BLD434 Section 1 Flashcards
Immunology
Antigen
pathogen component that binds to BCR or TCR
Innate Immunity
First line of defense (Non-specific) - Inflammation
- rapid pathogen recognition response (hours)
- fixed - based on the inherited receptors
- limited # of specificities
- constant during response
- neutrophils, eosinophils, basophils, mast cells, monocytes (B)/phagocytes (T), DC, NK cells, ILC
Adaptive Immunity
Third line of defense. Antigen-specific
- Slow pathogen recognition response
- Variable (not based on inherited genes)
- Numerous highly selective specificities
- Improves during response and each time infected
- B cells (plasma cells, CD19 and CD20), B-1 forms before birth, B-2 forms after birth
- T cells (CD3) - Helper T cells & T regulatory cells (CD4), Cytotoxic T cells (CD8)
Main advantages: more powerful & long-lasting protection (memory)
CD antigen (marker)
“clusters of differentiation” - cell surface molecules that identify immune cells
Sebum
Substance secreted by sebaceous glands that contains fatty acids and lactic acids which inhibit bacterial growth at the skin surface.
Lysozyme
Enzyme contained in tears and saliva that kills bacteria by degrading their cell walls.
Polymorphonuclear
having a nucleus with several lobes and a cytoplasm that contains granules (ex: neutrophils, eosinophils, basophils)
Primary lymphoid tissue
Bone marrow - where B & T cells form and multiply. where B cells mature.
Thymus - where T cells mature.
Secondary lymphoid tissue
Filters extracellular fluids for antigens and microorganisms. Site for lymphocyte activation by antigens, which develop into effector cells.
- Lymph nodes, spleen, tonsils, Peyer’s patches , appendix.
Lymph
fluid and cells (including WBCs) that are transported to the lymphatics and into the bloodstream
- Attack bacteria in the blood and body tissues
Naive lymphocyte
Immature B or T lymphocytes that have not been activated by an antigen
PALS (Periarteriolar lymphoid sheath)
A portion of white pulp in the spleen that is occupied by T cells.
GALT (Gut-associated lymphoid tissue)
Tonsils, adenoids, appendix, Peyer’s patches of the gastrointestinal tract
BALT (Bronchial-associated lymphoid tissue)
aggregates of the respiratory epithelium
- mucosal lymphoid tissue in the walls of airways (respiratory tract, bronchi)
MALT (Mucosa-associated lymphoid tissue)
Secondary lymphoid tissue that initiates immune responses to specific antigens along mucosal surfaces (ex: vaginal tract)
Mature immune cells from the common Myeloid precursor
Monocytes/Macrophages, Neutrophils, Eosinophils, Basophils, Mast cells, DC cells
Mature immune cells from the common Lymphoid precursor
B cells, T cells, NK cells, ILC (innate lymphoid cells)
Monocytes vs Macrophages
Same cell but is called a monocyte (inactive) when in the blood and a macrophage (active) when in tissue. Macrophages are phagocytic while monocytes are not
Polymorphonuclear leukocytes (granulocytes) of the blood - color of granules & # of lobes
Neutrophils (2-5 lobes) - pink/blue/lilac
Eosinophils (2 lobes) - orange-pink
Basophils (2 lobes) - purple-black
How does a naive lymphocytes enter a lymph node?
Naïve lymphocyte enters a lymph node via afferent lymphatic vessels and drains through the efferent lymphatic vessel in the medulla
M cell (Microfold cell)
Specialized intestinal epithelial cells covering GALT mucosa – Transport antigens to lymphoid follicles to initiate an immune response. Long-lived.
How does an antigen enter a lymph node?
Antigen enters lymph node via fluid draining from tissues (due to inflammation) in afferent lymph vessels
Where are B & T lymphocytes primarily located in the lymph node?
B cell - Lymphoid follicles in the cortex (circular areas in the outer part)
T cell - Medulla (middle part)/ T-cell area
Where are B & T lymphocytes primarily located in the white pulp of the spleen?
