Download Immunology Study Guide Exam I Introduction to Immunology innate

Immunology Study Guide Exam I
I.
Introduction to Immunology
A. innate
1. not specific
2. barriers
a) skin (first line of defense)
b) chemical
c) mechanical
(1) ex. ciliary action
3. cells
4. complement
B. adaptive
1. takes longer (7-10d) on first exposure
2. types
a) cell mediated
(1) cytotoxic T cells
(2) helper T cells (are both cell mediated and humoral)
b) humoral
(1) B cells
(a) Ab - plasma cells
II. Primary Lymphoid Organs
A. Thymus
B. Bone Marrow
1. Red Marrow is in:
a) spongy (cancellous) parts of bones
b) flat bones & epiphysis of long bones
2. Yellow Marrow is in:
a) hollow of bones
b) storage of fat cells (energy reserve)
c) converts to red marrow if needed
3. Stroma (area between sinuses)
a) contains cells that support hematopoiesis like
(1) endothelial cells, fibroblasts, stromal cells
(a) produce growth factors and cytokines
(2) endothelial cells
(a) barrier to prevent immature cells from leaving
(3) adipocytes
(a) source of energy, produce growth factors
(4) macrophages
(a) remove apoptotic cells, source of iron
(5) osteoblasts & osteoclasts
(a) remodels cancellous bone around marrow
4. Types of cells in bone marrow
a) hematopoietic stem cells (HSC)
(1) 0.05% of hematopoietic cells
(2) differentiate into RBC, WBC, platelets and others
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Immunology Study Guide Exam I
b) mesynchymal (stromal) stem cells (MSC)
(1) differentiate into adipocytes, chondrocytes and osteoblasts
III. Cells of Innate Immunity
A. Phagocytes
1. Neutrophils (“Segs” - segmented nucleus; “PMN” or “polys”
polymorphonuclear)
a) found in circulation, NOT in tissues
b) ~60% of WBC
c) lifespan is 12 hrs
d) first cell arriving at site of infection
e) ingests and kills microbes, but dies in process and found in pus
f) Segs are mature neutrophils in circulation
(1) “Bands” or “Stabs” are less mature neutrophils in circulation
g) Absolute Neutrophil Count (ANC)
(1) increased total neutrophils = inflammation
(a) bacterial infection, stress, necrosis/trauma, leukemia
(2) decreased total neutrophils = neutrophilia
(a) viral disease, overwhelming infection, anti-microbials or cancer
drugs
h) Granules
(1) Azurophilic (primary)
(a) bacteriocidal & fungicidal agents such as:
i) myeloperoxidase, lysozyme, cathepsins, defenins, BPI
(2) Specific (secondary)
(a) bacteriocidal
i) respiratory burst components and/or lysozyme
(b) migration
i) collagenase and/or elastase
(c) preformed microbial-sensing receptors (directionality)
i) FMLP receptor (detects bacteria)
2. Macrophages
a) found in circulation as monocytes, and in tissues as differentiated
macrophages
(1) M1 - inflammatory macrophage
(2) M2 - suppressor macrophage
b) ingest and kill microbes
c) produce cytokines and chemokines to initiate inflamation
d) can be antigen presenting cells (APC)
e) larger than PMN
f) serves as second wave of immune attack following neutrophil activity
g) functions:
(1) activated by INFᵧ
(2) contribute to acute & chronic inflammation
(3) serve as an APC
(4) produce more ROS than neutrophils
B. Immunosurveillance Specialist
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Immunology Study Guide Exam I
1. Natural Killer (NK) Cells
a) senses MHC class 1 receptors with a ubiquitous molecule (one found
everywhere)
(1) if the MHC class 1 receptor is not present, then the NK cell with kill it
b) kills target cells using perforin and granzyme
(1) perforin allows for the transfer of active granzyme into target cells by
the creation of a pore
(2) pro-granzyme is activated in the NK cell by Cathepsin C, it then
activates caspases in the target cell initiating an apoptotic cascade
c) apoptotic cell debris is removed by macrophage
C. Inflammatory Mediators
1. Mast Cells (Basophils)
a) IgE-coated cells
b) activation occurs when IgE (mast cell) cross links with FcεRI
c) degranulate upon activation
d) activation results in immediate and late phase response
(1) Immediate phase granules
(a) amines - histamines
lipid mediators - PAF, PGD2, & LTC4
(b)
(2) Late phase granules
(a) cytokines - TNF
lipid mediators - PAF, PGD2, & LTC4
(b)
(c) enzymes - tryptase
D. Parasite Specialist
1. Eosinophils
a) express Fc receptors for Abs (IgG & IgE)
b) eradicates parasites
c) contributes to chronic inflammatory reaction in allergic diseases
d) compounds in eosinophil granules:
(1) cationic granule proteins
(a) major basic protein (MBP) - destroy cell membrane, promotes
histamine release by mast cells/basophils
(b) eosinophilic peroxidase - ribonuclease
(2) enzyme
(a) eosinophilic peroxidase - creates hypochlorous & hypobromous
acid (degrades membranes, DNA & RNA)
E. Linker of Innate & Adaptive Immunity
1. Dendritic Cell (DC)
a) functions:
(1) present antigens for activation of T cells
(2) maintain tolerance to self-Ags
(3) indirectly drive development of B cell responses (Abs)
(4) Exogenous (MHC class II) vs Endogenous (MHC class I)
(5) DC go through 3 signals with T cells
(a) finding the right T cell
(b) receptor ligand interaction (turns away the wrong T cells)
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Immunology Study Guide Exam I
(c) soluble factor (cytokines) produced by DC, due to activation by
pathogen at toll-like receptor (TLR) (determines Th1 or Th2
response)
(6) DC Ag presentation
(a) MHC class I + peptides = recognition by CD8 T cells (killer T cell)
i) all nucleated cells have MHC class I
(b) MHC class II + peptides = recognition by CD4 T cells (helper T
cell)
i) only DC, macrophage, B cells and some thymic cells have
MHC class II
(7) Plasmacytoid Dendritic Cells (PDC) is primary producer of type I
interferon (IFNα), a cytokine important in antiviral immunity
IV. Cells of Adaptive Immunity
A. B & T lymphocyte generation & maturation
1. mature lymphocytes are those with an Ag receptor
2. Thymus
a) immature thymocytes(pro-T cells) form bone marrow enter thymus via
arterioles and mature in the thymus
b) cortex
(1) cortical thymic epithelial cells (CTEC)
(2) macrophages
(3) blood vessels
c) medulla
(1) medullary thymic epithelial cells (MTEC)
(a) potentially autoreactive T-cells were eliminated
(2) macrophages, DCs
(3) Hassall’s corpuscles
d) functions of barriers/layers
(1) blood-thymus barrier - CTEC w/ desmosomes & capillary endothelial
cells form dual basal lamina (Macrophages ensure no Ags contact
thymocytes)
(2) subcapsular layer - double-negative (DN), pro-T cells differentiate into
pre-T cells
(a) CTEC get rid of pre-T cells with problems
(3) cortex - pre-T cells acquire CD4 & CD8 (double-positive, DP) and a T
cell receptor
(a) only T cells that recognize the MHC molecule, but not self-Ags
survive while others undergo apoptosis
(4) medulla - MTEC produce self-Ags
(a) T cells that respond strongly with self-Ags undergo apoptosis,
while those that bind weakly survive
(b) cells that survive this process will only express CD4 or CD8, not
both (single-positive, SP)
(c) Hassal’s Corpuscles - composed of MTEC, produce thymic
stromal lymphopoietin (TSLP)
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Immunology Study Guide Exam I
i) TSLP allows presentation to occur. If you do not have this you
will have an autoimmune disease.
