exam 1 Flashcards
leukocytes that are phagocytes
neutrophils, monocytes, macrophages, eosinophils
phagocytosis: functions
- killing infected cells, removal of dead/dying cells and debris
- ROS
innate immune system: characteristics
immediate, initiating
crude screening
prevents extensive damage
little specialized training, no memory
resolution: what happens?
inflammation occurs until DAMPs, PAMPs have been removed
After: resolution and restoration of normal function
adaptive immune system: characteristics
delayed initial response, requires learning
precise response tailored to threat
components generated in response to threat, generates memory
barriers to entry: physical
skin, cilia, tears, mucus
barriers to entry: chemical
acid, enzymes
barriers to entry: biological
normal flora occupy spaces to block pathogens
alarm: what happens?
cells become active, secrete factors (proteins)
- cytokines, chemokines
recognition: what happens? (innate immune receptors)
recognize
DAMPs (danger/damage-associated molecular patters)
- damage, things outside cell that shouldn’t be
PAMPs (pathogen-associated molecular patterns)
- microbial structures
- RNA, DNA
naive lymphocytes
before encountering specific antigen, they transit between circulatory and lymphatic systems looking for their antigen
neutrophils: arrival, lifespan
first to arrive at infection site, short lived
macrophages: functions
phagocytosis, intracellular killing
extracellular killing of infected, altered self-targets
tissue repair
respiratory burst
dendritic cells: functions
antigen presentation, co-stimulation for activation of antigen-specific T cells
cytokine production
NK cells: functions
killing/lysis of virus-infected and altered self-targets
macrophage activation
mast cells: functions
rapid production of inflammatory mediators, important in allergic rxns and parasitic infections
sentinel innate cells
neutrophils, macrophages, mast cells, NK cells, dendritic cells
neutrophils: characteristics, functions
highly microbicidal and phagocytic
produce respiratory burst
function in inflammation, tissue damage, phagocytosis, intracellular killing
neutrophils: granules
lytic granules fuse w/ phagosome and discharge content
neutrophils: target
bacterial and fungal infections
mast cells: location
connective tissue
mast cells: granules
inflammatory mediators
macrophages: lifespan
long-lived
interferons: general functions
interfere w/ viral replication and activate NK cells
Phagocytosis: opsonization steps
- bacterium w/ opsonins attaches macrophage w/ opsonin receptor
- engulfment: becomes phagosome
- phagosome-lysosome fusion
- degradation
phagocytosis: degradation types
- binding to endocytic receptors induces engulfment and degradation
- component binding to signaling receptors induces cytokine synthesis
oxygen-independent killing in phagolysosomes
- antimicrobial peptides: damage microbial membranes
- lysozymes: hydrolyze peptidoglycan
- lactoferrin: deprives pathogens of iron
- hydrolytic enzymes: digests killed organisms
respiratory burst: process
cytoplasmic oxidase binds membrane oxidase, activates
NADPH needed
toll-like receptors: recognize, function
different microbial proteins, signal presence of microbes
- initiate, instruct adaptive immune response
ex) TLR4 recognizes LPS
rig-like receptors: recognize, function
cytoplasmic recognition of viral genomes (ssRNA, dsDNA)
induce production of proinflammatory cytokines, interferons
cGAS/STING: recognizes
cytoplasmic recognition of DNA
Nod-like receptors: recognize, function
cytoplasmic recognition of microbial products, danger signals, some viruses
inflammasome activation, which activates caspase-1 to cleave, activate IL-1B, IL-18
NF-kB functions
transcription factor proteins that regulate inflammation (innate cell differentiation, T cell survival)
IL-6: local, systemic effects
local: lymphocyte activation, antibody production
systemic: fever, acute-phase protein production in liver
TNF-a: local, systemic effects
local: activates vascular endothelium, increases permeability. leads to increased complement entry, fluid drainage
systemic: fever, mobilization of metabolites, shock
IL-1B: local, systemic effects
local: activates vascular endothelium, lymphocytes. local tissue destruction, increased access of effector cells
systemic: IL-6 production, fever
IL-12: local effects
activates NK cells
CD4 differentiation into TH1
IL-8 (CXC8): local effects
neutrophil, basophil recruitment
T-cell recruitment