Active B cell - Germinal center
Inactive B cell - lymphoid follicles
T cell - PALS (periarteriolar lymphoid sheath)
C (Complement proteins)
soluble zymogens (inactive enzymes) in the blood that are part of the innate immune system
First line of defense against infection
Defensins
small amphipathic proteins inserted into pathogenic membranes to cause lysis. Defend against bacterial, viral, and fungal infections
Opsonization
Coating or binds to the surface of a pathogen to help phagocytosis.
Complement fixation
Opsonization where C3b is the opsonin.
- C3b is covalently bonded to the pathogen’s surface to mark it as a target for destruction by a phagocyte
Anaphylatoxin
Complement fragments that float away (C3a, C4a, C2b)
- Substance that activates blood vessel endothelial cells to initiate inflammation by: causing degranulation, increasing vascular permeability and vasodilation.
Chemoattractant
A chemical substance that creates a gradient to attract cells (from low to high concentration) towards an infection
4 Main Functions of complement proteins in immune system
- opsonization
- anaphylatoxin
- chemoattraction
- direct lysis (pore formation - C9)
List the 3 Complement Pathways and what initiates them
- Classical (Antibody-initiated, C1 binds)
- CRP initiates without antigen binding
- Lectin (MBL binds)
- Alternative (spontaneous hydrolysis of C3, Factor B binds)
C3 covertase (Classical and Lectin)
C4b2a
C3 convertase (Alternative)
C3bBb
C5 convertase (Classical and Lectin)
C4b2a3b
C5 convertase (Alternative)
C3bBb3b
Major advantage that complement has compared to antibody in tagging pathogens for disposal?
Complement binds covalently (strong and permanent) to pathogen surface, while antibody binds non-covalently (not as strong and can be reversible)
Explain the similarities and differences between iC3 vs iC3b and iC3Bb vs C3bBb.
Identify which are enzymatically active and which have been inactivated.
iC3
- inactive
- soluble
- can bind Factor B to be cleaved into
iC3b
iC3b:
- inactive (C3b, by Factor I)
- opsonin
- bind to Factor D to be cleaved into
iC3bBb
iC3Bb:
- active
- soluble
- C3 convertase of alternative
pathway
C3bBb:
- active
- fixed (covalently bonded to pathogen
surface)
- C3 convertase of alternative
pathway
Which complement component fragment provides the greatest amount of amplification of the complement cascade, and why (i.e, C2b, C3b, C4b, C5b?)?
C3b - provides a way to activate the alternative pathway and add exponential activation of complement proteins.
Complement proteins of the MAC
C5b, C6, C7, C8, C9
Which complement component polymerizes a pore in the pathogen membrane?
C9
What protein can amplify complement activation? Which complement pathway? What mechanism?
Properdin (Factor P) binds to C3bBb (alternative C3 convertase) bound to a pathogen surface and protects it from protease degradation (Bacteria and parasites secrete proteases around their surface). Amplifies the alternative pathway.
List the two points at which complement activation can be inhibited, and identify the product of C3b cleavage produced by Factor I.
- Inactivate C3 convertase
- Prevent MAC formation
Product = iC3b
Describe how a2-macroglobulins, pentraxins and defensins function in innate immune system protection of the body.
- a2-macroglobulins inhibit proteases
- Pentraxins enhance phagocytosis
- Defensins are antimicrobial peptides that disrupt microbial membranes & cause lysis
Neutrophils
- short-lived
- highly mobile
- crucial in early stages of infection
- die after they phagocytize by apoptosis
- enter inflammatory site when called upon
Macrophages
- Long-lived
- Tissue residents
- First to respond
- Detect danger infection signal using inflammatory cytokines
- Clean up mess after pathogen is killed
- Help in tissue repair
- Function as sentinels (guards)
IL-1B
inflammatory cytokine released by macrophages that enhances the effects of TNF-a and IL-6
- Activates vascular endothelium and lymphocytes; local tissue destruction, increases access of effector cells
TNF-a
- inflammatory cytokine produced by macrophages
- makes blood vessels more permeable so cells, fluid, and soluble effectors can enter infected tissue.