ii) TSLP stimulates DCs
iii) immature DCs are antigen capturing, while mature have CD83
and can activate T cells
3. CD4 T cells
a) tissue DCs capture Ags & migrate to lymph node to activate CD4 & CD8 T
cells
b) functions
(1) Th1 (INFᵧ)
(a) macrophage - enhanced killing of ingested microbes
(2) Th2 (IL-4)
(a) B cell (plasma cell) - production of Abs
(3) Th17 (IL-17)
(a) neutrophils - recruitment/inflammation
4. CD8 T cells
a) functions
(1) CTL mechanisms activate pathways to induce cell death
5. B cells
a) can recognize Ags directly & differentiate into Ab-producing plasma cells
(1) goes from naÏve to activated (making Abs) to effector cells (releasing
Abs)
b) MZ & FO B cells are activated by circulating Ags
c) MZ B cells provide rapid response to invaders (Ag source)
(1) IgM+IgD+ (CD27-)
(a) “naÏve” B cells
(b) require CD4 interaction
(c) slow response (IgM, IgG, IgA)
(2) IgM+IgD+ (CD27+)
(a) “Memory-like” B cells
(b) do not require CD interaction
(c) Rapid response (IgM)
V. Secondary Lymphoid Organs
A. Spleen
1. newly formed (NF) B cells leave BM to enter spleen & lymph nodes
2. Red Pulp
a) filters blood, removes old RBCs & pathogens
b) contains vascular sinusoids separated by splenic cords
c) reserve store of blood
d) site of hematopoiesis if BM fails
3. White Pulp
a) contains central artery surrounded by sheath of T cells (periarteriolar
lymphoid sheaths; PALS)
b) lymphoid follicles contain NF B cells
(1) NF B cells differentiate to Transitional (TR) B cells in follicles (FO)
(2) FO B cells that recognize self-Ags are eliminated
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Immunology Study Guide Exam I
(3) MZ B cells migrate to the marginal zone
4. Marginal Zone
a) area between red & white pulp where Ag is captured
b) residence of marginal zone B cells
(1) DCs of red pulp present to marginal zone B cells to illicit Ab response
5. T Cell Zone is where T cells from circulation localize
B. Lymphatics
1. lymph is the clear fluid that is collected from fluids pushed out of capillaries
(interstitial) and what surrounds tissues
2. interstitial fluid is collected into lymphatic vessels, taken to lymph nodes and
filtered before returning to circulation
3. lymph flows from afferent vessel to cortex to medulla to efferent within the
node
a) like in spleen, fluid first comes in contact with B cells, then T cells and
macrophages
b) germinal centers are activated populations of B cells where they are
replicating and producing Abs
4. functions
a) maintain fluid balance
b) absorb digested fat in intestinal villi
(1) monoglycerides & fatty acids are absorbed by enterocytes and made
into TGs
(2) TGs are packed with cholesterol, lipoproteins and more into
chylomicrons and transported first into lymph
c) immunity
(1) humans have 600-700 lymph nodes
(2) damaged nodes do not regenerate
5. lymphatic vessels
a) vessels start as only a single cell layer, but are overlapping like shingles
b) afferent lymphatic vessels carry unfiltered lymph into nodes for filtration of
pathogens
c) efferent lymphatic carry filtered lymph out and back to circulation
d) lymphatic vessels contain valves similar to veins which force fluid up,
when muscles contract, towards nodes in the neck
e) lymph enters the bloodstream at the subclavian veins
f) mechanisms for movement of lymph:
(1) breathing
(2) skeletal muscle contractions
(3) segmental contractions
(4) posture changes
(5) massage or passive compression (OMT)
g) right drainage area
(1) right side of head/neck, right arm, upper right quadrant of body &
most of heart and lungs
(2) right lymphatic duct
h) left drainage area
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Immunology Study Guide Exam I
(1) left side of head/neck, left arm, upper left quadrant of body & both
lower quadrants and legs
(2) cisterna chyli temporarily stores lymph as it move up the thorax
(3) thoracic duct transports lymph upward and empties into left lymphatic
duct
6. osteopathic medicine
a) lymphatic pump - manipulation used to increase the rate of lymph flow to
reduce edema & fight infections
b) techniques
(1) thoracic pump
(a) thoracic cage is compressed intermittently
(2) abdominal pump
(a) increases leukocyte output via the lymphatic system to circulation
(b) also improves immune surveillance
(3) pedal pump
(a) mobilizes lymphatic fluid from lower extremities into central
circulation
(b) palms on ball of patient’s feet, exerting rhythmic flexion
(“sloshing” of the belly)
7. major lymph nodes
a) cervial - drains head and neck
b) axillary - drains upper arm & upper thoracic area including breast
c) thoracic cavity - drains organs of thorax (heart & lungs)
d) supratrochlear - drains lower arm
e) abdominal - drains areas of GI tract & trunk
f) pelvic cavity - drains pelvis including internal genitals
g) inguinal - drains legs and external genitals
8. lymph node compartmentalization
a) cortex - B cells in follicles
b) paracortex - T cells & dendritic cells
c) medulla - macrophages & plasma cells
9. tissue DCs capture Ags & migrate to the lymph node to activate CD4 and
CD8 T cells
C. Liver
1. largest glandular organ with 4 equal lobes
2. functions
a) breaks down fats, converts glucose to glycogen (and visa versa)
b) makes proteins
c) stores vitamins and minerals
d) contains Kupffer cells (liver macrophages)
(1) they capture Ags from blood
(2) remove Ags bound by Abs
D. Mucosal-Associated Lymphoid Tissue (MALT) “Tonsils”
1. lymphoid tissue found on both sides of throat
2. three sets of tonsils
a) palatine (back of throat)
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Immunology Study Guide Exam I
b) pharyngeal (adenoids)
c) lingual (base of tongue)
3. usually activated and palpable
E. Gut-Associated lymphoid Tissue (GALT)
1. “Peyer’s Patches”
a) aggregations of lymph tissue in mucosa of intestines
b) APC near surface sample gut contents
c) M cells are phagocytic
d) T cells reside between follicles
e) intraepithelial lymphocytes can produce cytokines to lyse infected cells
2. “Appendix”
a) Blind-ended pouch off of colon
b) site of cellulose digestion (horses, cows)
c) harbors commensal intestinal flora
d) contains lymphoid tissue similar to Peyer’s Patches
F. Bronchial-Associated Lymphoid Tissue (BALT)
1. similar to GALT PP
2. can change in size and are inducible
VI. Innate Immune System
A. all innate cells come from myeloid cells
B. features
1. it is the initial responses to:
a) microbes: essential early membrane to prevent, control or eliminate
infection
b) injured tissues, dead cells: critical for repair and wound healing
2. the most ancient according to evolution
3. immediate action (no latent period)
4. stimulates adaptive immunity through nonspecific factors
C. comparison of innate and adaptive immunity
1. innate
