Immuno CCOM 2 Flashcards
Do T cells recognize intracellular or extracellular contents?
intracellular
Moelcules from the exongenous pathwar are loaded onto which HLA class? And presented to which cell?
HLA class II CD4+ T cell
Molecules from the endogenous pathway are loaded onto which HLA? And presented to which cell?
HLA class I CD8+ T cell
On which chromosome are the MHC and HLAs found?
short arm of chromosome 6
How do MHCs exhibit genetic polymorphism
overall structure will be the same but a.a. sequence will vary
Describe the structure of HLA-1
1 cytoplasmic tail
monomer of : a1, a2, a3
B-microglobulin (not covalent)
Where do processed polypeptides and CD8 cells associate with HLA-1?
peptides: cleft bw a1 and a2
CD8: a3 subunit
Describe the structure of HLA-2
2 cytoplasmic tails
dimer: a chain and b chain
Where do processed polypeptides and CD4 cells bind to HLA-2?
peptides: cleft bw a1 and B1
CD4: B2 subunit
Where is HLA-2 synthesized?
ER
What is li?
What does it do?
A molecular chaperone for HLA-2 molecules
- stabilizes unbound HLA-2
- blocks incidental binding of endogenous self antigens
What is peptide exchange?
switch bw CLIP and foreign antigenic peptides on the HLA-2
HLA-DM catalyzes this
On which cells are HLA-2 expressed in all conditions?
In which cells can HLA-2 expression be induced?
constitutively: APCs (DCs of spleen/lymph node, theymic epithelial cells, B cells)
induced: tissue macrophages, endothelial cells
What is ubiquitin?
attaches to molecules in endogenous pathway to mark for proteolysis by proteasomes
What are the transporter molecuels involved in the endogenous pathway?
TAP1 and TAP2
they transport degraded molecules through ER membrane
What are teh chaperones involved in the endogenous pathway? What do they do?
calnexin
calreticulin
-These are released after HLA1 binds antigen
-they strenghtn B2-microglubulin binding
How do HLA-1:peptide complexes get transported?
Golgi’s exocytic pathway
On which cells are HLA-1 expressed?
Constitutively on all nucleated cells
Describe the cross presentation pathway
- APC presents exogenous peptides to CD8 via MHC 1
- prolly from escaped virus/cell debris
What is the molecule of interest in the cross presentation path?
CD1 : present lipid and glycolipid antigens to T cells
similar structure to MHC-1 but binding mechanism similar to HLA2
What cells can CD1 activate? Where are they found
activate CD4+, CD8+, NK cells
found on B cells and DCs
Where do T cells originally develop?
in bone marrow stem cells
When T cells exit the thymus, what differentiation level will they be?
mature but naive
What do Th1 cells influence?
Positively influence cellular immune repsonse
What do Th2 cells influence
up-regulate Ab response
What is it called when children are born without a thymus? What happens?
DiGeorge’s syndrome
there are no mature T cells
Describe how a T cell is educated in the thymus
- Acquires TCR -> specificity
- learns tolerance of self
- learns self-H:A restriction
What is the general a.a. length of antigen fragments involved in the exogenous and endogenous pathways?
exongenous: 12-17 a.a.
endogenous: 8-9 a/a/
How do the common lymphoid progenitors home to the thymus?
chenokines and
CD44 adhesion molecule
What makes up the TCR?
B chain
pre-Ta
CD3
zeta chain
What makes up the double positive cell?
a and beta chain of TCR (with TCR-a and TCR-b) CD3 CD4 CD8
Which cells do the double positives have to pass through to under go central tolerance?
thymic epithelial cells
interdigitating thymic DCs
Which cells express both HLA-1 and HLA-2 molecules?
thymic epithelial cells constitutively
What is positive selection?
if biding of HLA is not right -> apoptosis
Expansion of cells that respond to self HLA plus processed antigen
HLA restricted
What is negative selection?
Weeds out self-reactive cells through interaction with interdigitatin DCs
Now are self-tolerant
What is the gamma/delta TCR?
develop independent from thymus
not HLA restricted
no CD4 nor CD8
involved in innate defense
When does the adaptive immune response begin?
When antigen-laden tissue-based DCs migrate from infected tissue to lymph node
What is the main function of secondary lymphoid tissue?
to trap antigens and concentrate them with APCs and lymphocytes
What happens when a naive T cell is activated? How is the activated T diff than the naive T?
expression of different adhesion molecules and chemokines receptors
activated T cells recirculate via spearate/distinct pattern more specific
Why does the immune system need both B and T cells?
