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Flashcards in Immunology midterm Deck (109):
0

IL-1 and TNF (synergistic)

Source: IL-1 - MAC
TNF - MAC, Th1

1. Play an important role in inflammation
2. Activate (or enhance activation of) macrophages to secrete cytokines (IL-1, 6, 12, TNF) and chemokines (IL-8 and MCP-1)
3. Activate endothelial cells leading to de novo expression of ICAM-1, VCAM-1, and E-selectin, and enhanced expression of ICAM-2. Also induce endothelial cells to secrete chemokines IL-8 and MCP-1
4. Systemically, IL-1 and TNF act on hypothalamus to induce fever and play a key role in lowering of blood pressure leading to shock

1

IL-2

Source - Thp, Th0, Th1

1. Growth factor for T cells
2. Enhances NK cell cytotoxicity
3. Plays a role in pCTL to CTL differentiation

2

IL-3

Source - T cells

1. Hematopoiesis - important for both myeloid and lymphoid progenitor cell development

3

IL-4

Source - mast, Th0, Th2

1. Required to isotype switch to IgE
2. Downregulation of Th1 cytokine production
3. Downregulation of iNOS (not as effective as TGFB)
4. Shifts Th0 response to Th2 phenotype

4

IL-5

Source - mast, Th2

1. Hematopoiesis - differentiation of eosinophils
2. Chemotactic for eosinophils; recruiting eosinophils to tissues
3. Activation of eosinophils

5

IL-6

Source - MAC, Th2

1. Stimulus for the secretion of C-reactive protein from hepatocytes (inflammation)
2. In the presence of TGFB, IL-6 plays a role in the differentiation of Thp cells to Th17

6

IL-7

Source - BMS

1. Hematopoiesis - role for B and T cell differentiation. Bone marrow and thymus

7

IL-8 (CXCL8)

Source - mac, endothelial cells

Chemotactic for neutrophils

8

IL-10

1. Downregulates IL-12 secretion by dendritic cells and macrophages (leads to downregulation of Th1 cytokines)
2. Downregulates iNOS but not as effective as TGFB
3. Inhibitory molecule

9

IL-12

Source - MAC, den

1. Activates NK cells to secrete IFNy (enhanced if either IL-15 or IL-18 is present)

10

IL-13

Source - Th2

1. In lung, mediator of allergic asthma
2. Plays a role in helminth infections (nematodes - round worms)

11

IL-15

Source - MAC, den

1. Plays a role (along with IL-12) in inducing NK cells to secrete IFNy
2. Shares many in vitro biological activities with IL-2
3. Role in inflammation
4. Chemo attractant for T cells, NK cells, and neutrophils

12

IL-17

Source - Th17

1. Functionally, IL-17 induces expression of proinflammatory cytokines and chemokines from a wide range of cells (eg IL-6, IL-8, GM-CSF, G-CSF and metalloproteinases from macrophages and other cell types)
2. Autoimmune disorders if Th17 cells specific for self antigen
3. IL-17 is chemotactic for neutrophils
4. Plays a key role in fungal infections and in extracellular bacterial infections

13

IL-21

Source - Th17

1. Growth factor (amplification) of Th17 cells

14

IL-22

Source - Th17

1. Proinflammatory - has been shown to be elevated in several inflammatory conditions (eg rheumatoid arthritis and psoriasis)

15

IL-23

Source - den

1. Role in differentiation of Thp cells to Th17 in the presence of TGFB and IL-6 or IL-1
2. Proinflammatory cytokine that is composed of two subunits (p19 and p40). The p40 subunit is common to both IL-12 and IL-23
3. Elevated in multiple sclerosis, psoriasis, and Crohn's disease

16

IL-33

Source - mast, other

1. Activates mast cells
2. IL-33 is upregulated in intestinal parasite infection
3. Th2 cells have receptors for IL-33. Fxn???
4. IL-33 suggested to be member of the alarmin family, molecules that are released upon tissue necrosis. IL-33 is released when endothelial cells or epithelial cells undergo damage/necrosis. As such IL-33 can trigger multiple immunological processes as a result of trauma or infxn (eg activate mast cells). Some immune cells can secrete alarmins without developing necrosis.
5. Dysregulated IL-33 contributes to asthma, arthritis, and inflammatory bowel disorder

