Immunology Flashcards
Why can most invertebrates clear infections but be soon susceptible again?
they have no immunological memory
Variola major
smallpox; ~50% mortality
Variolation
- China; dried & powdered smallpox scabs used to immunize people; blown into nasal passage; 1-2% mortality +inflammation
- knowledge traveled the Silk Road to the Ottoman empire (Turkey) and Africa; African slaves introduced it to American and Lady Monatagu saw from Turkey and brought it to England
- Edward Jenner; cowpox; no mortality + less inflammation
Types of vaccines
- Attenuated (living but weak); ex: cowpox
- Inactivated (killed whole pathogen)
- Subunit (parts or components of a pathogen)
Vaccination risks
- Anaphylaxis (allergic response); involves two or more body systems like hives and difficulty breathing
- Vaccine quality or handling errors
Reproduction ratio (without vaccination)
- Ro
- transmissibility
- # of new infections caused by each infected person
- if high number, pathogen is highly transmissible
- Ro < 1 = not an epidemic and infection will die out in population
- Ro > 1 = epidemic and infection will spread in a susceptible host population
Herd immunity
- the proportion of a population that needs to be immune to prevent pathogen spread (achieved by infection or vaccination)
- based on Ro
- proportion to vaccinate = 1-1/Ro
- the more easily transmissible, the higher the population proportion that needs to be immunized to prevent spread (more infectious = vaccinate higher proportion of population)
How do we determine Ro values?
Case tracing!
Viral entry routes
- Conjunctiva (measles, coronavirus, rhinovirus, influenza, herpes virus)
- Respiratory tract
- Alimentary tract; oral-fecal (poliovirus)
- Urogenital tract, Anus; sexually transmitted ( HIV, herpes virus)
- skin, scratch injury, contact w/ blood/secretions (Hep B, rabies, ebola)
- capillary
- arthropods (West Nile virus, yellow fever)
Physical and chemical barriers to infection
- mucus and intact mucus membranes
- enzymes in mucus, tears, and saliva (pH 4.5-6)
- acid in sweat and sebum
- acid in stomach (pH 2)
- antibacterial proteins and zinc in semen
- competition from commensal bacteria in gut and genital tract
Skin covers ~2 m squared whole mucous membranes cover …
~400 m squared
- thin, permeable barriers
- gas exchange, food absorption, reproduction
Mucus
- goblet cells: secrete mucus and traps microbes
- ciliary escalator: cilia push bacterial cells back up; bacteria trapped by mucous and coughed out or swallowed and killed by stomach acid
- mechanical removal: coughing, sneezing
T or F. Generally, areas of higher moisture contain higher populations of normal flora
T (respiratory tract and gut)
Microbial antagonism
normal flora inhibits colonization by pathogenic microorganisms through occupation of habitat and competition for resources
Define chemical barriers
enzymes that can degrade microbial cell walls in saliva and anti-microbial peptides (AMPs)
AMPs
part of innate immune system; can punch holes in microbe membranes; part of an ancient defense system (found in so many organisms)
where are ‘captured’ pathogens taken?
- to closest lymph node or to spleen (screens blood) where circulating lymphocytes transit to see if they recognize it
- lymph goes through lymph nodes for surveillance of tissues whereas surveillance of blood occurs by blood moving through the spleen
1st line of defense
skin, mucous membranes, chemicals, AMPs
2nd line of defense
phagocytosis, complement, interferon, inflammation, fever
3rd line of defense
lymphocytes, antibodies
Complement factors
assemble in the membranes of the pathogens or cell walls sometimes of the pathogen and these can punch holes in the pathogens (rendering them unable to infect)
Interferons
once released (when an innate immune cells recognizes a pathogen), alerts other immune cells (whether innate or adaptive) that there is infection in an are! Can lead to recruitment of other cells (innate or adaptive)
Fever
can be induced ; systemic response by a local infection; # of pathogens like LOWER temps …; increase temp in mucosal areas and something like flu doesn’t have a chance
Fundamentals of Innate Immunity
- protective mechanism BEFORE infection
- rapid responses encoded within the germline (DNA in egg and sperm cells)
- Responses are typically identical upon repeat infection
Lymphocytes that are already armed to take on pathogens without any kind of long-term stimulation
NK cells
Mobilizing bodily defenses at sites of infection
Inflammation
- vasodilation
- increase in capillary permeability
- influx of immune cells to affected tissues
Four signs of inflammation
- redness: vessels dilate and blood volume increases; allows a lot more of innate immune cells to be in this area ; when there is an infection, there will be signals that tell them to stop at a certain place and enter tissues at dilated capillaries!