a) not antigen specific
b) depends on germline encoded receptors to recognize pathogens
(universal)
c) no time lag (immediate response)
d) no immunologic memory
2. adaptive
a) Ag specific
b) relies on recombination of gene segments that encode Ag receptors and
AgR selection
c) has a lag period
d) development of memory (lasting immunity)
D. three lines of defense
1. 1st line
a) skin, mucous membranes, chemicals
b) nonspecific defenses
c) barriers are:
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Immunology Study Guide Exam I
(1) physical
(a) epithelia and mucosal surfaces form a physical barrier
(b) tight junctions block passage
(c) stratum corneum (outer skin layer) flakes off removing pathogens
(2) mechanical
(a) mucous catches Ags and ciliary action causes an upward
escalator to be later swallowed or spat up
(b) other layers have flushing actions such as tears, saliva, mucous
and urine
(3) chemical
(a) defensins (human alpha and beta; HAD and HBD)
i) produced by mucosal epithelia, neutrophils, NK cells, CTL and
paneth cells of gut
ii) inhibits cell wall synthesis of bacteria and fungi
iii) can neutralize spread of viruses
iv) activate host responses through induction of
cytokine/chemokine release
v) action inhibited by serum proteins
(b) lysozyme
i) found in saliva and tears and contained within granules of
phagocytes
ii) these damage bacterial cells walls by catalyzing hydrolysis of
residues in peptidoglycan layer
(c) acidic pH in stomach
(d) cervical mucus, acidic pH of female GU tract
(e) prostatic fluid (antibacterial)
(f) urine (antibacterial)
(4) biological
(a) intraepithelial lymphocytes
i) secrete cytokines, activate phagocytes and cytotoxic functions
(b) commensal bacteria
i) outcompete pathogens and stimulate microbial surveillance by
immune system
2. 2nd line
a) nonspecific defense
b) neutrophils, monocytes/macrophages, NK cells, eosinophils
c) types
(1) complement system
(2) coagulation system
(a) increase vascular permeability
(b) recruitment of phagocytic cells
(c) B-lysin from platelets-a cationic detergent
(3) lactoferrin and transferrin
(a) compete with bacteria for iron
(b) lactoferrin is activated by airway epithelium and neutrophils
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Immunology Study Guide Exam I
(4)
(5)
(6)
(7)
(c) it is anti-biofilm, bacteriocidal, anti-inflammatory, anti-viral,
fungicidal,
lysozymes
(a) breaks bacterial cells walls
cytokines
inflammation
(a) C reactive protein (CRP)
i) produced by the liver in response to cytokines (IL-6)
ii) CRP test used for inflammation
(1) also a correlation cardiovascular disease
iii) CRP opsonizes bacteria and apoptotic cells facilitating their
clearance via complement system and phagocytosis
(b) steps
i) Inflammation
(1) chemical mediators of inflammation
(a) vasodilating chemicals - histamine, serotonin,
bradykinin, prostaglandins
(b) chemotactic factors - fibrin, collagen, mast cell
chemotactic factors bacterial peptides
(c) both vasodilating & chemotactic factors - complement
fragments C5a and C3a, interferons, interleukins,
leukotrienes, platelet secretions
ii) Vasodilation and Expansion of Blood Vessels
iii) Neutrophils and Macrophages “crawl” out of blood vessels
iv) Repair of tissue damage
fever
(a) steps
i) IL-1 secreted by phagocytes travels to hypothalamus
ii) hypothalamus secretes prostaglandin, which resets
hypothalamic thermostat
iii) nerve impulses cause shivering, higher metabolic rate,
inhibition of sweating and vasoconstriction
iv) these increase body temperature to the point set by the
hypothalamic thermostat
(b) vasoconstriction in the periphery causes “goose bumps” and
shivering induced to heat production combine to cause chills
3. 3rd line
a) lymphocytes, Abs
b) specific defenses
E. Physico-chemical Barriers to Infection
System/Organ
Active Component
Effector Mechanism
Skin
Squamous cells; sweat
Desquamation, flushing, organic acids
GI tact
Columnar cells
Peristalsis, low pH, bile acid, flushing, thiocyanate
Lung
Tracheal cilia
Mucocialiary elevator, surfactant
Nasopharynx and eye
Mucus, saliva, tears
Flushing, lysozyme
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Immunology Study Guide Exam I
System/Organ
Active Component
Effector Mechanism
Circulation and lymphoid organs
Phagocytic cells
Phagocytosis and intracellular killing
NK cells
Serum
Direct and antibody
dependent cytolysis
Lactoferrin and Transferrin
Iron binding
Interferon
Antiviral proteins
TNF-alpha
Antiviral, phagocyte
activation
Lysozyme
Peptidoglycan hydrolysis
Fibronectin
Opsonization and
phagocytosis
Complement
Opsonization, enhanced
phagocytosis, inflammation
VII. Innate Immune Receptors
A. Characteristics of Innate Immune Cells
1. do no need prior activation
2. can recognize many different Ags (PAMPS)
3. do not have “memory”
B. innate immune recognition
1. microbial nonself - nonimmune phagocytes (macrophages & neutrophils)
2. missing self (no MHC class I) - NK cells
C. Detection of pathogens
1. innate receptors
a) cellular barrier cells & immune cells express innate receptors, which
recognize “conserved” receptors among classes of microbes
2. portion of the “conserved” structure that is recognized by innate receptors is
the pathogen associated molecule pattern (PAMP)
a) microbes of different classes express different PAMPs
3. so the pattern recognition receptor (PRR) of the innate cell can recognize the
PAMP
D. PRRs bind both danger-associated molecular pattern (DAMPs) & PAMPs
E. PAMPs
1. recognized by immune cells as foreign
2. PRRs bind PAMPs which allow phagocytosis of the pathogen & up regulation
of adaptive immunity
3. PAMPs are polysaccharides and polynucleotides that differ little from one
pathogen to another, but not found in host
a) gram - bacteria - LPS
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Immunology Study Guide Exam I
b) gram + bacteria - lipoteichoic acid
c) flagellin
d) peptidoglycan
e) dsRNA
f) unmethylated CpG
F. DAMPs
1. examples
a) altered membrane phospholipids
b) heat-shock proteins
G. PRRs
PRR
Toll-like Receptors
(TLR)
C-type Lectin Receptors
2+
(Ca dependent glycan
binding proteins)
Scavenger Receptors
Nucleotide-binding
domain Leucine Rich
Location
Cell and endosomal
membrane
(Neutrophils, DC,
Endothelial cells,
Macrophages)
Cell
membrane
(Neutrophils,
Macrophages)
Examples
PAMPs
CD36
Various bacterial
and viral
molecules
(EX- LPS)
Surface
carbohydrates
with terminal
mannose or
fructose
Diacylglycerides
Fungal glucans
NOD1, NOD2
NALP
Peptidoglycans
Flagellin, LPS
Most cells
Retinoic acid
inducible gene-1
(RIG-1)
Viral RNA
Cell membrane
(Neutrophils,
Macrophages)
FPR (formyl
peptide receptor),
FPRL1
Cell membrane
(Neutrophils,
Macrophages)
Cytoplasm
(Neutrophils,
Macrophages)
TLR 1-13
(EX- TLR4)
Mannose receptor
