Midterm Flashcards
Immunization Types
Active-Natural: Infection
Active-Induced: Vaccination
Passive-Natural: mother’s breast milk & mother to fetus
Passive-Induced: antiserum
Primary (central) Lymphoid Organs
Bone Marrow
Thymus (above heart)
Secondary (peripheral) Lymphoid Organs
Lymph nodes
Spleen
Malt/Payer’s Patch (in gut)
Leukocyte
immune system cell (white blood cell)
Lymphoid lineage cells
B cells T cells NK cells innate lymphoid cells some dendritic cells
Myeloid lineage cells
macrophages
neutrophils (and other granulocytes)
monocytes
some dendritic cells
Leukocyte lineages
Lymphoid, Myeloid
Lymphocytes & properties
B cells and T cells (adaptive immunity)
Arise from bone marrow
Lymphocyte receptors
BCR: - secreted or membrane bound - bounds antigen in natural form TCR - membrane bound - binds MHC with small piece of antigen on it
MHC
Major Histocompatibility Complex
Clonal Deletion
lymphocytes binding self-antigens are eliminated
Naive lymphocyte
mature lymphocyte not yet activated by an antigen
Innate immunity barriers/obstacles
Barriers: skin, epithelium (gut, respiratory tract)
Obstacles: saliva, hair, mucus, tears
Lyzozyme
digests peptidoglycan
Defensins
disrupts cell membrane by forming pores
Phagocytosing cells
macrophages
neutraphils & other granulocytes
immature dendritic cells
Phagocytosis steps
- receptors bind pathogen
- phagosome formed by invagination
- phagolysosome formed by fusion with lysosome
- digestion
Phagocytosis digestion methods
acidification
ROSs
enzymes
antimicrobial peptides
microglia
- phagocyte working in the central nervous system
- cleans up myelin debris from neurons
multiple sclerosis
demyelination of neurons
Leukocyte migration process
cytokines/chemokines released at site of infection
- > blood vessels dilate and adhesion molecules expressed
- > leukocytes extravasate
- > bloot clotting, pain, redness, edema
Extravasation process
chemokines bind to endothelial cell
- > leukocytes roll into and bind tightly to endothelium
- > cells change shape
- > induced diapedesis
diapedesis
Passage of cells through wall of capillaries, inducing inflammation
Monocyte
circulating leukocyte
Neutrophil
- innate immune system phagocyte
- circulating - must be recruited
- pus is product of dead/dying neutrophils
- produces NETs (neutrophil extracellular traps) matrix that traps microorganisms
Complement molecule properties
- mostly proteases
- usually named C_ (number), and C_a, C_b… when cleaved
- mostly produced by liver
- part of chain reactions that amplify inflammation and clearing of pathogens
Complement mechanisms of action
Increase vascular permeability and chemotaxis
Destroy pathogen membranes
Opsonization
Opsonization
- Coating a pathogen to make it more easily ingested by phagocytes (by antibodies and similar molecules)
C3b coats bacteria
- > binds C3b receptors on phagocyte
- > cascade leading to phagocytosis
Complement Activation (general)
Complement components begin as inactive pro-proteases
Cascade of events leads to proteolotic cleavages
- small piece that has a function
- large piece that acts as protease to another substrate
All pathways converge to C3 convertase cleaving C3 to C3a and C3b
Main pathways:
- lectin pathway
- classical pathway
- alternative pathway
Lectin Pathway
Specific PRRs bind directly to pathogen cell membrane
- > signaling cascade on surface
- > C3 convertase generated
- > C3a and C3b produced
PPRs:
- mannose-binding lectin, ficolins
- circulating in blood
- upregulated during infection
Classical Pathway
C1q in blood binds either to pathogen cell membrane (direct) or to antibody bound to pathogen membrane (indirect)
- > signaling cascade on surface
- > C3 convertase generated
- > C3a and C3b produced
Alternative Pathway
Triggered by existing C3b present due to spontaneous hydrolysis, or production from other pathways
