Immunology Review

Front 1

Where do T cells develop?

Back 1

Thymus, which arises from the endo and ectodermal layers of the 3rd pharyngeal pouch and brachial cleft.

A bone marrow derived lymphoid progenitor cell colonizes at 8 wks gestation.

From birth to adulthood, get 50 million thymocytes each day, only 1 million survive.

Front 2

TCR Co-receptors

Back 2

CD4 = helper T cells
CD8 = cytotoxic T cells

Stregthen TCR engagement w/ MHC/peptide complex; reduce amount of MHC:peptide complexes needed for optimal activation of T cells by 100 fold

Front 3

THC Structure

Back 3

- a & b chains (bind peptides to MHC) coupled to 3 dimers for signal transduction

- 30,000 TCR/cell

Front 4

Composition of thymic epithelial cell

Back 4

- express high density of MHC class I and II associated peptides

- role in positive (cortical epith. cells) and neg. selection (medullary epith. cells)

- chemoattractant production for thymocyte migration

Front 5

Composition of thymic dendritic cells and macrophages

Back 5

- mainly found in the medulla

- role in negative selection

Front 6

Thymic architecture
(immature--> mature)

Back 6

(1) subcapsular region = immature CD3-4-8- double neg. thymocytes

(2) cortex = immature CD3+4+8+ double pos. thymocytes

(3) cortico-medullary junction = mature CD4+8- and CD8+4- thymocytes

(4) medulla

Front 7

Double negative (DN)

CD4-CD8-

Back 7

- 3-5% thymocytes

- 2/3 are triple negative based on TCR expression, can be further divided on CD44 and CD25

- 1/3 are TCR yd+

- TCR b, y, and d rearrangements occur at this stage

- B selection (checkpoint 1) rearranged b chain product pairs with pre a chain to make a functional TCR for survival and maturation signals

Front 8

Douple positive (DP)

CD4+CD8+

Back 8

- 85-90% total thymocytes

- TCR a rearrangement occurs here

- most have rearranged TCR ab genes and express low levels of mature TCR

- small subset have high levels TCR

- cells that don't recognize self are discarded

- cells that react with self antigens are discarded (Checkpoint #2)

- death by neglect --> 95% apoptosis

Front 9

Single positive (SP)

CD4+CD8- and CD4-8+

Back 9

- 5-10% thymocytes

- most mature cells with high levels CD3 and TCR ab

- CD4:CD8 ration 2:1

- most SP are functionally mature and destined to leave the thymus

Front 10

Checkpoint 1

Back 10

- TCRbeta VDJ gene rearrangement and expression of functional beta-chain protein to make preTCR

- occurs at DN3 stage

- beta chain BEFORE alpha chain

- uses helix-loop-helix (HLH) family of transcription activators and repressors (turn on/off genes)

- uses RAGs (recombination activating genes)

- lack of RAGs can lead to Omenn's, a rare autosomal-recessive SCID disorder where NK cells are normal, but T & B cells are not--fatal w/in first few months

- preTCR forms a nucleation center with CD3 complex that recruits signaling molecules

- need inframe version, otherwise death

Front 11

RAGs

Back 11

- recombination activating genes

- join the different segments together

- used for TCRbeta gene rearrangement

- without these, get Omenn's

Front 12

Omenn's Syndrome

Back 12

- rare, autosomal recessive SCID disorder affecting B & T cells, but not NK

- one cause is lack of RAGs

- usually fatal w/in first months of life

Front 13

Double Neg. Stages

Back 13

Stage 1: CD44+25-

Stage 2: CD44+25+

Stage 3: CD44-25+

Stage 4: CD44-25-

Front 14

TCRalpha chain rearrangement

Back 14

- occurs during DP phase

- DP cells die after 3-4 days

Front 15

preTCR components and signaling

Back 15

- preAlpha + beta chain

- CD3 (gamma and epsilon subunits)

- signaling is NOT antigen driven (pre-alpha has intrinsic signaling abilities

- zeta dimers

- Zap70 and Lck (signaling)

Front 16

Lck

Back 16

- member of the SRC family of tyrosine kinase

- activates Zap70

- primarily expressed in lymphoid cells of developing thymocytes and mature T cells

- associated with plasma membrane due to palmitoylation/myristylation

- non-covalently associates with cytoplasmic domains of CD4 and CD8

- deletion in mice results in profound block in thymocyte development

Front 17

Zap70

Back 17

- member of Syk family of tyrosine kinases

- expressed primarily in developing thymocytes and mature T cells, also NK cells

- located in cytosol

- binds to ITAM-P residues of Zeta chains of the CD3 complex

- activated by Lck at specific tyrosine residues

- deficiency is rare, autosomal recessive SCID characterized by absence of CD8+ T cells, presence of CD4+ Tcells that are unresponsive to TCR-mediated stimuli (defective Tcell signaling and abnormal tymic ontogeny)

- genetic deletion --> reduced SP CD4 or CD8 T cells, but normal DN and DP thymocytes