B cells target extracellular anitgens w Abs
T cells target intracellular or cell-associated antigens via chemokines or cytotoxicity
Describe how a TCR is clonally distributed
each T cell clone bears a unique TCR
Describe the signaling process after presentation of the antigen to the TCR
conformational change of TCR
CD3 and zeta ITAM activated
signal cascade to activate T cell
What is the funciton of CD3
chaperones transport of TCR to membrane
cell signaling molecule
Activation of CD4 includes the transcription of which chemokine?
IL-2 (growth factor)
When are CD4 and CD8 expressed at the same time?
Very short period of time on immatrue T cell (double pos)
Otherwise, they are mutually exclusive
What are the roles of B7 and CD28? WHere are they located?
B7 is on APC, CD28 on T cell
critical to activation of naive T cell but not required fro activation of memory T cell
What is the first cytokine produced after activation of T cells?
IL-2
During what develpmental stage of T cells is central tolerance achieved?
double positive T cell
What will you see be expressed on the surface right before T cells enter the thymus
just chemokine receptors
What chemokines are involved when naive T cells circulate randomly?
CCL21 (from HEV endothelial)
CCL18 (from DCs in nodes)
What cytokines does Th2 produce:
IL4
IL5
IL10
IL13
What cytokines do Th17 cells produce?
IL17
IL21
IL22
What cytokines do Th1 cells produce?
IL2
IFN-gamma
What cytoines do Treg cells produce?
TGF-B
IL-10
IL-4
What diseases are RESOLVED by Type 1 immune responses?
Chlamydia HIV Intracellular parasites Leprosy Tb
What diseases are RESOLVED by Type 2 responses?
Pneumococcal pneumonia
Heominth-worms
Diptheria
Meningococcal disease
What diseases are CAUSED by Type 1 responses?
Contact hypersensitivity
Delayed Hypersensitivity
Silicosis
What diseases are CAUSED by Type 2 responses?
Lupus
Allergies
Lepromatous Leprosy
Asthmal
What is required in order for CTL to be activated? Where does it come from?
IL-2
Comes from either CD4 cell secretion or from itself in autocrine fashion
How do CTL kill target cells?
Via perforin- binds to membrane and polymerizes to make channels
granule release- induces apoptosis via TNF-B, TNF-a, Granzymes
What other structure is perforin very similar to?
C9 complement component
also similar function in membrane attack complex
What is fragmentin?
Granzyme that induces DNA fragmentation and apoptosis
What is the minor pathway in T cell cytotoxicity?
Fas-FasL
FasL on CTL binds FAS on target
activates caspases that induce apoptosis
What is the surface expression of NK cells?
CD56/CD16
What is the mechanism of NK cells in killing?
NK cells have KIRs
When MHC binds KIR, NK is inhibited
If no MHC binds, cell is killed
SO KN recognize lack of MHC expression
How can NK cells be upregulated?
IL-2
IFN-gamma
How can macrophages be cytotoxic?
lysosomal content release
release TNF-a
N and O radicals
How does ADCC work?
Killer cells that have Fc receptors for IgG (CD16 in NK) bind to Ab-labelled cell
What does non-sterilizing elimination entail? example?
controlling replication of pathogen but not actually eliminating it
ex: Herpes virus
How does the immune system target encapsulated bacteria?
Opsonization with C3b against capsule. Overcomes inability of macrophages to ingest hydrophilic substances
What are examples of bacteria that avoid the circulatory system by colonizing mucosal surfaces w low phagocytic and complement levels?
Cholera Diptheria Pertussis (These orgasnisms never penetrate epithelium) (They release toxins)
Endo-toxins are produced by what type of bacteria? example?
produced by gram-negative
ex: LPS
Which endogenous pyrogens are induced by LPS?
IL-1
TNF-a
IL-6
Are endotoxins or exotoxins neutralizing to Abs? Why
Exotoxins
Since there is very little variance in antigenic structure, Abs can bind it
What are superantigens and what do they do?
type of exotoxin
bind to HLA-II
activate T cells that posess certain TCR allele
cytokines–> toxic shock
What does IFN-gamma do in terms of intracellular bacteria immunity?
restricts protein synth decrease membrane fluidity NO alters cell metabolism Increased HLA-1
What factors, in order of effect, increase macrophage/monocyte phagocytosis?
TNF-a
LPS
IFN-gamma
(LPS and INF-gamma are synergystic)
How can obligate intracellular pathogens evade the immune response?
- they result in a Th2 response that is ineffective against intracellulars
- they become latent until immune response wanes
How is humoral immunity inolved in viral infections?
Abs can block viral attachment
Abs can opsonize
Classical pathway -complement
ADCC
What is the antiviral state?
decrease membrane fluidity
enzymes that destroy virals
inhibits viral protein synth
upregulates HLAs
How can virals escape immune reponse?
