Lecture 4 Flashcards
Can pathogens remain latent in the body?
Yes. The immune response can control the pathogen to prevent spreading, but it does not eradicate it.
What happens if we lack the innate immune system?
We get a very quick expansion of the pathogen.
What happens if we lack our adaptive immune system only?
The innate system can keep the pathogen under the control, but it will not completely get rid of it.
All antibodies are made from _______ cells in _______ and ______.
All antibodies are made from PLASMA CELLS in primary and secondary lymphoid organs.
What are the 4 effector functions of antibodies?
- Neutralize the toxin
- Opsonize them for phagocytosis.
- Sensitize them for ADCC (antibody-dependent cellular cytotoxicity)
- Activate the compliment system
NOSA
Polio
Vaccine: Oral atenuated poliovirus
How does it work?
IgA will neutralize the virus
Tetanus, Diptheria
Vaccine: Toxoids
How does it do so?
IgG will neutralize the toxin
Hepatitis A/B
Vaccine: Recombinant viral envelope proteins
How does it do so?
IgG or IgA can neutralize the virus.
Pneumococcal, Pneumonia, Haemophilus
Conjugate vaccines: composed of bacterial capsular polysacchride attached to a carrier protein.
How does it do so?
IgM and IgG will opsonize and phagocytoze.
-Directly or secondary to compliment activation
What part of the antibody controls its effector functions?
Fc portion
IgM effector function
Activates the compliment system
IgG effector functions
- Neutralize the toxin
- Opsonize the antigen for phagocytosis by macrophages and neutrophils
- Sensitize it to ADCC mediated by NK cells
- Activate the compliment system
- Neonatal immunity
- Feedback inhibtion of B cell activation
ISOTYPE SWITCHING results in the production of Abs with distinct ______ capable of different effector functions
Fc regions
Affinity maturation is induced by ______________. What does this result in
repeated stimulation to protein antigen
This allows the antibody to better bind the antigen and neutralize it.
Why do doctors suggest giving multiple rounds of immunizations with the same antigen so that we can generate protective immunity?
Administering multiple rounds will stimulate the B cell, which will increase the affinity of antibodies.
IgG have a half life of 3 weeks and has a neonatal Fc receptor (FcRn) that transports Abs from the mother circulation to the fetus.
FcRn can be found where and what is its function?
FcRn is located inside the endosome in endothelial cells and phagocytes.
It binds IgG that have been phagocytozed, protecting it from intracellular catabolism.
FcRn-IgG will then take IgG back into circulation or to the tissue fluid to avoid being degraded from lysosomes.
- Antibodies neutralizes toxins.
How?
Antigen binds to the microbe.
Binding will prevent the microbe from interacting with its receptor because of steric hinderance.
How would having no antibodies affect our ability to neutralize toxins?
We couldnt.
The toxin would bind to its receptor and infect the cell.
How do gram-negative bacteria infect their hosts?I
They use pilli to attach to the host and infect it.
How does the influenza virus affect their host?
It uses its envelope protein hemagluttin to infect respiratory epithelial cells.
T/F: Anibodies also prevent the infection of ADJACENT cells.
True
What are virulance factors?
Give 4 examples
Molecules made by products of bacteria that add to their effectiveness and allow them to cause disease.
They include:
- Bacterial toxins
- Cell-surface proteins that bacteria attach to
- Carbs and proteins on the surface that protect the bacteria
- Hydrolytic enzymes that contribute to the pathogenity of the bacteria
- Ab-Mediated Opsonization and Phagocytosis
How do IgG antibodies coat/opsonize microbes and promote their phagocytosis?
Bind to Fc receptors on phagocytes
FcyRI (CD64)
High affinity for Fc
Found?
Function?
Found: macrophage, eosinophil, neutrophil
Function: phagocytosis and cell activation
FcyRIIb (CD32):
low affinity for Fc
Found on?
Function?
- Macrophages, neutrophils DCs, B cells, NK cells
- Phagocytosis, cell activation, feedback inhibition
FcyRIII (CD16)
Low affinity for fc
Found:
Function
- NK cells
- Function: ADCC
FcERI:
High affinity for Fc (binds IgE),
Found on:,
Function?
Found on: mast cells, basophils and eosinophils
Function: cell activation (degranulation)
FcyRI (CD64) mechanism
- IgG opsinizes a multivlaent microbe
- Bind to FcyRI receptor
- Activates phagocyte
- Phagocytosis occurs
IgG3* and IgG1 are the best opsinizers for FcyRI receptors.
Kd for FcyRI
10-8 M
FcyRII (CD32) mechanism
See last note card deck
- Ab-Ag complex will bind to BCR and CD32
- Src kinases to phosphorylate the ITIM
- Tyrosine phosphotases SHP and SHIP will come and bind to the phosphorylated ITIM
- PIP3–> PIP2
- signaling is blocked
Kd for FcyRII
2 x 10-6
Since worms are too large to be engulfed by phagocytes, Mø and N cannot do anything. IgE, mast, and eosinophils work together to mediate the killing of parasites. What is the mechanism?