- heat: increased blood volume brings warmth to affected tissues
- edema: swelling due to accumulation of fluid from blood in affected tissue
- pain: some inflammatory mediators trigger the pain response ; alters function
Evidence of inflammation
- Elie Metchnikoff (1800s)
- insult to star-fish larvae
- rapid localization of cells to site of insult
- breakdown of thorn by cells
- first observation of process known as phagocytosis
Mast cells
- first responders
- vacuoles with lots of enzymes that can be secreted to attack pathogens
Neutrophils
highly representative in blood; very often first to deal with pathogens; move towards higher concentration of chemicals where infection is at (chemotaxis)
Describe phagocytosis
After bacteria are recognized, cell membrane of neutrophils extend on either side of bacteria and bacteria are being bound by receptors on neutrophils and extensions of plasma membrane of neutrophil surrounds bacteria and ultimately, bacteria are endocytosed (membrane forms a vesicle around the bacteria that then parts way from PM and becomes an endosome)
-> phagocytic cells = lysosomes (from golgi); neutrophil has the endosome fuse with lysosome and contents of lysosome (enzymes) are released into the endosome and attack pathogen
THEN two fates: -> phagolysosome (lysosome plus endosome) will fuse with PM and secretion of garbage that’s left over (after the lysosomes degrade)
-> OR phagolysosomes simply degrades the components COMPLETELY ; and can come back and have further rounds of fusion
T or F. Phagocytosis is highly conserved throughout evolution
T
Examples of phagocytes
macrophages, monocytes, neutrophils
Phagocytosis process
- phagocytes detects and engages microbe
- microbe engagement initiates cytoskeletal rearrangements that drive phagocytosis
- the microbe is internalized in a phagosome
- phagosome fuses with lysosome = phagolysosome
- lysosomal enzymes destroy ingested microbes
- reactive oxygen and nitrogen intermediates destroy microbial proteins, genomes, and walls (Reactive O2 and N2 intermediates are very oxidative and attack various products of the microbe and render them useless and destroyed )
Macrophage development
- like all blood cells, macrophages arise from undifferentiated stem cells in the bone marrow
- some stem cells differentiate into short-lived monocytes that circulate in the blood
- inflammation recruits monocytes to sites of infection where they differentiate into resident macrophages
- resident macrophages are long-lived ‘professional’ phagocytes that ingest large amounts of extracellular material
Phagocytes don’t just eliminate microbes. They …
activate neighbouring cells through the release of cytokines and chemokines
Cytokines
secreted proteins that drive immune and inflammatory reactions
innate = cytokines are produced by macrophages and NK cells
Induce proteins in the endothelium that make the endothelium more adherent for passing leukocytes
Cytokines
Chemokines
large family of structurally related, low molecular weight cytokines that stimulate leukocyte movement and regulate the migration of leukocytes from the blood to tissues
T or F. Inflammation is always good!
F, NOT all inflammation is good - inflammation may not stop at the end of an immune response or injury = chronic inflammation; results in disorders
The first step in innate immunity
detection of microbes by resident cells
This triggers inflammation at the site of infection
Microbe engagement
These contain granules and can release them upon recognition of inflammation/pathogen
Eosinophil, Basophil, and Neutrophils
Primary APC for priming T cells
Dendritic cells
Immune response mediated by B and T lymphocytes to infectious agents and non-infectious molecules
Adaptive Immunity
Innate vs Adaptive Immunity
- detects common microbial structures vs vast repertoire of molecules
- receptors encoded in the germline vs receptors generated by somatic recombination
- same response upon repeat exposure vs improved “adapted” response to repeat exposure
Types of antigens recognized by B cells
proteins lipopolysaccharides lipids nucleic acids **broader spectrum than T cells
Types of antigens recognized by T cells
peptides derived from proteins
APCs
primary dendritic cells, also macrophages
-> induces T cell response
Humoral Immunity
- directed against extracellular microbes
- mediated by B lymphocytes
- B lymphocytes secrete antibodies that neutralize and eliminate microbes and microbial toxins
Cellular Immunity
- directed against intracellular microbes
- mediated by T lymphocytes
- T lymphocytes activate phagocytes and lymphocytes
- or kill infected host cells
T or F. B cells remain naïve circulating blood or lymph nodes awaiting to encounter a pathogen, be activated, and then secrete pathogens
T!