Dectin-1
(NLR) protein receptors
Caspase Activation and
Recruitment Domain
(CARD)-containing
N-formyl
Met-Leu-Phe
proteins or
RIG-Like
Receptors
(RLR)
Receptors
Peptides
containing Nformylmethionyl
residues
1. two functional classes:
a) endocytic pattern-recognition receptors
(1) found at the surface of phagocytes & promotes attachment of
microorganisms to phagocytes
(2) types:
(a) C-type lectin receptors
i) mannose receptors recognize terminal sugars
ii) dectins recognize fungal oligosaccharides
iii) signals promote phagocytosis & cytokine production
(b) scavenger receptors
i) SR-A and CD36 mediate uptake of lipoproteins
ii) signals promote phagocytosis & cytokine production
(c) N-formyl Met receptors
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Immunology Study Guide Exam I
i) FPR and FPRL1 recognize N-formlmethionyl residues
ii) promotes movement of phagocytes
(d) opsonin receptors
i) example is C3b of complement pathway that can improve
opsonization among phagocytes
b) signaling pattern-recognition receptors
(1) binding of PAMPs to signaling PRR promotes synthesis & secretion of
cytokines
(2) locations
(a) extracellular
i) cellular surface
(1) function to bind bacteria/fungi cell components and
stimulate the production of inflammatory cytokines
(2) toll-like receptors (TLR) 1, 2, 4, 5, 6
(a) recognize PAMPs on innate immune cells
(b) they are homodimers (TLR 1, 6 are hetero)
(c) each has specificity for specific microbe
(d) TLR 1 - bacterial lipoprotein
(e) TLR 2 - bacterial glycolipids, lipoproteins, lipoteichoic
acid, fungal zymosan
(f) TLR 4 - LPS
(g) TLR 5 - flagellin
(h) TLR 6 - mycoplasma lipopolypeptides
(i) TLR 10 - unknown ligands
(3) CD14
ii) secreted
(1) cause opsonization and phagocytosis
PRR
Location
Examples
Pentraxins
Plasma
C-reactive protein
(CRP)
Collectins
Plasma
Mannose-binding
lectin (MBL)
Ficolin
Plasma
Ficolin
Complement
Plasma
C3
PAMPs
Microbial
phosphorylcholine
and
phosphatidylethan
olamine
Carbohydrates
with terminal
mannose and
fructose
Nacetylglucosamine
and lipoteichoic
acid components
of the cell walls of
Gram-positive
Microbial surfaces
bacteria
(b) endosomal
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Immunology Study Guide Exam I
i)
bind to viral components and trigger the synthesis of
cytokines called interferons
ii) TLRs
(1) TLR 3 - viral dsRNA
(2) TLR 7 -viral ssRNA
(3) TLR 8 - viral ssRNA
(4) TLR 9 - Unmethylated CpG oligonucleotides (ODN)
(5) TLR 11 - toxoplasma profilin
(6) TLR 12 & 13 - unknown ligands
iii) different TLRs respond to different PAMPs, but all activate
similar signaling mechanisms, including:
(1) inflammation
(2) chemotaxis
(3) endothelial adhesion
(4) antiviral activities
(5) stimulation of adaptive immunity
iv) TLR signaling
(1) PAMP binding causes TLR dimerization
(2) NF-�β & AP-1are activated by TLR signaling
(a) TNF, IL-1, chemokines, endothelial adhesion
molecules
(c) cytoplasmic
i) examples
(1) Nucleotide-binding domain leucine rich protein receptors
(NLR) - produce inflammatory cytokines
(2) Rig-like receptor (RLR)
(3) Caspase Activation and Recruitment Domain (CARD)containing proteins - produce interferons
ii) NLR protein receptor (NLR)
(1) Nucleotide oligomerization domain-containing protein like
receptor (NOD-Like Receptor)
(2) NOD1 recognizes peptidoglycan & substances from gramneg bacteria
(3) NOD2 recognizes muramyl dipeptide from both gram-pos
and gram-neg bacteria
(4) signals promote phagocytosis, cytokine and defensin
production
iii) RIG-like receptor (RLR)
(1) recognize viral dsRNA, ssRNA & mRNA
(2) promote production of type I IFNs
H. PAMPs and DAMPs associated with disease
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Immunology Study Guide Exam I
G. cytokines are small signaling proteins/peptides/glycoproteins secreted by
immune cells for intercellular communication
1. concentration may increase 1,000 fold during infection
2. short-lived
3. can be autocrine, paracrine or endocrine
4. share pleiotropism, redundancy, synergy & antagonism with other cytokines
to tightly regulate them
VIII. Phagocytosis
A. Endocytosis
A. engulfing some extracellular fluid with its material
B. performed by all nucleated cells to engulf polar molecules and other
hydrophobic molecules that cannot pass through the membrane
C. functions
A. nutrient and drug uptake
B. cell adhesion and migration
C. receptor signaling
D. pathogen entry
E. neurotransmission
F. receptor downregulation
G. antigen presentation
H. cell polarity
I. mitosis
J. growth and differentiation
D. types
A. receptor mediated (clathrin-mediated endocytosis)
A. a type of micropinocytosis
B. small vesicles (pits) containing proteins (100nm)
C. cells internalize molecules by inward budding of plasma
membrane vesicles using receptors specific to the
molecules being internalized
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Immunology Study Guide Exam I
D. this is how all eukaryotes internalize nutrients, Ags,
growth factors, pathogens (viruses) and recycle receptors
B. caveolae
A. a type of micropinocytosis
B. very small pits (50nm) w/ no proteins (clathrin)
C. abundant in muscle, lung, fat, endothelium and fibroblasts
D. types
A. transcytosis
A. transporting of proteins from luminal side to
interstitium between underlying tissues
B. caveolae-mediated
A. caveolae bud off from membrane & fuse
with intracellular compartments
C. potocytosis
A. caveolae mediate uptake of small solutes by
pinching off but remaining associated with
cell membrane
C. macropinocytosis
A. extracellular fluid taken up by ruffles or invaginations of
cell membrane (0.5-5 µm diameter)
B. dependent on actin-mediated remodeling of cell
membrane, but does not require action of dynamin
C. endosomes with large volume fuse with lysosome for
digestion
D. phagocytosis
A. process where a special cell binds and engulfs particles
>0.75 mm to form an internal phagosome
B. pathogens nutrients, minerals, cell debris can be engulfed
C. phagosome fuses with lysosome leading to digestion
B. Phagocytes
A. structure
A. phagocytic receptors
A. integrins & complement receptors
B. lectins
C. Fc receptors
B. adhesion receptors
A. selectins
B. integrins
C. secondary granules
D. primary granules
E. phagolysosome
F. activation receptors
A. chemokine and f-MetR
B. interferon-R
C. TM F-R
D. TLR & IL-1 receptors
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Immunology Study Guide Exam I
G. MHC I and II
B. properties of activated phagocytes
A. enhanced rate of phagocytosis
B. enhanced production of toxic RO intermediates
C. enhanced production of NO
D. enhanced phagosome-lysosome fusion
E. increased number of MHC class II molecules
F. secretion of IL-12: differentiation of CD4 T cells
C. phagocytes encounter microorganisms at injury, lymph nodes, tissue