- Parasite sends allergens to DC, presents to T cell.
- Effector T cell will then
- A. Sends IL4/6 –> B cell –> IgE
- B. Send IL4/13 –> mast cell
- Fc3RI binds IgE and release granules
- C. Send IL4/IL5 –> eosinophil
- Fc3RI binds IgE
Major Basic Protein is then released by granules from the eosinophil and kills the parasite.
Kd of Fc3RI
High
10-10
ACDCC Mechanism
- Ab binds to antigens that are located on the target cell.
- FcyRIII receptors on the NK cell recognize the bound Ab
- FcyRIII receptors cross link, signaling the NK cell to kill the target cell
- Target cell diez by ap0pt0s!s
Kd of FcyRIII
Low
10-6
Compliment system
serum and surface proteins that work together to fuck up microbes
Compliment system is an effector mechanism what immune systems?
Humoral and innate
What activates compliment system?
- Microbes
- Ab-microboes
Products of the compliment activation become ________ attached to microbes, [ab+microbe] and [apoptotic bodies].
Covalently
What inhibits the compliment activation?
Regulatory proteins present in normal host cells and absent in microbes
What proteolytic enzymes does compliment activation depend on?
C3 convertase and C5 convertase.
Classical pathway is activated when C1 binds to [Ag-Ab]. How are alternative and lectin pathways activated?
Alternative: (spontaneously) C3 to C3a C3b
Lectin: mannose binding lectin (MBL) binds to mannose, activates MASP1/–> cleaves C4/C2
In alternative pathway: C3b binds to surface of microbe–> binds _____–> cleaved by ______
Factor B
Factor D
In the alternative pathway, what stabilizes C3 convertases?
Properidin
In alternative pathway, Serum concentration of ____ is the highest;_____ is the lowest.
C3–> highest
Factor D–> lowest
Classical pathway: C1 structure and function
C1: C1q, C1r, C1s
C1q–> binds to antibody. It is made up of 6 identical subunits with arms. At the end of each arm is a globular H head that binds Ab.
C1r and C1s are proteases. C1r cleaves C1s to make it active. C1s then cleaves C2 and C4.
C1r and Crs form a tetramer (2 C1r and 2C1s) that have cataltic domains.
C1 must bind to two or more Fc regions of antibodies. Soluble (free floating) IgG or IgM will not bind to C1, what do the Abs need to be doing in order for C1 to bind?
Need to bind to antigen bound Ab.
Activated C1s cleaves the next protein in the cascade, C4, to generate C4b. • C4b contains an internal thioester bond that forms covalent bonding with microbe to which the Ab is bound. Why?
Makes sure that compliment activation occurs on the surface.
Cleavage of C3 results in the removal of the small C3a fragment, and C3b can form covalent bonds with cell surfaces. Once C3b is deposited, what happens?
It binds factor B to make more C3 convertase via alternative pathway.
Fx of MBL
- Agluttin
- Opsonin
- Complement fixing
MASP 1 Function
Forms a complex with MASP 2, collectins or ficollins and activates MASP3
MASP2
Forms complex with lectins, especially ficolin‐3
MASP3
Associates with collectins or ficolins and MASP1 and cleaves C4
Function of
- C5a
- C7
- C8
- C9
1, C5a- stimulates inflamation
- C7- Component of the MAC: binds to C5b,6 and inserts into lipid membranes
- C8- polymerization of C9
- C9- polymerizes to form membrane pores
CR1 (CD35) is a high affinity receptor for C3b,C4b. It phagocytosises particles coated in C3b and C4b and clears them from the immune system.
CR1 also transduces signals that activates killing mechanisms on what?
On phagocytes such as neutrophils, B/Tcells, eosinophils, FDCs, which use CR1 to bind and internalize microbes and debris
How does C3b naturally degrade into C3d?
C3b–> [factor I and cofactors: FH, MCP, CR1]–> iC3b–> [factor I and cofactor CR1]–> C3dg
Plasma proteases then cleave C3dg into C3d
CR2 (CD21) is located on B cells and follicular DCs. What does it do?
- CR2 will binds what products made from cleaving C3b, helping B cells better respond to antigens.
- FDC CR2 traps iC3b in germinal center
- A receptor for EBV, allowing the virus to remain latent in the cell for life
CR3 (complement receptor), known as ________ or _________
Mac-1
CD11bCD18
CR3 function
- Binds iC3b
- Binds to ICAM-1 on endothelial cells, recruiting leukocytes to infection/ injury
CR4 (CD11cCD18)
Same as CR3
C1 inhibitor
Serine protease inhibitor that displaces C1r and Crs from C1q and terminates classical activation.
DAF, decay accelerating factor, dissociates what to regulate complement pathway?
C3 convertase on both classical (C4bC2a) and alternative (C3bBb).