Block IFN pathways Block HLA expression Block complement activation mutating themselves immune suppression
What type of immunity is directed twoards parasites?
Humoral (Ab and complement) befcasue it is extracellular
What are two hallmarks of helminth parasites?
-High IgE levels
-esoinophelia
so you will see symptoms mimicking allergies
What type of T cell response is induced from parasites? What cytokines are involved?
Th2 immune response
IL-4 and IL-5
What can cause SIRS?
LPS gram-pos peptidoglycan or teichoic acid f-met-phe-leu mCPG bacterial and viral superantigens
Describe the presentation of SIRS
circulatory collapse DIC hemorrhagic necrosis multiple organ failure spetic shock
What disease are some people susceptible to after getting streptococcal pharyngitis?
rheumatic fever -
Some will develop Abs against carbs on strep bacteria that are similar to those found on heart valves. These Abs bind heart tissue
What is herd immunity?
If enough members of a population are immunized, transmssion of disease is interrupted
What is attack rate?
Number infected compared to number exposed
How do scientists kill organisms for vaccines?
physical - heat or irradiation
chemical- formaldehyde, glutaraldehyde
What type of immune response is generally seen after a killed/inactivated vaccine is given>
exogenous antigen processing pathway and Th2 response
boosters are often needed
Describe the nature of live/attenuated vaccines and how they are safe?
They lose their virulence yet retain their ability to replicate within the host
Why are live vaccines better than killed ones?
1) processed exogenously and endogenously so Ab and cell-mediated responses
2) sustained immune response so lesser need for booster
What are some disadvantages of the live vaccines?
-less stable and can revert back to virulent form
What are some examples of recombinant vaccines?
Hep B
HPV - Quad
HPV- Bi
Lyme Disease
What are the valencies of acellular pertussis, Gardasil, and pneumococcal vaccines?
pertussis: 4
Gardasil: 4
pneumococcal: 23
What are potential concerns of formaldehyde as an inactivating agent?
hypersensitivity -hand eczema
not carcinogenic
What is the advantsage of FluMist?
intranasal adminisration of ‘cold-adapted’ virus allows growth in cool mucosa but cant spread to warmer areas in body
Which two adjuvants are liscensed for human use? How do they work?
alum
AS04
-restrict Ag dispersion to form depot and slow release and granuloma forms for proonged immune response
How does neomycin interfere w bacteria?
it binds to 30S subunit of bacterial ribosomes
used in vaccines to prevent contamination
Why is 2-PE added to vaccines
it’s a preservative
effective against pseudomonas aeruginosa (and broad spectrum)
What are the two main components of the preservative Thimerosal?
organic Hg
thiosalicylate
What are the complications of Thimerosal?
allergies - periorbital dermatits possible
But generally it is ok in vaccines
What are some contraindications of vaccines?
- an immunocompromised person and live vaccines
- allergy to vaccine products
- pregnancy
What are the benefits of maternal immunization w regards to the neonate?
- If it is not viable, then it is safe to give in 2nd tri
- enhances passive immunity through transplacentally acquired IgG
For how long can HISG prtect a hypogammaglobulinemic pateitn?
one month
What are donors for HISG screened for
Screened for pathogens
Not screened for Ab titers
What is the difference bw IGIM and IGIV?
IGIV - processed to prevent clumping
IGIM - may cause anaphylaxis if given i.v.
When is IGIV used?
Group B streptococcal infections
Kawasakis disease
What is SHIG? How is it different form HISG?
donors have high levels of specific Ab
What must you consider when given patient serum from heterologous animal species?
Serum sickness
What are contraindications for polyclonal preps?
- shouldnt be given IV unless stated - anaphylaxis
- in IgA deficient pts. cuz they may have anti-IgA Abs (anaphylactic rxn through IgE production)
What are most monoclonal Abs derived from?
mouse myeloma cell fused with a mouse spleen-derived plasma cell producing desired Ab
What is the most common monoclonal Ab used for Allograft rejection prevention?
anti-CD3
What type of bacteria is normal gut flora i general?
gram neg
Define Sepsis
SIRS + infectious etiology
Define severe sepsis
Sepsis + 1 organ failure
What cytokines are released from macrophages in toxic shock syndrome?
IL1
IL6
TNFa
What cytokines are released from T cells in toxic shock syndrome?
IL2
IFN gamma
How much Ab is produced from exotoxins?
usually very little so they may be susceptible to similar disease
Why would a PPD show up negative when someone has AIDS?
normally: assess cellular immune response by seeing delayed hypersensitivity
AIDS: no CD4 , so no CMI, so no rxn
How does decreased CD4 in AIDS effect other immune cell populations?
very low levels of cytokines will yeld ineffective immune repsonses