- Can cause septic shock if produced in abundance
IL-6
- inflammatory cytokine produced by macrophages
- induces metabolism of fat and muscle cells –> heats infected tissue
- Induces the production of acute-phase proteins CRP and MBL to activate complement opsonization
CXCL8
- chemokine released by macrophages
- recruits neutrophils from the blood into infected tissue
CCL2
- chemokine released by macrophages
- recruits monocytes from the blood to infected tissue
IL-12
- recruits and activates NK cells to secrete cytokines to strengthen macrophage response to infection
TLR
Toll-like receptors
- activate immune cells in innate immunity and are involved in cell signaling & the production of inflammatory cytokines
TLR subfamily I
- TLR 1, 2, 4, 6, 10
- Located in plasma membranes of immune cells (mostly granular sites, DC, and some B)
- Recognize lipid components in the membranes of pathogens (bacteria, parasites, fungi) to activate macrophage or DC response
TLR subfamilies II & III
II = TLR 7, 8, 9, III = TLR 3 homodimer
- Located in endosomal membranes
- Virus release viral DNA/RNA when phagocytized, and then these TLR will have access, activating immune cells to produce cytokines and other mediators
TLR subfamily IV
TLR 5
- Expressed on intestinal epithelial cells in their plasma membrane to recognize bacterial flagellin protein
- Activates intestinal epithelium to send immune signals to call in help
TLRs located in plasma membrane
TLR subfamilies 1 and 4
- recognize extracellular pathogens
- target antigen: bacteria
TLRs located in endosomes
TLR subfamilies 2 & 3
- recognize intracellular pathogens
- target antigen: viruses (attack gene irregularities
NFKB
Protein transcription factor that initiates inflammatory cytokine production and secretion to regulate innate immunity.
- Activates transcription of genes for inflammatory cytokines, which are synthesized in the cytoplasm and secreted from the ER
IRF3 & IRF7
- phosphorylated and travel to nucleus to
act as transcription factors - they induce Type I interferon production
and secretion (IFN-a & IFN-B)
IRF3 = for single-stranded RNA
IRF7 = for double-stranded RNA
Type I Interferons
IFN-a and IFN-B, which fight viral infections
What is the outcome of activation of MAVS receptors?
MAVS = Mitochondrial antiviral-signaling proteins
Type I interferon (IFN-a & IFN-B) production by the cell
Plasmacytoid dendritic cells
Dendritic cells specialized in secreting high levels of Type I interferons - response to viral nucleic acid during early infection
Respiratory burst
the consumption of O2 by phagocytes, pumping H+ ions out of the phagolysosome, raising the pH and activating neutral proteases to digest the microbes consumed.
Chronic Granulomatous Disease - identify the immune system defect
Caused by a mutation of the genes encoding subunits of the NADPH oxidase enzyme complex.
Leads to:
- Defective respiratory burst
- Reduced ability of phagocyte to kill pathogens
- Infected cell forms a granuloma, a wall, around itself to prevent infection spread
Identify the major macrophage cytokine that triggers the “acute phase” response and the proteins that are produced as a part of the acute phase response.
IL-6 - by inducing liver hepatocytes to produce acute phase proteins (CRP, MBL, LPS-binding protein).
Importance of an acute phase reaction (response) and which tissues/organs of the body are primarily responsible?
Response to a pathogen by creating a hospitable environment for pathogens and trying to kill the pathogen until the adaptive immune system can step in.
- Liver
Acute-phase proteins (CRP and MBL)
activate complement opsonization - Bone marrow
Neutrophil mobilization (5-day supply) causes phagocytosis - Hypothalamus
Increases body temperature via shivering –> decreasing viral and bacterial replication - Fat and muscle cells
Metabolism increases body temperature via fever –> decreasing viral and bacterial replication
Necrosis
cell death by trauma (inflammation, damage, osmotic pressure) - releases inflammatory cytokines
Netosis
Neutrophils get overstimulated and extrude their DNA and granule contents (NETs) to trap extracellular bacteria
Trogocytosis
Neutrophils extend membrane to take a “bite” out of a cell (parasite) that is too large to phagocytose.