fluid, epithelium & spleen
D. phagocytes can kill microorganisms
A. extracellular killing
B. oxygen-dependent killing system
A. NADPH mediates production of ROS
C. oxygen-independent killing system
A. release of granules containing proteolytic enzymes:
defensins, lysozyme, cationic proteins
D. intracellular killing
E. ways pathogens avoid being killed
A. cytotoxicity
A. streptolysin O (strep)
B. adenylate cyclase (bordetella pertussis)
B. inhibit opsonization
A. capsule (S. pneumoniae)
B. M protein (S. pyrogenes)
C. survive intracellular killing
A. inhibit lysosome fusion (M. tuberculosis)
B. escape phagosome (Rickettsia)
C. survive lysosomal enzymes (Salmonella)
F. rolling occurs as the leukocyte approaches the site of inflammation
where Sialyl-Lewis and E-selectin receptors on the epithelia are
exposed where they bind L-selectin and integrin respectively on the
neutrophil to slow it down and allow it to enter at the site of the problem
G. steps of phagocytosis
A. recognition of target (directly or by opsonization)
B. engulfment
C. actual process of internalization
D. enters the lysosomal system where degradation takes place
H. phagocytosis cells
A. neutrophils
B. monocytes
C. macrophages
D. dendritic cells
E. mast cells
F. eosinophils, basophils
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Immunology Study Guide Exam I
I. receptors engaged in phagocytic process will determine what
associated cell responses will be triggered
J. phagocytosis signals
A. Ig-opsonized particle
A. cytokine production/release
B. prostaglandin and leukotriene production/release
C. degranulation
D. respiratory burst
B. apoptotic cell
A. TGF-β production/release
B. down-regulation of pro-inflammatory cytokines
K. various stimuli potentiate signal molecules regulating phagocytic
process
A. spleen tyrosine kinase (Syk)
A. cytoplasmic Try kinase expressed by most hematopoietic
cells
B. generates cascade for activation of B cells, mast cell
degranulation, PMN/macrophage phagocytosis and
platelet activation
L. phagosome made by actin remodeling
M. after particle is engulfed it joins with the lysosome to become the
phagolysosome
N. early phagosome (O2-dependent)
A. ligation of PRR triggers flushing of phagosome contents with
antimicrobial compounds
A. respiratory burst - increased O2
B. NADPH Oxidase - produces superoxide (O2-) radicals
from O2
C. superoxide dismutase (SOD) - produces H2O2 and
singlet oxygen from superoxide
D. myeloperoxidase (MPO) - generates hypochlorous acid
and hydroxyl radicals and contains heme pigment
(forming green pus)
E. inducible nitric oxide synthetase (iNOS) - produces NO
from L-arginine and O2, requires 5 redox cofactors,
expression is induced by PRR ligation or cytokines
O. late phagosome (O2-independent)
A. transition from early to late phagosome involved delivery of more
destructive enzymes and molecules via secretory vesicles
A. vacuolar ATPase - lowers pH of phagosome lumen (~4.5)
B. defensins - disrupt cell membrane synthesis (repair)
C. cathepsin H - endopeptidase/aminopeptidase
B. lysosome fuses with late phagosome
A. lysosomal acid phosphatase (LAP) - membrane-bound
enzyme that cleaves AMP, G6P...
B. nucleases - DNase, RNase
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Immunology Study Guide Exam I
C. proteases - collagenase, cathepsins (B)...
D. carbohydrases - β-glucosidase, hexosaminidase A, αmannosidase, α-fructosidase, sialidase...
E. lipases - sphingomyelinase and esterases
C. PMN granules - fuse with the phagolysosome
A. O2 - dependent
A. myeloperoxidase generates hypochlorous acid
from hydrogen peroxide and ClB. O2 - independent
A. cationic proteins damage bacterial membranes
B. lysozyme breakds down peptidoglycan
C. lactoferrins capture Fe
D. proteases and acid hydrolases destroy bacterial
proteins
P. Neutrophils
A. live for 5 days
B. can leave blood and reach site of infection within 30 min of
injury/infection
C. phagocytose, digest and die
Q. macrophages
A. monocytes leave blood and arrive at site of infection in 20-40 hrs
B. more efficient at respiratory burst (more active in chronic
inflammations)
C. second wave to finish what PMN started
D. become APCs which direct cell debris from phagolysosomes to
the MHC for Ag presentation
R. Ag processing/presentation
A. foreign particle is phagocytized into small pieces (Ags) and
present it to helper T cells
B. sometimes they also present self-Ags to double check selfreactive T cells
S. phagocyte can be an APC
A. may present to adaptive immune system
B. phagocyte travels to the lymph node and “presents” the Ag to the
adaptive immune cells
T. mast cells
A. express TLR and interact with DC, B cells and T cells
B. phagocytose and some Ag presentation
C. destroy gram - bacteria
D. produce pro-inflammatory cytokines to activate other cells/attract
more phagocytes to the site of infection
U. non-professional phagocytes
A. dying cells and foreign organisms are consumed by cells other
than “phagocytes”
A. epithelium
B. endothelium
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Immunology Study Guide Exam I
A. thin cytoplasm, round nucleus
B. line vessels, keeping plasma and cells inside
C. exposure of underlying collagen elicits
inflammation
D. damaged endothelium secrete prostaglandins
(vasodilation) and adhesion molecules
(extravasation)
C. fibroblasts
A. long spindle-shaped cells in ECM
B. functions
A. wound healing
B. stimulated by local tissue damage
C. produce ground substance
(glycosaminoglycans) and fibers (reticular,
collagen and elastin) to heal a wound and
repair ECM
D. mesenchymal cells
B. can only take up a limited type of particles
C. do not produce ROS
IX. Complement
A. What is it?
1. consists of over 30 serum & membrane proteins
2. synthesized in liver, GI and gut
3. enzymes cleave proteins unevenly generating fragments
a) smaller are “a”, larger are “b”
B. what does it do?
1. recognizes pathogens, injured cells & transformed cells
2. promotes/enhances cell-mediated effector
3. activate/direct inflammatory response
4. directly cytolytic
5. important for removal of apoptotic cells and immune complexes
C. summary of complement function
1. opsonization and phagocytosis
2. stimulation of inflammatory reactions
3. complement-mediated cytolysis
D. how is complement activated?
1. classical pathway
a) triggered by bound Abs (both innate & adaptive immunity)
b) steps
(1) complement protein 1 complex q (C1q) binds to Fc region of Ig (IgM or
IgG)
(a) must have 2 adjacent Ig
(2) C1r cleaves and activates C1s, C1s cleaves C4 and C2, which forms
C3 convertase
(a) active forms are C4b and C2a
(3) this activates C3 to C3b and begins the terminal pathway
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Immunology Study Guide Exam I
E.