C3b binds other factors
- > produce a particular unstable C3 convertase
- > stabilized by Properdin
- > more C3b produced
Properdin
aka Factor P
Produced by neutrophils
Stabilizes the alternative pathway C3 convertase
Complement induced inflammation
C3a & C5a increase vascular permeability and chemotaxis
(too much -> anaphylactic shock)
C3a & C5a bind receptors on granulocytes and macrophages
-> stimulate release of proinflammatory cytokines & degranulation
Complement induced pathogen lysis
Cascade of events creating MAC (membrane attack complex)
- > pore on pathogen surface
- > cell lysis
Innate Lymphoid Cell
- three types (ILC1, ILC2, ILC3)
- mainly tissue resident (recent studies show otherwise)
- important in gut mucosa
- activated by cytokines (IL-25 is well known to)
- release other cytokines that contribute to pathogen death
- recent finding shows migration of ILC2 between guts and lungs through lymph vessels
Natural Killer Cells
- kills own infected cells
- found in tissues and in circulation
- receptors are germ-line encoded
- recognize MHC1 & similar proteins
Non-Disease State: inhibitory signals on cell prevent NK activation
Disease State: inhibitory signal not present
-> NK releases toxic granules -> apoptosis
OR
-> receptor-mediated apoptosis
Common Proinflammatory Cytokines
TNF-alpha, IL-1beta, IL-6
Proinflammatory Cytokine effects
- vascular permeability and chemotaxis
- have different effects on different tissues/organs
ex: hypothalamus -> fever, liver -> acute inflammatory response
Local infection process
local TNF-alpha release
- > vasodilation & leukocyte migration
- > clearing of infection
- > draining of extracellular fluids to lymph nodes
Sepsis process
systemic TNF-alpha release
- > system vasodilation
- > lowering of blood pressure
- > collapse of blood vessels
- > intravascular coagulation
- > organ failure and death
TNF-alpha
released by macrophages
target of some autoimmune drugs
Acute Inflammatory Response
Increased production from liver:
- mannose-binding lectin
- complement components
- C-reactive proteins
Positive feedback loop until clearing of infection
PRRs
- Recognize PAMPs
- Activate signaling pathways, typically involving phosphorylation and ubiquination cascades
- expressed by many cells
PRR groups
Toll-like receptors NOD-like receptors RIG-like receptors C-type lectin receptors ficolins
Toll-like Receptors
Location:
- cellular membrane (for bacteria, parasites)
- endosome membrane (for viruses, bacteria)
Usually have adapter proteins
Activates TFs -> proinflammatory cytokine genes Common Pathways: - NF-kB - IRF - MAP kinase
RIG-like Receptors
Location: cytosol
Recognize viral dsDNA
Triggers TFs
Common Pathways:
- NF-kB
- IRF
NOD-like Receptors
Location: cytosol
Recognize peptidoglycans
Can trigger NF-kB TFs
Can activate caspase-1 (protease)
- cleaves IL-1/IL-18 to activate them, then release
PRR Signaling Downstream Effects
- cytokine production (IL-1, IL-6, IFN)
- B7.1 B7.2
- migration to secondary lymph organs (for APCs)
Type 1 IFN
IFN-alpha and IFN-beta
- triggers transcription of genes that inhibit viral replication
Cytokine
small glycoprotein
Cytokine communication mechanisms
Autocrine (self)
Paracrine (nearby)
Endocrine (far)
Cytokine categories
Interleukins Interferons (type 1, type 2) Tumor Necrosis Factor Hematopoetins or growth factors Chemokins
Lymph Node Migration
Activated DCs: enter by afferent lymph vessel
T Cells:
- enter by High Endothelial Venules (HEV)
- leave by efferent lymph vessel
Plasmacytoid DC
- stays at infection site
- produces large amount of type 1 IFN
- produces many PRRs
Unactivated DC Characteristics
Highly phagocytic
Many dendrites
PAMP Induces what on DC
- receptors that target DC to LT
- antigen processing genes (MHC)