Cytokines activated by T cells
goes to phagocytes; improves phagocytes ability to kill microbe
Granzymes
endosomal comportment contain enzymes (dysregulate cytochrome C) that can be secreted by killer cell and be deposited in target and end up triggering host cell to commit suicide (effective for killing reservoirs – cells actively producing pathogens)
- cytotoxic and natural killer cells
Phases of the Immune Response
- Recognition: Naive lymphocytes recognize corresponding antigen
- Activation: Lymphocytes differentiate and start clonal expansion
- Effector phase: differentiated lymphocytes initiate microbial elimination
- Decline: after microbial elimination, the signal for lymphocyte activation disappears; most cells activated by antigen die by a process of programmed cell death (apoptosis)
- Memory: the remeaning cells are memory lymphocytes, which may survive for months or years; remain in bone marrow or circulate
Activation requires two signals:
Signal 1 - Antigen receptor binds antigen
Signal 2 - microbial or innate immune signals are also required for lymphocyte activation
**both signals required
T or F. We have millions of B cells, each with its own unique BCR and each BCR recognizes a limited number of antigens
T
T or F. There is a lag time with adaptive immunity reaction after second exposure.
F; Memory response - no lag (memory cells already differentiated) also encountering antigen a second time, lag is much shorter bc they proliferate much faster (compared to naïve cells) ; just inherently better cells at producing antibodies
What do BCRs recognize?
recognize distinct microbial 3-dimensional structure;
B cell that has never previously encountered its target structure (naive) has BCR that is restricted to the plasma membrane of B cell
What does B cell activation result in?
- clonal expansion
- differentiation into effector cells that actively secrete antibodies
- BCR is modified in such a way that the BCR is secreted as an antibody
Functions of antibodies
- released into circulation and mucosal fluids by B cells upon infection
- neutralized microbes and microbial toxins
- stops microbes from gaining access to or colonizing host cells
- does NOT have access to intracellular microbes
APCs reside in…
potential sites of microbe entry = skin, GI tract, respiratory tract, etc.
What do APCs do?
capture, process, and present antigens to T lymphocytes in peripheral lymphoid tissues
T or F. Just like B cells, each T cell expresses a unique TCR
T, they also require co-receptors to assist antigen recognition
Two major subsets of T lymphocytes
- CD4+ helper T cells detect antigens presented by professional APCs; secrete cytokines to activate other components of the immune response (macrophages, B cells, etc.)
- CD8+ cytotoxic T cells detect microbial antigens presented by all nucleated cells and destroy the presenting cells
Which cells will clean up after killer cells?
Macrophages
How do you bring the right lymphocyte together with its cognate antigen upon infection quickly enough to activate the appropriate immune reply?
- the peripheral lymphoid organs (lymph nodes, spleen, mucosal and cutaneous lymphoid tissues) concentrate antigens and lymphocytes to optimize interactions
- Lymphatics will take fluid from tissues and drain them into lymph nodes
- Antigens coming by APCs via lymph into lymph nodes and the lymphocytes are coming into lymph nodes from blood = interaction!!!
- Spleen = lymphocytes can circulate here from blood to potentially encounter APCs
A network that transports fluids from tissues through lymph nodes and ultimately to the circulatory system (initially to veins)
Lymphatic system
- excess interstitial fluid is collected by the lymphatic system and is processed by lymph nodes prior to being deposited into the circulatory system
- unlike circulatory system, the lymphatic system is not closed and has no central pump
What happens in the lymphatic system?