NK cells: mechanism of action
killer inhibitory receptor recognizes MHC-1, prevents lysis of normal cells
killer activating receptors express endogenous self-molecules that act as ligands to activate NK
if there is no MHC, lysis occurs
inflammatory response: pathological consequences
activation of adaptive immune system can lead to autoimmunity, tissue damage, sepsis
tissue repair response can lead to fibrosis, tumor growth
homeostasis can lead to a shift in homeostatic set points, development of autoinflammatory diseases
inflammation: physiologic purposes
host defense, activation of adaptive immune system
tissue repair
adaptation to stress, homeostasis, restoration
rubor
increased blood flow, elevated cellular metabolism
coordinated delivery of blood components
- soluble mediators released after infection, injury (dolor)
- vasodilation, increased blood flow (rubor, calor)
- vascular leakage, increased interstitial osmotic pressure leads to edema (tumor, dolor)
- extravasation of fluid, leukocyte influx
- phagocytosis, toxic compound release
tumor
extravasation of fluid, leukocyte influx
outcomes of inflammation
- complete resolution: tissue capable of regeneration w/ little damage
- abscess formation: occurs w/ some bacterial, fungal infections
- scarring (fibrosis): in tissues unable to regenerate. excessive fibrin deposition
- progression to chronic inflammation
vasoactive amines
inflammation mediator
- histamine, serotonin
- produced when mast cells, platelets degranulate
- increases vascular permeability and vasodilation
vasoactive peptides
inflammation mediator
fibrin degradation products, kinins, fibrinopeptide A and B
- stored in active form in secretory vesicles, generated by proteolysis of precursors
proteolytic enzymes
inflammation mediators
ECM, basement membrane degradation, host defense, tissue remodeling, leukocyte migration
lipid mediators
eicosanoids, platelet-activating factors
- lipoxins: inhibit inflammation, promote resolution and repair
- prostaglandins: vasodilation, pain
- leukotrienes: neutrophil recruitment, vasoconstriction
anti-inflammatory drugs
NSAIDS:
- block COX1 to inhibit physiologic functions
- block COX2 to inhibit inflammatory stimuli
glucocorticoids:
- block PLA2, inhibits formation of arachidonic acid
neutrophil recruitment: steps
rolling, adhesion, arrest, diapedesis
adhesion
integrins LFA-1 and Mac-1 on the leukocyte bind ICAM-1 on the endothelium
rolling
1st step of neutrophil recruitment
mediated by selectins
arrest
neutrophil activation by chemokines
diapedesis
transmigration through the endothelium
resolution of inflammation: key mechanisms
- switch from pro-inflammatory prostaglandins to anti-inflammatory
- switch from neutrophil recruitment to monocyte (clearance of dead cells, debris)
resolution: edema timeline
peaks on the first day, subsides after ~36 hours
resolution timeline: neutrophils
peak after about 24 hours
resolution timeline: macrophages
peak after about 48 hours
complement pathway: main functions
- formation of membrane attack complex on pathogen membrane leads to lysis of pathogen
- opsonization
- B cell activation, antibody production
- clearance of circulating immune complexes
- promotion of inflammation
classical pathway: what happens?
C1q binds pathogen, antigen-antibody complex
C1r activates C1s, which cleaves C2 and C4 to make C3
complement activation depends on:
precursor zymogen cleaved to yield active enzyme, which cleaves next zymogen in cascade
alternative pathway: what happens?
spontaneous hydrolysis of C3 to form C3-H2O
binds B, cleaved by D to form C3bBb
MB-lectin pathway: what happens?
binds mannose on pathogen surfaces
- proteases MASP-1 and 2 cleave C2, C4 to make C3
C3 convertase: activates
anaphylatoxins C3a and C5a for increased phagocyte migration
opsonizing proteins (C3b)
terminal complement component: formation of membrane attack complex
complement regulation: DAF
permanently dissociates C3 convertase
Complement receptors: location, functions
C3b on bacterial cell surfaces, CR1 on macrophage binds
endocytosis of bacterium, phagosome formation, phagolysosome formation
membrane attack complex formation, function
C5b initiates construction of membrane pore from proteins 6-9
leads to lysis, destruction of cell
complement regulation: factors I, H
cleaves C3b bound to host, important in limiting alternative pathway
complement regulation: C1 INH
dissociated C1r and C1s from active C1 complex
complement regulation: how?