Apoptosis
NK cells and Tc cells induce another cell to digest itself from the inside out.
- Virus-infected cells, cancer, damaged cells
Pyroptosis
Inflammatory cell death - Macrophages get highly activated and inflammasomes form, leading to the release of inflammatory cytokines (IL-1B)
- ALL infections
Phagocytosis
Neutrophil and macrophage cell receptors bind to target and wrap its plasma around pathogen and engulfs it in a phagosome.
LTi (Lymphoid Tissue inducers)
Responsible for creating lymphoid tissues (lymph nodes and white pulp organization in spleen)
NK cells
Cytotoxic ILC of lymphoid lineage
- circulate blood & kill infected cells (virus, bacteria, protozoa)
- Perforin mediator creates a hole in an infected cell, allowing granzymes in to induce apoptosis. IFN-Y further activates macrophages
ILCs (Innate Lymphoid Cells)
- Facilitates the development of secondary lymphoid structures
- Secrete cytokines that help to activate the effector cells of innate immunity (e.g. macrophages, granulocytes) & phagocytosis
- ILC1, ILC2, ILC3 (Tissue residents - for immediate response)
ILC1
- Respond to intracellular infections to any invading pathogen
- Either stops the infection or limits its spread until NK cells are recruited from the blood (by IL-12)
ILC2
- Present at mucosal surfaces
- Respond to large extracellular parasites (i.e. worms)
ILC3
- Respond to extracellular bacterial or fungal infections
- Abundant in mucosal tissues
Type 1 Immunity
- Intracellular bacteria and viruses
- Mediated by IFN-Y, NK cells, ILC1,
neutrophils - Cell-mediated toxicity (NK cells) & inflammatory activation of macrophages
Type 2 Immunity
- Parasites in the gut
- Mediated by ILC2, IL-4, IL-5, IL-13, mast cells, eosinophils, and basophils
- Non-inflammatory activation of macrophages
Type 3 Immunity
- Extracellular bacterial or fungal infections
- Mediated by ILC3, which produces IL-17 and IL-22
- Promotes phagocytosis and secretion of antimicrobial peptides
How do Type I interferons activate NK cells to combat infections?
(IFN-a and IFN-B) by promoting NK cell maturation and recruitment into virally-infected cells
How do Type II interferons activate NK cells to combat infections?
(IFN-Y)
- Macrophages produce IL-12 and IL-15, causing NK cells to proliferate and differentiate
- NK cells secrete IFN-Y, which binds to and activates macrophages to increase phagocytosis and secretion of inflammatory cytokines to kill ingested viruses
Macrophage and NK cell interaction
Synergistic
1. Virus activates macrophage, which then secretes cytokines:
- CXCL8 recruits the NK cell
2. IL-12 & IL-15 activate the NK cell via the
synapse
3. NK cells proliferate into effector cells and secrete IFN-Y
4. IFN-Y binds to macrophage to increase phagocytosis and cytokine secretion
What are the three types of interactions that can occur between DC cells and NK cells?
- DC cells drive NK cells activation, proliferation, and differentiation
- Immature DC cell takes up antigen,
gets activated, and secretes IL-15 to
drive NK cell proliferation - This produces effector NK cells that
secrete cytokines and kill virus-
infected cells
- Immature DC cell takes up antigen,
- Abundance of NK cells
- NK cells outnumber and kill DC cells
- There are enough NK cells to
terminate the viral infection, so
there’s no need to activate adaptive
- Scarcity of NK cells
- NK cells signal DC cells to mature and
initiate an adaptive immune response - DC cells move to secondary lymphoid
tissues to present antigen - Innate immunity fails; need adaptive
- NK cells signal DC cells to mature and