- APCs drain from peripheral tissues into lymph nodes
- T lymphocytes enter lymph nodes
- APCs activate T lymphocytes
- Lymphocytes exit lymph nodes and enter circulation, then exit circulation into inflamed tissue where they mediate microbial destruction
Lymph node Cortex
B cells concentrated here; they can aggregate into the centers (germinal centers)
Lymph node Paracortex
combo of T cells and dendritic cells and these APCs can get into all of the areas to present antigens
Lymph node Medulla
area where cells can enter into efferent lymphatic vessel and head out into circulation
Lymphocytes in the lymph nodes, what happens?
- where they encounter APCs
- activated there and differentiate as well
- exit lymph nodes and enter circulation, head to inflamed tissues where they mediate microbial destruction
Where do APCs capture antigens?
in tissues
- they transport these Ags to peripheral lymphoid tissues (lymph nodes usually) where lymphocytes are concentrated to present those Ags to T cells
T or F. Dendritic cells will either carry intact Ags for B cells or process fragments for T cells
T! -> happens in lymph nodes
T cell antigens are _______ peptides bound and presented by ___ molecules
linear; MHC
collection of genes found in all mammals that code for MHC molecules
MHC locus; the locus contains two sets of highly polymorphic genes (class I and II)
MHC locus originally discovered as…
principle determinant of graft rejection
Class I vs Class II MHC-expressing cell types
Class I - all nucleated cells; CD8+; Cytotoxic; can kill any virus-infected cell
Class II - Professional APCs (B cells, dendritic cells, macrophages); CD4+; helper T; can also express Class I
MHC Class I Structure
- alpha 1 and 2 form groove/cleft
- two alpha non-covalently linked to beta 2
- polymorphic residues located at alpha 1 and 2 domains, thereby affecting peptide binding and T cell recognition
- alpha 3 domain is invariant and contacts T cell CD8 co-receptor; so only CD8+ T cells respond to class I MHC-bound antigens
Antigen Processing by Class I
- microbe growth and reproduction in cytoplasm
- microbial proteins in infected cells
- cleaved by proteasome complex
- class I MHC molecules loosely attached to the transporter associated with antigen presentation (TAP) - cellular pump that drives transport of cytoplasmic peptides into ER
- peptides pumped to ER lumen by TAP where they connect with class I
- stable binding = complex sent to surface via Golgi and exocytic vesicles
- surface = where interact with CD8+ T lymphocytes
T or F. The Class I pathway response to extracellular microbes
F! Intracellular!
- presented by Class I MHC molecules on the surface of all nucleated cells
- TCR activation = T cell differentiation to kill infected cells
MHC Class II Structure
- alpha 1 and beta 1 form peptide-binding groove; noncovalently linked
- polymorphic residues are in the alpha and beta 1 domains affecting peptide binding and T cell recognition
- beta 2 domain is invariant; contacts T cell CD4 co-recptor; so only CD4+ T cells respond
Antigen Processing by Class II
- several means to ingest microbes: PRR binds microbes OR receptors bind antibodies bound to microbes OR APCs sample their environment through pinocytosis
- go to lysosomes
- cleaved by lysosomal enzymes = numerous peptides
- in ER, invariant chain blocks peptide binding groove of MHC II, preventing peptides associating with MHC II in ER
- class II transported to cell surface in exocytic vesicles
- endosomal vesicles with microbial peptides fuse w exocytic vesicles; invariant chain degraded and MHC II binds peptides
- stable binding = go to cell surface
Properties of MHC
- Co-dominance: both parental alleles are expressed equally; each indiv can express up to 6 different Class I and 10-20 diff class II molecules
- Polymorphism: multiple MHC alleles means that at least some members of the population will be able to present any given microbial antigen
Features of peptide binding to MHC
- each MHC molecule displays one peptide at a time
- broad specificity
- very slow-off rate
- stable expression requires peptide
- MHC molecules bind only peptides
Co-stimulatory functions of APCs
- APCs present antigens and provide second signals for T cell activation
- microbial substances stimulate APCs to express costimulators on their surface and secrete cytokines
- costimulators and cytokines provide second signal that triggers T lymphocyte differentiation
Ag-Ab/BCR interactions
- BCR detect three-dimensional antigens
- B cells are active only against extracellular antigens
BCR/TCR Activation
- antigen receptors associate with cell signalling proteins in BCR/TCR complex
- adjacent receptors bind two + antigens = aggregate
- cross-linking brings signalling proteins together and initiates signal transduction
- same in each clone
This drives lymphocyte activation
antigen recognition
Type of glycoprotein produced by B lymphocytes
antibodies (immunoglobulin)
- bind antigen (various 3D shapes) with a high degree of specificity and affinity
Antibody consists of four polypeptides:
- two identical light chains
- two identical heavy chains that for a Y
- each light chain connected to a heavy chain by a disulfide bond
- 2 heavy chains connected by disulfide bonds
Antibody structure:
- each light chain = one V and one C domain
- heavy chain each have one V domain and at least 3 C domains
- each domain folds into a characteristic 3D shape (Ig domain)
- variable v region varies between clones and is involved in antigen recognition
- constant c region is conserved among clones and is required for structural integrity and effector functions
T or F. Antibodies bind antigens by reversible non-covalent interactions
T; still strong!