- costimulation proteins
Activated DC Characteristics
- can no longer phagocytose
- less dendrites
- homes into lymphoid tissues
Three Activation Signals
Activation
Survival
Differentiation
T-Cell Migration through Endothelium
rolling -> tight binding -> diapedesis -> chemokines
selectins and integrins guide T-Cell to different sites
T-Cell classes
CD8+ becomes Cytotoxic T Lymphocyte
CD4+ becomes helper T Cell of a particular subtype
CD4+ subtypes
TH1, TH2, TH17, Treg, Tfh
- each subtype:
- activated via different cytokine
- has distinct cytokine profile
- regulates distinct activities
Immunological synapse
tight binding between pMHC and TCR during activation
CD3
- flank TCR, helps with binding
- all T Cells express it
Zeta chains
transmembrane protein part of TCR
ITAM Motif
part of zeta chains on TCR
get phosphorylated as part of signalling cascade
TCR subunits
Heterodimer made of alpha and beta chains, or gamma-delta
(90% alpha-beta)
- conneced by disulfide bridge
Clonotypic
each cell expresses own type of something
MHC1
present endogeous peptides (usually) activates CD8+ T Cells alpha chain with 3 domains beta microglobulin domain (non-transmembrane) binds short 8-10 aa peptides expressed by all nucleated cells
MHC2
present exogenous peptides (usually) activates CD4+ T cells alpha chain with 2 domains beta chain with 2 domains only expressed by professional APCs binds peptides of any length
MHC Genetic Variation
Peptide binding cleft has lots of allelic variation
Rest of MHC is highly conserved
Co-Receptors Structures
CD4 - single chain, 4 Ig-like domains
CD8 - heterodimer linked by S bridge, alpha and beta Ig like domains
TAP
- transmembrane protein on ER
- deliver peptides from cytosol to ER
- site of peptide loading on MHC1
Calnexin
chaperone holding together partially folded MHC1 alpha chain
Tapasin
chaperone that links MHC1 and TAP
Invariant Chain
- binds and blocks peptide binding groove of MHC2
- directs MHC2 to vesicles (using tail)
- degrades to CLIP
CLIP
- piece of invariant chain
- blocks peptide groove of MHC2
HLA-DM
- inside MHC2 vesicle
- binds MHC2 and releases CLIP
Cross-Presentation
CD4+ T cells license APCs to cross-present
- back and forth cytokine signal
Autophagy Ag presention
sends endogenous antigen to exogenous pathway
MHC Restriction
given T-cell can only recognize specific peptide bound to a specific self MHC
Allorecognition
1-10% of all T cells recognize and react to non-self MHC, regardless of presented peptide
MHC Gene
human leukocyte antigen (HLA)
codes for MHC
MHC1 Genes
HLA-A, HLA-B, HLA-C, code for the alpha chain
MHC2 Genes
HLA-DR, HLA-DQ, HLA-DP, etc. code for alpha and beta chains
MHC polymorphism
> 100 different alleles
usually amino acid changes in peptide-groove
SH2 Domain
Adaptor/scaffold structure that bind protein to bring them in proximity/orientation
pMHC:TCR Signaling
pMHC:TCR
- > co-receptor binding
- > recruitment of Lck
- > Lck phosphorylates ITAMs
- > ZAP-70 is phosphorylated
- > ZAP-70 activates four different signaling pathways
- > transcription of genes necessary for T cell activation
Costimulation proteins
Ligands on APC:
CD80 (B7.1)
CD86 (B7.2)
Receptors on T Cell: CD28
CD28
Transmembrane glycoprotein. Homodimer.
Found in close proximity to TCR
Expressed on all naive T cells at resting condition
Binds CD80, CD86 -> triggers phosphorylation of CD28
Required for activation and proliferation
Clonal Anergy
Signal 1 in absence of Signal 2 results in transcription of anergy genes
Anergetic T cell no longer responsive to stimulation
IL-2
Cytokine working in autocrine manner
IL-2 cascade
Signal 1 + Signal 2
-> cascade leading to binding promoter region of IL-2 gene and IL-2Ralpha (or CD25) gene
IL-2R subunits
alpha, beta, gamma
beta and gamma are expressed at baseline level