F.
G.
H.
I.
2. alternative pathway
a) triggered by spontaneous deposition on surfaces
b) steps
(1) spontaneous cleavage of C3
(2) once C3b is deposited on the pathogen’s surface it can bind Factor B
(3) cleavage of Factor B by Factor D with stabilization by properdin
(4) cleavage of more C3 by C3 convertase
(5) C3b binds to cell surface and forms C3bBb (C5 convertase)
(6) continues down terminal pathway
3. lectin pathway
a) triggered by microbial carbohydrates (& IgM?)
b) steps
(1) mannose-binding lectin (MBL) forms clusters of 2-6 carb-binding heads
around a central collagen-like stalk
(2) on binding of MBL to bacterial surfaces, MASP-1 & MASP-2 (MBLassociated serine proteases) activate complement by cleaving C4 & C2
(forming C3 convertase)
activation pathway is everything before and including C3 and the terminal
pathway is everything beyond the activation of C3 leading to the formation of the
MAC
components
1. activation is only stable if complement proteins are attached to microbes or
Abs
2. activation is inhibited by regulatory proteins that are present on normal host
cells and absent from microbes
Complement protein 3 (C3)
1. C3b may covalently attach to cell surface using thioester bond, causing
complement to proceed
2. C3b may remain unattached because the thioester bond is hydrolyzed,
inhibiting complement
late stage of complement activation
1. steps
a) C5 is cleaved by C5 convertase (C3bBb) forming C5b and C5a
(1) C5a is released causing inflammation
b) C5b binds C6 and C7
c) C7 is hydrophilic and inserts into the membrane of target cell
d) membrane C7 serves as receptor for C8
e) C9 polymerizes at the site of C5b-C6-C7-C8 complex forming membrane
attack complex (MAC)
(1) a pore allowing free movement of water and ions
f) cell expands and ruptures
regulation of complement
1. necessary because low-levels of complement damage our cells
2. types/places of regulation
a) fluid phase inhibitory proteins
(1) C1-INH (classical pathway)
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Immunology Study Guide Exam I
(a) binds to activated C1r2s2 preventing its proteolytic activity on C4 &
C2
(2) Factor H (alternative)
(a) works in three ways:
i) it can bind and block Factor B from binding C3b
ii) causes dissociation of C3bBb to C3b which does not allow it
to activate C5
iii) with the help of Factor I it can inactivate C3b to iC3b
(3) S-protein (all pathways)
(a) binds to soluble C5b-C6-C7 before insertion in the membrane
b) membrane-bound inhibitory proteins
(1) decay accelerating factor/ complement receptor 1 (DAF/CR1)(all
pathways)
(a) bind to C3 convertase (C4b2a and C3bBb) causing the release of
2a and Bb respectively
(2) membrane cofactor protein/complement receptor 1 (MCP/CR1)(all
pathways)
(a) act as cofactors for Factor I-mediated proteolytic cleavage of C3b,
producing iC3b and release of C3f
(3) CD59 (all pathways)
(a) incorporates into scaffold made by C5b-C6-C7-C8 and inhibits C9
addition
J. biological activities of complement
1. opsonization
a) complement binds bacterium forming C3b/iC3b/C4b which is recognized
by phagocytes complement receptors inducing phagocytosis
b) receptors on cells and effects of opsonization
(1) C1qR
(a) cells that have this receptor are mono/macs, PMN, endothelium
(b) this receptor binds C1q and cause phagocytosis
(2) CR1
(a) cells that have this receptor are mono/macs, B cells, erythrocytes
(b) this receptor binds C4b/C3b and leads to immune cell clearance
and phagocytosis
(3) CR3
(a) cells that have this receptor are mono/macs, NK cells, PMN
(b) bind iC3b and cause phagocytosis, cell adhesion and oxidative
burst
(4) CR2
(a) cells that have this receptor are B cells & FDC
(b) bind to C3dg/C3d and cause an adaptive immune response
(c) C3 bound to Ag provides costimulatory signal to B cells via CR2
receptor (lower activation threshold)
(d) CR2 on FDC mediate long term retention of Ag-C3d complex for
maintenance of long term memory
2. inflammation
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Immunology Study Guide Exam I
a) C3a & C5a promote inflammation by:
(1) activating neutrophils, increasing neutrophil adhesion, helping
neutrophil migration and chemotaxis, activating monocytes & mast cell
degranulation
3. cell lysis
K. complement and immune response
1. immune complex clearance
2. clearance of apoptotic cells
a) apoptotic bodies fix complement, allow opsonization and phagocytosis
3. induction/enhancement of humoral immune response
4. B-cell memory
5. induction/enhancement of T cell response
a) complement activation products signal for T cell proliferation
L. deficiencies in complement
1. C1, C4, C2 - lupus-like disease
2. C2, C3, fH, fI, MCL, MASP-1, MASP-2, fB, fD
3. properdin - neisserial infection
4. C5, C6, C7, C8, C9 - recurrent neisserial infection
X. Cytokines & Cellular Response
A. cytokines are small signaling protein/peptide/glycoproteins
B. cytokine groups
1. monokines - produced by mononuclear phagocytes
2. lymphokines - produced by activated lymphocytes (T helper cells)
a) can act as chemokines for macrophages/other lymphocytes and
upregulate adaptive immunity
3. interleukins - act as mediators between leukocytes
a) largest group of cytokines
b) act in development of immune cells
4. chemokines - small, responsible for leukocyte migration
a) difference between cytokines and chemokines
(1) chemokines are chemotatic cytokines
(2) chemokines characteristics:
(a) small proteins
(b) 4 cysteine residues
(c) pro-inflammatory/recruit immune cells
(d) can be homeostatic
C. cytokine properties
1. Can be secreted by immune cells
2. Used for intercellular communication
3. Usually present in small amounts and action is short-lived
4. Exert action by binding to a receptor on target cell/organ
a) Autocrine- excites itself
b) Paracrine- excites those nearby
c) Endocrine - enters blood stream and excites cells systemically
5. Antigen nonspecific
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Immunology Study Guide Exam I
6. Pleiotropic-different cell types can secrete same cytokine or a single cytokine
can act on several different cell types
a) pleotropy - one cytokine from one cell can activate multiple cells because
they all have a receptor for that cytokine
7. Redundency of function-similar functions can be stimulated by different
cytokines
a) IL-2,4 and 5 stimulate B cells to proliferate
b) redundancy is due to the nature of the cytokine receptors which are
heterodimers (sometimes heterotrimers)
c) many receptors have a subunit that is common to all members
8. Influence synthesis of other cytokines
a) produce cascades
b) enhance or suppress
c) exert + or – mechanisms of immune inflammatory responses
9. Influence actions of other cytokines
a) Antagonist
(1) IFNᵧ has an opposite effect than IL-4 on the B cell to stop switch to IgE
b) Additive
c) Synergist
(1) IL-4 + IL-5 cause B cells to switch to IgE
10.Bind to specific receptors on target cells with high specificity
D. Jak-STAT signaling pathway
1. cytokine binds α-chain of receptor which recruits β-chain (heterodimer)
2. Janus kinase (Jak) phosphorylates tyrosine residues
3. phosphorylation of STAT dimerizes into pSTATs
4. pSTAT functions a transcription factor in nucleus
5. cytokine receptors using Jak-STAT