Epitope
parts of an antigen recognized by antibody; can be recognized on the basis of sequence or shape
Affinity
strength with which one antigen-binding surface of an antibody binds an antigen
Features of antibody-mediated antigen recognition:
- antibodies recognize a large array of 3D structures
- each clone specific for a single antigen
- antigen recognition is mediated by specific domains of the antibody
- signalling triggers B lymphocyte activation
Ig isotype: 2 molecules that is joined by a j chain
IgA
- j chain facilitates transport of IgA across mucosal epithelia
- also transfer of IgA to newborns to confer neonatal passive immunity
IgD
- function poorly understood
- restricted to membrane and barely expressed on active B lymphocytes
- IgD knock-out mice do not have any major defects
- found on naive B cells; act as a marker for B cell development
IgE
- secreted as a monomer
- binds Fc epsilon receptor on mast/basophilic cells
- binds allergens and facilitates degranulation
- protection against parasites
- possible role in cancer immunity
- additional C terminal domain – more than IgG (binds Fc epsilon)
Ig Isotypes
five types of antibodies that differ in their C region ; differs in their physical/biological properties and effector functions
IgG
- secreted as monomer
- most abundant
- can transfer to fetus
- neutralization of toxins
- opsonization for inducing phagocytosis via complement system
- antibody-dependent cytotoxicity on NK cells
Antibody-Dependent Cellular Cytotoxicity (ADCC)
- Fc receptors mediates this
- IgG binds Ag on surface of target cell
- Fc gamma receptors on NK cells bind Fc of Ig
- cross-linking of Fc receptors signals to the NK cell to kill target
- target cell dies by apoptosis
IgM
- pentamer
- 10 different Ag binding sites
- J chain for secretion
- first antibody expressed in mature B cells
- important for activation of complement pathway (neutralization, phagocytosis)
- appears early after infection and usually not seen upon re-infection
Avidity
combined strength of multiple binding site interactions an Ab can make with antigen
-> IgM has greater avidity than IgD as it can bind bind MORe epitopes at once than IgD can
IgM only expressed
immature B cell
T or F. Light chains associate covalently with the heavy chains on the Igs
T!
2 light gene loci hat can produce light chains
kappa and lambda
The light chain loci displays a similar organization to the heavy chain locus, except…
it lacks any D segment
What does the constant region on the Ig structure represent?
conserved effector function
Stages of B cell development: (5)
- pluripotent stem cells in bone marrow
- mature IgM+ B cell
- mature, naive B cell circulate peripheral lymphoid organs
- no antigen encounter = apoptosis
- antigen encounter (1st signal) = second signal = activation
Stages of B cell activation (6)
- naive B cell - antigen
- helper T stimulate B cells
- activated B cells = clonal expansion
- some differentiate in to antibody secreting plasma cells
- others = memory cells
- others switch class
Terminally differentiated B cell
can’t differentiate into anything else; plasma cells
-> cant respond to external signalling b/c dedicated to production (producing soluble IgM)
Memory lymphocytes
- produced from naive lymphocytes bc of antigen exposure
- persist for years (quiescent state)
- rapidly activated by repeat exposure
Class Switching
changing of an antibodies constant region
- clone of B cells not committed to make a single Ig isotype forever (all start out as IgM though)
These induce rearrangements at the heavy chain locus (constant region)
cytokine signals
T or F. Class switching also affects the variable region
F! Antigen specificity is retained; effector function is what’s changed; usually depending on environment of activated B cell