Front 18

formation of preTCR nucleation center

Back 18

- results from preTCR associated with epsilon, delta, and gamma chains of the CD3 complex

- recruits several signaling molecules as result of phosphorylation of tyrosine residues contained within immunoreceptor tyrosine based activation motifs (ITAMS)

Front 19

ITAMS

Back 19

- immunoreceptor tyrosine based activation motifs

- contain tyrosine residues phosphorylated by the preTCR nucleation center

Front 20

Chronic Granulomatis Disease

Back 20

- inherited defect of NADPH oxidase complex

- recurrent infections with catalase positive organisms

- these include: Staphylococcus, Burkholderia cepacia, Nocardia, Mycobacteria, Serratia, Klebsiella, Pseudomonas species

- fungi, esp. Aspergillus and Candida

- recurrent infections lead to lymphadenitis, abscesses and granuloma formation w/in first 2 years of life

Front 21

Formation of ROS in oxidative burst

Back 21

(1) O2 -> O-2 (NADPH oxidase)

(2) O2- -> H2O2 (superoxide dismutase)

(3) H2O2 + Cl- -> HOCL (myeloperoxidase- MPO)

Front 22

Pseudomonas aeruginosa fighting back

Back 22

modifies phagocytic receptors to prevent phagocytosis

Front 23

Yersinia virulence factors

Back 23

disrupts ingestion stage of phagocytosis

Front 24

Listeria and Shigella virulence factors

Back 24

escape from phagosome and enter cytosol

Front 25

M. tuberculosis and Legionella virulence factors

Back 25

stall phagosome maturation

Front 26

Salmonella virulence factors

Back 26

uneffected by lysosomal enzymes

Front 27

Peroxynitrite formation (reactive nitrogen series)

Back 27

(1) O2 -> O2- (NADPH oxidase)

(2) O2- + NO -> ONOO- (peroxynitrite)

Front 28

Non-oxidative killing mechs of phagocytes

Back 28

- proteins w/in granules released when cell is stimulated

- lysozyme (disrupts peptidoglycan), lactoferrin, proteases, defensins (also in Paneth cells in GI) and other cationic proteins

Front 29

How does phagocytosis of apoptotic bodies not produce inflammation?

Back 29

TGF-beta secreted (anti-inflammatory)

Front 30

What does TGF-beta do?

Back 30

anti-inflammatory

Front 31

What does somatic recombination mechanism do?

Back 31

generates a diversity of TCR to recognize diverse pathogens

Front 32

What does MHC polymorphisms do?

Back 32

- gives species a large number of alternative MHCs that differ in binding pockets

- this combats pathogenic mutation around a stereotyped defense system

Front 33

How does clonal selection work in the thymus?

Back 33

Stage 1: POSITIVELY select clones that recognize self-peptide in an individual's own MHC molecultes

Stage 2: NEGATIVELY select overly self-reactive clones with high affinity for self peptide-MHC complexes

* this allows T cells to bind and recognize pathogen peptides prior to encountering pathogens

Front 34

What is immunologic self?

Back 34

set of self-peptides and self-MHC molecules that generates and is recognized by the individual's adaptive T cell repetoire

- TCR repetoire selected on self-peptide-self MHC is nearly unique for each individual

Front 35

What do you do with a cytosolic virus or pathogen?

Back 35

- bind it on class I MHC

- present it to CD8 T cells

- Tcells cause death of cell presenting the viral antigen

-

Front 36

What do you do with an ingested bacteria or endocytotic pathogen?

Back 36

- bind peptides to MHC class II or I

- present it to CD4 or CD*

- Tcells cause activation of cell to enhance pathogen killing

Front 37

What do you do with extracellular pathogen or toxin?

Back 37

- bind peptide to MHC class II

- present it to CD4 Tcells

- Tcells provide help to B cell for production of Abs

Front 38

What is the structure of MHC class I?

Back 38

- 3 alpha chains and 1 beta

- alpha chain combines with separate beta2 myoglobin

Front 39

What is the structure of MHC class II?

Back 39

- 2 alpha chains and 2 beta

- peptide more exposed than on class I

Front 40

CD4+ --> Th1

Back 40

IL-12
IFN-y

(IL-2 autocrine loop after activation)

INHIB: IL-4

Front 41

CD4+ --> Th2

Back 41

IL-4

(IL-4 = autocrine loop)

INHIB: IFN-y

Front 42

Cd4+ --> Th17

Back 42

IL-17
IL-6

Front 43

CD4+ --> Treg

Back 43

TGF-B
IL-10

Front 44

What does Th1 produce?

Back 44

IFN-y
TNF-a
IL-2

Front 45

What does Th2 produce?

Back 45

IL-4 (induces class switching in B cells)
IL-5
IL-10
IL-13

-> B cell activation

Front 46

What does Th17?

Back 46

IL-17
IL-6

Front 47

What does Treg produce?

Back 47

TGF-B
IL-10

Front 48

How are peptides loaded onto Class I MHC?