a) Type I IFN (IFN-α/β)
b) Type II IFN (IFN-ᵧ)
c) IL-2 through IL-4
d) IL-6 through IL-7
e) IL-9 through IL-12
E. Mediators/Regulators of innate immune response
1. produced by activated macrophages, DCs, PMN and NK cells in response to
microbial infection
a) binding of bacterial LPS, viral molecules & NA variants, mannose,
bacterial flagellin, lipoteichoic acid in G+ bacteria, and peptidoglycan to
TLRs are a powerful stimulus
2. mainly act on endothelial cells and leukocytes to stimulate early inflammatory
response to microbes
3. fight both intra and extra cellular pathogens
a) intra
(1) Type I IFN (α/β)
(2) Type II IFN (ᵧ)
b) extra
(1) TNF-α, IL-1, IL-6
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Immunology Study Guide Exam I
4. functions
a) recruit and activate neutrophils and monocytes to site of infection
b) IL-12 - stimulates production of Th1 cells (adaptive)
c) IL-6 - suppresses regulatory T cells (double negative)
5. PRR signals lead to production of early response cytokines
6. cytokines trigger fever to limit pathogen growth
a) pyrogenic cytokines (IL-1 & 6. TNF, IFN) and microbial toxins stimulate
hypothalamic endothelium
b) stimulation of PGE2 and cyclic AMP
c) elevated thermoregulatory set point
d) heat conservation and heat production increase giving you a fever
7. IL-1/IL-6 and TNF-α - have synergism (meaning they increase the effects of
the others)
8. Cytokines
a) IL-1
(1) IL-1α in macrophages/mono, DCs, fibroblasts, hepatocytes,
adipocytes, oligodendrocytes, keratinocytes, eosinophils
(2) IL-1β - in all of the above as well as NK cells, neutrophils, adrenal
cortical cells, osteoblasts, neurons, Schwann cells, platelets
(3) local effects
(a) activates vascular endothelium
(b) activates lymphocytes
(c) local tissue destruction
(d) increase access of effector cells
(4) systemic effects
(a) fever
(b) production of IL-6
(5) other effects
(a) release of IFNᵧ at NK cells
(b) express MMP, facilitates monocyte migration, degrade IL-1 to limit
local inflammation (fibroblasts)
b) TNF-α (tumor necrosis factor)
(1) mast cell, macrophage (also NK cells, CD4+, CD8+)
(2) local effects
(a) activates vascular epithelium
(b) increase vascular permeability
i) leads to increased entry of IgG, complement and cells to
tissues and increased fluid drainage to lymph nodes
(3) systemic effects
(a) fever
(b) mobilization of metabolites
(c) shock
(d) acute phase proteins (liver)
(e) express MMP facilitate monocyte migration, production of IFNβ
(fibroblasts)
(f) bone resorption (osteoclasts)
25
Immunology Study Guide Exam I
c)
d)
e)
f)
(4) low-moderate quantities (in local tissue) of TNF lead to proper removal
of infection and adaptive immunity, but high quantities (systemically)
can lead to systemic edema, shock and death
IL-6
(1) macrophages/mono, B cells, CD4+ Th2 cells, fibroblasts,
keratinocytes, endothelial cells
(2) local effects
(a) lymphocyte activation
(b) increased Ab production
(3) systemic effects
(a) fever
(b) induces acute-phase protein production
(c) increase output of PMN (bone marrow)
(d) bone resorption (osteoclasts)
(e) platelet production (megakaryocyte)
IL-8
(1) endothelia, macrophages
(2) local effects
(a) chemotactic factor recruits neutrophils, basophils and T cells to
site of infection
i) chemokine for PMN expressing CSCR1 & CXCR2
ii) acPGP is a cleavage product of collagen which can also serve
as a chemoattractant
IL-12
(1) machrophages/mono, PMN, DCs
(2) local effects
(a) activates NK cells
(b) induces the differentiation of naive CD4 T cells into Th1 cells
(c) promotes Th1/Tc1 response
(3) stimulates NK cell production of IFN-ᵧ, and IFN-ᵧ stimulates IL-12
synthesis
(4) uses Jak/STAT pathway
Type I IFNs (IFN-α/-β)
(1) α - 13 proteins made mainly by plasmacytoid DC (also macs and PMN)
(2) β - 1 protein made by many cells
(3) IFNAR1/IFNAR2 (receptors) expressed on all nucleated cells and bind
both Type 1 IFNs
(4) functions (antiviral)
(a) activates Ser/Thr protein kinase (PKR)
i) protein synthesis is inhibited by inactivating EIF2α
(b) activates 2’,5’-oligoadenylate synthatase
i) activates RNase L which degrades RNA molecules
(c) activates Mx GTPases
i) interfere with intracellular transport of viral components,
limiting nuclear translocation and virion assembly
26
Immunology Study Guide Exam I
(d) activates NK cells & macrophages, inhibits replication in
neighboring uninfected cells and increases MHC I expression/Ag
presentation
(5) disease being treated with IFN
(a) α - hepatitis B & C and leukemias
(b) β - multiple sclerosis, ulcerative colitis
(c) effect of treatment is to degrade mRNA and inhibit protein
synthesis
F. Mediators/Regulators of acquired immune response
1. produced mainly by T lymphocytes in response to specific recognition of
foreign Ags
a) Th cells are “middlemen”
b) no phagocytic/cytotoxic ability
c) they bind APCs, pass into to adaptive immune system
(1) facilitate isotype switching in B cells
(2) activate cytotoxic T cells
(3) maximize phagocytic and bacteriocidal abilities of mac/PMNs
d) after activation by APC, they secrete IL-2 (autocrine) to proliferate and
become Th1 or Th2
e) types of T helper cells
(1) Th1
(a) produce IL-2, IFNᵧ, TNFβ to activate cytotoxic T cells & macs
(b) also produce IL-3 & GM-CSF to stimulate more leukocyte
production
(c) upregulates CMI
(2) Th2
(a) secrete IL-4, 5, 6 and 10 to stimulate Ab production from B cells
(b) upregulates humoral immunity
(3) Th0
(a) produce IL-2, 4 & IFNᵧ
(b) then differentiate to Th1 (if IL-12 is present) or Th2 (if IL-4 is
present)
27
Immunology Study Guide Exam I
2. Cytokines
a) IL-2
(1) produced by Th1 lymphs
(2) functions/actions
(a) growth, proliferation & activation of T, B and NK cells
(b) stimulation of potent T cell proliferation
b) IL-3
(1) produced by T lymphs and NK cells
(2) functions/actions
(a) stem cell growth/differentiation
(b) mast cell growth and histamine release
c) IL-4
(1) produced by Th2 lymphocytes
(2) functions/actions
(a) B cell proliferation, differentiation, production of Abs (IgG, IgE)
(b) Ag presentation (MHC expression on macs)
(c) proliferation of T cells
d) IL-5
(1) produced by Th2 cells, mast cells, eosinophils
(2) functions/actions
(a) proliferation/differentiation of activated B cells
(b) eosinophil activation, involved in allergies and asthma
e) IL-7
(1) produced by bone marrow stroma and thymus stroma
(2) functions/actions
(a) differentiation of stem cells into progenitor B & T cells
f) IL-10
(1) produced by Th2 cells
(2) functions/actions
(a) cytokine production by macrophages
(b) activation of B cells
g) transforming growth factors
(1) produced by T cells, macs & other body cells
(2) polypeptide growth factors
(3) functions/actions
(a) chemotaxis and production of IL-1 by macs/mono
(b) synthesis of IgA by plasma cells
h) INF-ᵧ
(1) produced by NK and T cells
(2) functions/actions
(a) activates granulocytes, macs, T cells, B cells(differentiation stops
cell division), endothelial & NK cells
(b) in many cells types it induces MHC class I or II presentation, weak
anti-viral activity, stops cell division and haematopoiesis
G. Stimulators of haematopoiesis
1. produced by bone marrow, stromal cells and leukocytes
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Immunology Study Guide Exam I
H.
