
1) Cell-contact dependent OR cell-contact independent
2) Mediated by germ-line encoded receptors OR mediated by V(D)J generated receptors
3) Pro-inflammatory OR Anti-inflammatory
Germline-encoded receptors (characteristics)
- The gene segments that encode the receptor are already arranged in the genome of all cells
- Each cell of the body expresses the same transcript from this gene
- Heritable
Receptors produced by somatic recombination (characteristics)
- The gene segments that you inherit are unarranged
- Arrangement only occurs in select lineages
- Prior to clonal expansion, each cell has a different arrangement of each gene segment, and thus each expresses a different transcript
- Sequences express are not necessarily the receptor sequences expressed in your mother and father
Innate lineages are activated following the interaction of pathogen associated products with __________ ___________ ___________
Pattern Recognition Receptors (PRRs)
Example of a PRR
Toll-Like Receptors
Most well characterized PAMPs are those derived from:
Bacterial and viral pathogens (least characterized are from fungal and helminth pathogens)
Intracellular TLRs
3, 7, 8 and 9
Extracellular TLRs
1, 2, 4, 5, 6, 10
Principle Cell Sources of TNF
Macrophages, T-Cells
Principal cell sources of Interleukin (IL-1)
Macrophages, endothelial cells, some epithelial cells
Principal Cell sources of IL-6
Macrophages, endothelial cells, T-cells
Part 1: Pathogen Encounter (Cytokines and receptors)
PAMP, PPR, IL-1, IL-6, TNFα
Part 2: Neutrophil Influx (Cytokines and receptors)
IL-8, G-CSF, GM-CSF, Chemokines
G-CSF and GM-CSF
Granulocyte and Granulocyte-monocyte colony stimulating factor - released from Macrophages and Th cells - induce proliferation in the bone marrow
IL-8
Interleukin-8 - Circulating PMNs (Chemotatic - causes PMN migration toward injury)
Four families of Chemokines
CC chemokines: Two cys residues that are adjacent
CXC chemokines: Two cys residues separated by one amino acid
C chemokines: One cys residue
CX3C: Two cys residues separated by three amino acids
Function of Chemokines
Formation of gradient to which PMNs are attracted
There are greater than ______ different chemokines
40
4 stages of PMN extravasation
Stage 1: Rolling
Stage 2: Integrin activation by chemokines
Stage 3: Stable adhesion
Stage 4: Migration through endothelium
Part 3 Of Immune Response
T-Cell activation
Germline genes in T-cell activation
MHC, CD28, CD80, CD86 (B7)
CTLA-4
Serves to negatively regulate response - competes with B7 to provide a “stop” signal through CD28
IL-2
A cytokine that provides autocrine, cell-contact independent, pro-proliferative feedback to the Th cell producing it
Part 4: T cell differentiation into:
TH1 cells
TH2 cells
TReg cells
IL12
Promotes Th expression of IFNγ (Th1 Pathway)
TGFβ
Produced by many cell types, including APCs. Promotes development of TReg cells
IL10
Promotes TReg pathway
What happens when no APC cytokines are released
Th cells “default” to Th2 development
IFNγ
Provides autocrine signal to promote additional Th1 gene expression
Suppresses the expression of IL-4
TGFβ and IL10
Provides autocrine signal to promote further TReg development
IL-4 and IL-5
Promotes autocrine skewing towards a Th2 cell
Th17
Overabundance is associated with autoimmunity; deficiency associated with susceptibility to bacterial infection
Development directed by combination of IL-6, IL-23 and TFGβ
What is the TReg master-regulator
Foxp3 (positively regulated by TFGβ)
Therapies that alter Th cell differentiation signals
Alum
Ustekinumab
Helminth therapy
Part 5:
B-cell activation
Steps of B-Cell activation
B-cell recognition of native protein antigen
Receptor-mediated endocytosis of antigen
Antigen processing and presentation
T-Cell recognition of antigen
Helper T-cell is activated; expresses CD40L, secretes cytokines
B cells are activated by CD40 engagement cytokines
B-cell proliferation and differentiation
Signaling pathway for B-cells is enhance if _________ is bound to the antigen
Complement (C3d)
B-cell antibodies
IgM - Complement activation (Default antibody)
IgG - Fc receptor-dependent phagocyte responses
IgE - Immunity against helminths; mast cell degranulation
IgA - Mucosal immunity
Part 6:
Part 7:
Part 6: Granulocyte degranulation
Part 7: Complement cascade; phagocytosis; antibody-directed cytotoxicity (ADCC)
FcγRI
Phagocytosis; activation of phagocytes - high affinity for Ig
FcγRIIA
Phagocytosis; cell activation - low affinity for Ig
FcγRIIB
Feedback inhibition of B-cells - low affinity for Ig
FcγRIIIA
Antibody-dependent cellular cytotoxicity (ADCC)
FcεRI
Activation of mast cells and basophils (degranulation) - High affinity for Ig (IgE)
Histamine
A vasoactive amine stored in the granules of mast cells
Prostaglandin D2
Made by mast cells; activates G-protein coupled receptors and promotes PMN chemotaxis
Leukotrienes
Made by mast cells - inflammatory mediators derived from arachidonic acid
Part 8:
Macrophage activation; CD8 T cell mediated cytotoxicity; NK cell lysis
Cytokine associated with Macrophage activation
IFNγ
Cytokine associated with CD8 T cell cytotoxicity
Type I IFNs (IFN-α and IFN-β)
Cytokines associated with NK cell lysis
IL-15
IL-18