1/2 of complement proteins are regulatory, destroy complement components deposited on their surface
complement regulation: MCP
displaces Bb, makes C3b susceptible to cleavage by factor I
immunogen definition
molecule that induces immune response, such as antibody production from B or T cells
epitopes
portion of antigen bound by antibody
larger antigens may have several
immunodominant epitopes are more easily recognized
antigen definition
any molecule that can be recognized by a component of the adaptive immune system
- structural components of pathogens, allergens, tumors, drugs, vaccines, toxins
factors influencing immunogenicity: contribution of immunogen
foreignness: non-self better than self
size: bigger is better
physical form: particulate, denatured better than soluble and native
chemical nature: proteins, glycoproteins
degradability: processing by APCs
haptens, hapten-carrier complex
haptens are small molecules that can elicit immune response when attached to a large carrier (hapten-carrier complex)
small, simple molecules don’t provoke antibodies without protein carrier
haptens: clinical relevance
drugs attach host proteins, induce immune rxn to drugs
ex) conjugated vaccines for poorly immunogenic bacteria
- pneumococcal vaccine
- diptheria vaccine
antibody structure
has a constant region (Fc portion) and variable region
- constant region has 2 identical heavy and light chains, bound by disulfide bonds
- interact w/ immune complexes of other cells
- variable regions bind antigen
variable region of antibody
different in all antibodies
first 100 AAs highly variable (HV region)
HV region is antigen-binding site
avidity vs affinity
avidity: depends on affinity and number of interacting sites (monovalent). low affinity can have high avidity if valence is high
affinity: depends on Ka of binding site, monovalent, depends on specificity. increases after immunization w/ same antigen
IgG: structure, functions
most abundant, equal distribution between intra and extravascular
biological properties: antibody-dependent cell mediated cytotoxicity, neutralization, opsonization, complement activation
IgM: structure, functions
- first immunoglobulin made during primary infection, primary antibody response to challenge
- agglutination of viruses, bacteria
- most efficient for complement fixation
IgA: structure, functions
dimer w/ J chain, secretory component in secretions, abundant on mucosal surfaces as first line defense
- bactericidal for gram negative in presence of lysosomes
- viral agglutinator, preventing viral attachment to epithelial cell
- transcytosis across membrane
IgE: structure, functions
monomer
-doesn’t fix complement, mediates type I hypersensitivity rxns
- binds mast cells, basophils
- Ag binding induces degranulation, secretion of histamine
primary and secondary responses: IgM, IgG
IgM arrives first after primary stimulus, magnitude doesn’t change
IgG arrives later, magnitude changes in secondary response
polyclonal vs monoclonal
normal response is polyclonal: clones of B cells make antibodies of different specificities
monoclonal produced artificially, from 1 B cell, monospecific
multiple myeloma: cause , effect
neoplastic disorder of plamsa (B) cells characterized by clonal proliferation of malignant plasma cell
common primary bone malignancy: plasmocytoma
thymus structure, function
cortex packed w/ lymphocytes, immature T-cells
medulla w/ mature T cells, epithelioreticular cells
spleen structures
red pulp: RBC disposal
white pulp: enriched for lymphocytes, other immune cells
PALS: T-lymphocytes
follicles: B-cells
marginal zone: where blood is filtered. has macrophages, dendritic cells
mucosal associated lymphoid tissue: function, structure
diffuse lymphoid tissues, Peyer’s patches, follicles
mechanisms: IgA secretions, activated T-cells
down-regulate immune responses
M-cells: location, function
on folded luminal surface of peyer’s patches instead of microvilli, lack thick surface mucus
direct exposure to antigens, preferred route for entry into peyer’s patches
bind microbes, internalize by transcytosis by macrophages, dendritic cells, which present to T-lymphocytes