I.
J.
K.
2. induce stem cell factors IL-3, IL-7 and GM-CSF
3. primarily involved in directing the division and differentiation of bone marrow
cells and precursors of blood leukocytes
a) G-CSF (granulocyte colony stimulating factor)
b) M-CSF (macrophage CSF)
c) GM-CSF (granulocyte-macrophage CSF)
many of these cytokines together is what leads to septic shock
1. together they cause the activation of coagulation cascade,
prostaglandin/leukotriene production, activation of complement cascade which
leads to
a) endothelial cell damage, multiple organ failure, disseminated intravascular
coagulation (DIC) and adult respiratory distress syndrome (ARDS)
Neutrophils (PMN, Segs)
1. most abundant leukocyte in the blood
2. PMN production increases immediately following infection
3. usually first to arrive at infection
4. kill by phagocytosis and release of ROS (respiratory burst)
5. neutrophil granules (phagolysosome)
a) azurophilic (primary) granule
(1) myeloperoxidase - degrades membranes, DNA/RNA
(2) bacterial permeability increasing (BPI) protein - binds LPS and inhibits
incorporation in G- bacteria cell walls
(3) lysozyme - hydrolysis of glycosidic bonds between elements of
peptidoglycan layer
(4) cathepsin - protease
(5) defensins - inhibit cell wall synthesis
(6) phospholipase A2 - breakdown of membranes by cleaving fatty acids
from glycerol
b) specific (secondary) granules (extracellular)
(1) lysozyme, phospholipase A2, defensins, cathepsins
(2) lactoferrin - iron chelator, to limit bacterial enzymatic activity
(3) collagenase - ECM degradation enzyme
(4) gelatinase - similar action as collagenase
monocytes/macrophages
1. less abundant that PMNs
2. circulate as mono and differentiate to macs in tissue
3. functions
a) activated by innate receptors and/or IFN-ᵧ from T & NK cells
b) professional APC
c) major cell in phagocytosis
d) better respiratory bursts that PMNs
e) contribute to acute and chronic inflammation
NK cells
1. express activating and inhibition receptors allowing for recognition of
transformed, stressed or infected host cells
2. utilize perforin/granzyme to lyse cells
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Immunology Study Guide Exam I
3. secrete IFN-ᵧ in order to activate macs to kill microbe
4. participate in antibody-dependent cell-mediated cytotoxicity (ADCC)
a) NK cell’s Fc Receptor interacts with Igs bound to microbe resulting in
perforin/granzyme release and lysis of microbe
5. has both activating (AR) and inhibitory receptors (IR) that interact with normal
cells
a) AR
(1) activation of these induces release of cytotoxic granules and IFN-ᵧ
b) IR
(1) killing is inhibited
6. tumors/intracellular microbes often reduce expression of MHC class I on
surface trying to provide a way of escaping cytotoxicity
a) this limits activates NK cells to lyse infected cells
7. NK cells can lyse cells that are “stressed” even if they have normal MHC class
I using other special AR-AR interactions
L. Mast cells
1. common at sites in the body exposed to environment
2. localized close to blood vessels to regulate permeability and cell recruitment
3. activated by binding of microbial products to TLR, complement or FcR
interactions with IgE or IgG bound to Ag
4. Immediate response
a) preformed granule contents
(1) histamine - increase vascular permeability and promote smooth muscle
spasm
(2) proteases - increase mucous secretion and degrade complement
factors into chemotactic factors
(3) chemotactic factors - chemokines for eosinophil and PMN recruitment
b) early lipid mediators
(1) prostaglandin D2 (PGD2) - vasodilation, bronchoconstriction, increased
mucous secretion
5. late phase
a) secreted cytokines
(1) IL-2/IL-6/TNF-α - increased vascular adhesion, activates APC and
phagocytes
(2) IL-4/IL-5/IL-13 - increased Th2 response (IgE and IgG production)
b) late lipid mediators
(1) platelet activating factor (PAF) - platelet aggregation/histamine release,
vasodilation, bronchoconstrictino
(2) leukotriene B4 - eosinophil, monocyte and PMN chemotaxis
(3) leukotriene D4 - increase vascular permeability bronchoconstriction
M. Eosinophils
1. IL-5 (from Th2) activates them
2. recruited to late phase
3. degranulation upon FcR binding to IgE-Ag
4. preformed granules
a) lysosomal hydrolases (toxic to helminths) - damages cell membranes
30
Immunology Study Guide Exam I
b) eosinophilic-specific proteins (toxic to helminths and bacteria) - damages
cell membrane & degrades RNA
c) eosinophilic peroxidase - degrades membranes & DNA/RNA
5. lipid mediators
a) PAF, prostaglandins, leukotrienes
N. Basophils
1. activation similar to mast cells
2. produce/degranulate similar molecules as mast cells
3. functions
a) amplify vascular permeability
b) vasodilation
4. basophilic specific factor:
a) eosinophil chemotactic factor of anaphylaxis (ECF-A) - attracts eosinophils
5. can also act as primary APCs in lymph nodes activating Th2 cells against
parasitic helminths
O. Plasmacytoid DC (PDC)
1. functions through NF-𝛋β pathway releasing type I IFN and TNF-α, IL-6, IL-12
P. myeloid DC (mDC)
31