2. Immune ch18-21

What happens after “innate immune response by infected cells and local macrophages via PRRs.”

activated DCs process and present viral antigens, while migrating to LNs

What happens after “activated DCs process and present viral antigens, while migrating to LNs”

DCs interact with naive T cells to initiate the adaptive response.

What happens after “DCs interact with naive T cells to initiate the adaptive response.”

Effector and memory T and B lymphocytes are generated.

what happens after “Effector and memory T and B lymphocytes are generated.”

Cells go to the lung to fight infection 

What happens after “cells go to the lung to fight infection.”

Memory T cells specific for COVID antigens remain in the lung as first responders in case of a re-infection.

What does CTL stand for

cytotoxic T lymphocytes

What is the two mechanisms of CTLs

Release of cytotoxic granules, Fas-FasL interactions

What is the first step of CTL-mediated killing of target cells

MHC I dependent target recognition

What is the second step of CTL-mediated killing of target cells

Formation of a cell-cell conjugate is formed with a “kiss of death”

What is the third step of CTL-mediated killing of target cells 

a Ca2+ triggering and reorganization of the microtubule organizing center 

What is the fourth step of CTL-mediated killing of target cells 

release of granules via exocytosis

What is the fifth step of CTL-mediated killing of target cells 

CTL dissociate and moves on

What is the sixth step of CTL-mediated killing of target cells 

CTL can kill multiple cells through serial engagement 

perforin

a pore-forming protein 

granzymes

serine proteases

What is the 1 in the picture

TCR-dependent Ca2+ triggering 

What is the 2 in the picture

granules are delivered to the site of cell-cell interaction

what is the 3 in the picture

In presence of Ca2+, perforin monomers are inserted into the target membrane

What pathway, of CTLs kill target cells, activate apoptosis

Both pathways

active caspases induce

apoptosis

both granzymes and FAS induce cleavage of

pro-caspases to generate active caspases

caspases are normally present in

inactive forms (pro-caspases)

anti-CTLA-4 and anti-PD-1 antibodies can release the brakes off…

CD8 T cells (checkpoint blockade therapy)

Th1 effector cells are critical for control of intracellular pathogens. what is the primary function of Th1 cells

to activate infected macrophages by contact-dependent on target delivery of IFNy and CD40L

Match descriptions to the effector cells (Th1, Th2…). Generation of reactive nitrogen and oxygen species (NO and O2)

Th1

Match descriptions to the effector cells (Th1, Th2…). Phagosome acidification. 

Th1

Match descriptions to the effector cells (Th1, Th2…). Elicits heighted microbial intracellular killing

Th1

Match descriptions to the effector cells (Th1, Th2…). Additional production of inflammatory cytokines and chemokines

Th1

Match descriptions to the effector cells (Th1, Th2…). __ cells recruit and activate M2 macrophages via IL-4 and IL-13, which increase smooth muscle contraction and enhance tissue remodeling and repair 

Th2 

Match descriptions to the effector cells (Th1, Th2…). __ cells produce IL-13 which induces epithelial cell repair and mucus. which increase cell turnover and movement helps shedding of parasitized epithelial cells

Th2

Match descriptions to the effector cells (Th1, Th2…). IL-13 produced by __ increase smooth muscle contractility that enhances worm expulsion, which increased contractility of mucosal smooth muscle enhances worm explusion.

Th2 

Match descriptions to the effector cells (Th1, Th2…). IL-5 produced by Th2 cells recruits and activates eosinophils, which produce MBP that kill parasites and also mediate ADCC using parasite-specific ig

Th2 

Match descriptions to the effector cells (Th1, Th2…). IL-17 and IL-22 produced by __ induce the production of antimicrobial peptides by epithelial cells, which direct killing/growth inhibition of bacteria attached to the epithelium

Th17

Match descriptions to the effector cells (Th1, Th2…). IL-17 produced by __ cells activates stromal cells and epithelial cells to produce chemokines that recruit neutrophils, which recruitment of neutrophils to the site of infection 

Th17 

Match descriptions to the effector cells (Th1, Th2…). IL-22 produced by ___ increase epithelial cells turnover, which increase epithelial cell division and shedding impairs bacterial colonization 

Th17 

What does T regulatory cells (Treg) do

competition with Teff for pep-MHC, stealing CD80/86 from DCs surface, steal IL-2 from T cells, secrete regulatory cytokines (TGFb, IL-10), generate adenosine (anti-inflammatory), treg expansion, convert more T cells into Tregs

antibody isotypes are

encoded in Fc regions of the antibody

Isotype switching is

regulated by the inflammatory cytokines that B cells sense during activation (many come from TfH) 

Isotypes determine

the effector functions of the antibodies

Neutralization is a type of antibody-mediated effector functions. what is it? 

blocks ability of pathogens or toxins to target and infect cells 

Opsonization is a type of antibody-mediated effector functions. what is it? 

promotes and/or enhances the engulfment of antigens by phagocytes

Complement Activation is a type of antibody-mediated effector functions. what is it? 

results in the generation of the membrane attack complex (MAC), creates pores in pathogen membranes and killing the microbes.