Classical binds C4b and cleaves C2a, Alternative binds C3b and cleaves Bb
MBC/CR1, membrane bound cofactors, act in the same way as complement regulator DAF. When present, MCPandCR1 will bind C3b or C4b and bring in Factor I, which does what?
Factor I, with the help of Factor H cofactor for C3b, will cleave C3b or C4b into an inactive form- iC3b.
Stopping complement activation (CANT FORM C3 CONVERTASE)
MAC is formed on cell surfaces (C7 and C8 or inside membrane) as a result of complement activation. Membrane protein CD59 and plasma S protein can dowhat?
CD59 binds to C5b and inhibits poly-C9 assembly, NO PORE TO ENTER CELL
Plasma S protein inhibits membrane insertion of C7, so does not bind to C8 = NO MAC!!
= NO MAC ASSEMBLY
3 Fx of Complimentary System
- Opsonize & phagocytize (C3b)
- Inflammation (via C5a and C3a recruiting leukocytes)
- Compliment mediated cytolysis (MAC complex)
The proteolytic complement fragments ___, ____, ___induce ACUTE INFLAMMATION by activating mast cells, neutrophils and endothelial cells
C5a, C4a, and C3a*
Microbes on which COMPLEMENT is activated by the alternative or classical pathway (most sensitive) become COATED with ____________ and are phagocytized by the binding of these proteins to specific receptors on macrophages and neutrophils
C3b, iC3b, or C4b
The ___ protein generated from C3 binds to CR2 on B cells and facilitates B cell activation and the initiation of humoral immune responses
C3d
___ DEFICIENCY is the most common human complement deficiency
C2
____, ___ and ___ DEFICIENCIES are associated with Systemic Lupus Erythematosus.
Defects in complement activation lead to failure to clear circulating immune complexes. They can deposit in blood vessel walls and tissues, where they produce local inflammation.
C1q, C2 and C4
___ and __deficiencies are not usually associated with increased susceptibility to infections because the alternative pathway may compensate the deficiency.
C2
C4
___ DEFICIENCY is associated with frequent serious pyogenic bacterial infections that may be fatal.
DEFICIENCIES in _____ and ____result in increased susceptibility to infection with pyogenic bacteria.
C3
Properidin and factor D
C5,C6,C7,C8 and C9 deficiencies may lead to?
Neisseria bacteria
Complement system can cause tissue damage.
Bacterial infections may be due to complement‐mediated acute inflammatory responses to infectious organism
COMPLEMENT ACTIVATION is associated with intravascular thrombosis and can lead to _______?
ischemic injury to tissues.
In an autoantibody mediated kidney disorder, what can happen caused by complement pathway?
Membranous nephropathy, damage to glomerular epithelia cells can be mediated by the MAC that is generated after Ab binds to a glomerular auto-Ag
Neonates lack the ability to mount effective immune responses against microbes, and for several months after birth, their major defense against infection is what?
passive immunity provided by maternal antibodies
Newborns are protected agains infection by maternal Abs that are transported across the placental into fetal circulation. The transport of IgG from mom to kid is mediated how? What else can protext them
IgG-specific Fc receptor called the neonatal Fc receptor (FcRn)
IgA in BREAST MILK ingested by the nursing infant.
Along with IgG, ingested IgA by breast milk can neutralize pathogenic organisms that attempt to colonize in the childs gut. How is IgA from milk transported inside the bb?
It is transported across the gut epithelium of newborns by a process know as TRANSCYTOSIS
During fetal months, maternal IgG is increased around 2months until birth and then decreases. IgM is made by fetus starting around month 5. What is the total percentages of Abs at 12 months.
IgG is main component at 60% IgM next main compenent IgA is last main component at 20% At around months 2-3 after being born if when there is the lowest amount of antibodies which means highest chance of getting sick!
What are the three ways extracellular bacteria can evade innate immune?
- inhibit of complement activation (many do this)
- Resist phagocytosis (Pneumococcus/Neisseria meningitidis)
- Scavenging of ROS (catalase positive staphylococci (cationic positive)
What are the three ways bacteria and viruses can evade humoral immunity?
- Antigenic variation-cant be recognized by Abs produced (flu virus, HIV, E coli, Rhinovirus, trpanosome parasite)
- Inhibition of complement activation (many bacteria)
- Blocking by hyaluronic acid capsule-resisting opsonization and phagocytosis (streptococcus)
Conjugate vaccines are composed of microbial polysacchride antigens coupled to carrier protein. What are Subunit vaccines?
Vaccines composed of microbial proteins and polysacchrides
the main focus of vaccines are how they can stimulate CMI againt intracellular microbes.
Injected/orally administered vaccines/Ags are extracellular and induce mainly Ab responses. What are two new approaches that are being tested?
- Microbial Ags are incorporated into viral vectors, which will infect host cells and produce Ags inside the cell
- DNA encoding a microbial Ag in bacterial plasmid can be ingested by host APCs, and Ag is produced inside the cell