Back 48

- MHC Class I molecules noncovalently assoc. w/ B2M in ER
- chaperones displaced as AG presentation occurs
- in cytosol, viral proteins synthesized, chopped up into peptides, transported into ER by TAP, loaded on MHC Class I

Front 49

WHat does TAP do?

Back 49

transports viral peptides into ER for loading onto MHC Class I

Front 50

How are viral proteins degradated in the cytosol?

Back 50

Targeted for degradation by proteosome

Front 51

How does T cell stimulate B cell for class switching?

Back 51

CD40 on B cell makes contact w/ CD40L on T cell

Front 52

What do you need for CD8 memory cells?

Back 52

CD4 help

Front 53

What are the markers for naive T cells?

Back 53

L-selectin/CD62L: peripheral LN homing

CCR7: chemokine receptor (same as APCs S.T. migrate to same area)

no IL-2R (CD25)

Front 54

What are the markers for effector T cells?

Back 54

adhesion molecules (integrins, CD44)

secrete cytokines

CCR5, CXCR4: recognize chemokines secreted by activated cells in periphery

IL-2R (CD25)

FasL

no CD62L (don't stay in LN)

Front 55

What are the markers of central memory cells?

Back 55

CD62L: in LN

CCR7

IL-2R: respond to small amounts of IL-2 by proliferation

secrete IL-2

adhesion mols

phenotype similar to naive, but have IL-2R

Front 56

What are the markers of effector memory cells?

Back 56

phenotype similar to effector, but don't all have IL-2R

adhesion mols

secrete IL-2

CCR5 & CXCR4

FasL
no CD62L: in periphery

secrete cytokines (IL-5, IFN-y)

Front 57

What is CCR7?

Back 57

chemokine receptor that brings naive and central memory cells together in Tcell zone of LN

Front 58

What is CCR5 and CXCR4?

Back 58

chemokine receptor recognizing secreted chemokines from activated cells in periphery

on effector and effector memory T cells

Front 59

What is CD25 and where?

Back 59

=IL-2R, on effector and central memory T cells

Front 60

What are some regulatory proteins inhibiting complement activation?

Back 60

DAF (Decay accelerating factor) = membrane protein disrupting binding of Factor B to C3b or C4b2a to C3b

MCP (membrane cofactor protein)= cofactor for proteolysis of C3b into INACTIVE frags, mediated by plasma enzyme Factor 1

C1 INH = reg protein, stops complement activation early (C1 stage)

Front 61

What do deficiency in C3 cause?

Back 61

susceptibility to infections, early fatal

Front 62

What does deficiency to C2 and C4 (classical) cause?

Back 62

NON LETHAL

incr. incidence of immune complex dxs resembling SLE

Front 63

WHat do deficiencies in C9 and MAC cause?

Back 63

incr. susceptibility to Neisseria

Front 64

What does deficiency of C1INH cause?

Back 64

hereditary angioneurotic edema

(excessive C1 activation and production of vasoactive protein frags leading to edema in larynx and other tissues)

Front 65

WHat does deficiency in enzyme that synthesizes glycolipid anchor for DAF and MCP cause?

Back 65

paradoxymal nocturnal hemoglobinuria

(uncontrolled complement activation on erythrocytes leading to lysis of erythrocytes)

Front 66

Which AIDs are class I, CD8 (HLA A, B, C)?

Back 66

psoriasis
psoriatic arthritis
Reiter's symdrome
ankylosing spondylitis

Front 67

Which AIDs are class II, CD4 (HLA DR, DQ, DP)?

Back 67

MS
RA
SLE
Pemphigus vulgaris

Front 68

What does AIRE deficiency cause?

Back 68

APECED

Front 69

WHat does Foxp3 deficiency cause?

Back 69

IPEX
- Foxp3 used by reg CD4 T cells
I= immune dysregulation (Coombs, anemia)
P= polyendocrinopathy (T1DM)
E= enteropathy (celiac like epithelium)
X= X-linked

Front 70

What does deficiency in CTLA4 cause?

Back 70

autoimmune disorders

Front 71

What does deficiency in Fas?

Back 71

-failure of apoptosis
- ALPS = autoimmune lymphoproliferative syndrome
- hemolytic anemia, thrombocyopenia

Front 72

What does gain of function of PTPN22 cause?

Back 72

autoimmunity

Front 73

WHat does an increase in memory effector T cells cause?

Back 73

no need for CD28 stimulation

lower threshold of activation by stress

Front 74

Pemphigus vulgaris

Back 74

blistering skin disease affecting skin and cornified epi of esophageous

threapy = immunosuppressive

autoantibodies IgG to desmoglien 3

HLA DRB1*0402 = susceptibility

Front 75

RA

Back 75

mapped to specific MHC binding pocket (P4)

susceptibility assoc. w/ DR1, DR4, DR10, DR14

BUT DRB1*0402 (pemphigus vularis) NOT assoc, nor is DRB1*1401