ADCC is a type of antibody-mediated effector functions. what is it? 

activates the killing activity of several types of cytotoxic cells (NK cells)

What does ADCC stand for 

Antibody-Dependent Cell-mediated Cytotoxicity 

Antibody-dependent degranulation and mediator release is a type of antibody-mediated effector functions. what is it? 

triggers mediator release from granulocytes 

FcR signaling through ITAMs (activation)/ITIMs (inhibition)

see T/B signaling - elicits different functions

what does ITAMs do

activation

what does ITIMs do

inhibition

Degranulation

crosslinkinh of FceR on mast cells elicits granule release

Opsonization

FcyR expressed on macrophages binds to complexed IgG or IgA. induces phagocytosis

Mother/Fetus interface

FcRn(neonatal) expressed on placental cells transports IgG into the fetal circulation

ADCC

FcyR expressed on NK cells binds on IgG bound to surface of infected cells and elicits NK mediated killing

Transport into mucosa

Poly-Ig receptor expressed on mucosal epithelial cells transport IgA into mucosal lumen (gut, airways)

Fc receptors distinguish free antibodies from those bound to a pathogen via 

aggregation and cross-linking, lead to ITAM activation (phosphorylation) and signaling 

IgG can

stays in the circulation to protect against dissemination and transferred across the placenta via the neonatal Fc receptor (FcRn) 

IgA can

transported into the lung mucosa via pIgR for immediate protection and transferred to the newborn via breast milk

IgE can

bound to mast cells and eosinophils localized in barrier surfaces

What are two types of diversity generated BEFORE exposure to antigen (during b development)

combinatorial diversity (VDJ recombination) and Junctional diversity (random nucleotides added (TdT)) 

What are the types of diversity generated AFTER B cell development 

IgM vs IgD surface expression, surface expression vs secretion, affinity maturation through somatic hypermutation, isotype class switching 

What does RNA processing determine 

IgM vs IgD and membrane vs secreted 

What does DNA mutation determine 

hypermutation

What does DNA rearrangement determine

class switching

Alternative polyadenylation regulates

production of IgM vs IgD

What determines if a Ig is a transmembrane IgM

pA2; yellow membrane coding (MC) exons encode a hydrophobic transmembrane domain not present in the orange secretion coding (SC) exon 

What determines if a Ig is secreted Ig 

pA1 ;regulated use of an “internal” polyadenylation site that precedes the exons encoding the transmembrane domain

What are the three ways to modify DNA of rearranged Ig locus

somatic hypermutation, class switching recombination, and gene conversion

What is somatic hypermutation (SHM) 

single base pair mutation in V genes, can change receptor affinity for Ag 

what is class switching recombination

replacement of constant genes encoding one isotype, modify effector function, but not Ag specificity. 

Gene conversion 

only for birds? DNA sequnce replace a similar one, causing them to be identical 

CSR and SHM occur only after

B cell get “help” from tfh.

B cells express AID only after

they get “help” from Tfh cells

What does AID stand for

Activation-induced cytidine deaminase (AID)

What does AID do 

initiates both somatic hypermutation and class switch recombination 

AID initiates a

nucleophilic attack on the pyrimidine ring of cytidine

What are things that happen in the DNA that causes SHM

replication, mismatch repair, base excision repair

What enzyme does mismatch repair use to excision

MSH 2/6

What is the enzyme used in Base excision repair 

UNG 

what can happen to the DNA for class switching to occur

single strand cut by enzyme APEI

What does switch regions do

they determine where AID generates nicks, are CG-rich stretches of DNA in the intron just upstream of the first exon of each Ch gene (except Cs)

In class switching, cytokines signals determines which

switch regions are activated at the level of transcription (IL-4 opens Se)

In class switching, where do the cytokines come from 

CD4 T cells, which have been trained by DCs about the nature of the pathogen

which enzymes introduce clustered nicks on both strands of DNA

APE1, UNG, AID

Coordinated deamination at donor and acceptor switch regions by

AID-UNG-APE1, which results in double stranded DNA breaks (DSBs)

Only these events of diversity can be reversible

IgM vs IgD expression, and the membrane vs secreted form

Pt with AID deficiency have 

hyper-IgM syndrome type 2, which include no class switching, no somatic hypermutation, lymph node hyperplasia d/t enlarged germinal centers, recurrent infection with pathogens 

Deficiency in ___ also causes hyper-IgM syndrome

CD40L (X-linked)

plasmodium is a type of parasite and can stimulate germinal center and cause

chronic (but asymptomatic) infection in endemic regions, lives in the blood, so there’s tons of antigen available for B and T cells, and periodically changes the antigens on the surface of the infected RBC, so antibody response needs to keep evolving

Evidence of gene conversion in humans

pt infected with malaria found that 5-10% of them have antibodies that include part of the LAIR1 protein in the heavy chain, which is good at binding to RIFIN proteins that malaria inserts on the surface of infected RBC

Malaria + Epstein barr virus (EBV) + AID =

Burkitt’s lymphoma 

Plasmodiumin burkitt’s lymphoma 

drives long-lasting germinal centers filled with AID-expressing B cells

EBV (epstein barr virus) in burkitt’s lymphoma

specifically and persistently infects B cells and can replace the survival signals normally provided by BCR signaling

AID in Burkitt’s lymphoma

off-target activity can cause chromosomal translocations, such as insertion of the myc oncogene into the BCR locus, which is the hallmark of burritt’s lymphoma 

with the important exception of the skin, most immune responses occur

at mucosal surfaces 

Intestinal Orientation. where is the lumen?  

the outside near apical membrane

Intestinal orientation. where is the lamina propria?

Inside near the basal membrane

the microbiome helps us synthesize and extract nutrients from our diet because

commensal bacteria express enzyme that we lack.

Mucosal defense: mucus. microbes are restrained from

encroaching through the mucus layer

Mucosal defense: epithelium. what transmembrane proteins interact with actin cytoskeleton to regulate the permeability of tight junctions 

claudin and occludin associated with zonulin(ZO) 

mucosal defense: epithelium. What is Enterocytes

absorptive cells of the intestine (most abundant)

mucosal defense: epithelium. what is goblet cells

make the vast majority of the mucus