17

GM-CSF

Source - Mac, T cells

1. Role in hematopoiesis; role in differentiation of myeloid progenitor to GM progenitor
2. Role in mobilization and activation of dendritic cells

18

G-CSF

Source - mac

1. Role in hematopoiesis; role in differentiation of GM progenitor to granulocyte/neutrophil

19

M-CSF

Source - mac

1. Role in hematopoiesis; role in differentiation of GM progenitor to granulocyte/neutrophil

20

TGFB

Source - Th2

1. Downregulation of iNOS
2. Critical for differentiation of Th0 cells to a/i Tregs
3. In the presence of IL-6 or IL-1 and IL-23 -> differentiation of Thp cells to Th17

21

IFNy

Source: NK cells, Th0, Th1

1. Activate iNOS
2. Enhances activation of NADPH oxidase
3. Downregulates production of Th2 cytokines
4. Critical for Th0 differentiation to Th1 phenotype
5. Along with IL-2, promotes pCTL to CTL differentiation
6. Enhances expression of Class I MHC on nucleated cells
7. Enhances expression of Class II MHC on antigen-presenting cells

22

TNF alone

Source - MAC, Th1

1. TNF enhances NADPH oxidase activity
2. TNF: role in the activation of inducible nitric oxide synthase

23

MCP-1 (CCL2)

Source - mac, endothelial cells

Chemotactic for monocytes

24

Eotaxin (CCL11)

Source - epithelial cells, fibroblasts

Chemotactic for eosinophils

25

IFNa and IFNB

Source - virally infected cells, particularly double stranded RNA viruses

1. Triggers production of enzymes (2'5' oligoadenylate synthetase)
2. Inhibition of T cell proliferation
3. Increase expression of Class I MHC on nucleated cells

26

Cytokines and chemokines secreted by macrophages

Cyto: IL-1,6,12,18, TNF
Chemo: IL-8 (CXCL8) -> neutrophils and MCP-1 (CCL2) -> monocytes

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Recall steps for B cell humoral immune response to protein antigen

.

28

C3a

Anaphylatoxin, causes degranulation of mast cells and basophils -> histamine release, degranulation

29

C4bp

Binds/competes with C4b (ONLY IN CLASSICAL COMPLEMENT PATHWAY)

30

C5a

Anaphylatoxin. Also chemotactic for neutrophils

31

Properdin

Stabilizes C3 convertase in alternative complement pathway by increasing t1/2 by 6-10 fold. Enhances complement reaction

32

C1 INH

Inhibits C1. Protease inhibitor and is most important physiological inhibitor of plasma kallikrein

Deficiency of C1 INH permits plasma kallikrein activation -> production of vasoactive peptide bradykinin

33

IgA

- Monomer, dimer, or trimer
- t1/2 = 1 week
- Located in MALT, tears, sweat, saliva
- Secreted for immuno surveillance
- Major in milk and colostrum

34

IgD

- Mostly membrane-bound
- Expressed on naive B cells
- Low detectable serum levels -> products of B cell death

35

IgE

- Monomer
- Mostly bound to FcER -> barely detected in serum
- Mast cells and basophils
- X-linking -> release histamine

36

IgG (1, 2, 3, and 4)

- Monomer
- 75% if total antibodies
- Longest t1/2! = 3 weeks
- Crosses placenta and some colostrum
1. Opsonization (phagocytes)
2. ADCC (NK cells) via target cell-bound IgG binding low affinity FcyR receptors on NK cells
3. Complement activation (C1)
4. Neutralizes viruses and toxins by binding Ags and inhibiting Ag's ability to bind cell surface receptor

IgG1 in highest conc, Ig4 lowest. IgG3 t1/2 is one week, but most effective CCP activator of all IgG subtypes. IgG4 doesn't activate complement at all or bind to FcyR. All IgG subtypes cross placenta

37

IgM

- Free pentameter with J chain or membrane-bound monomer
- 15% of total antibodies
- t1/2 = 1 week
- Only isotype expressed on immature B cells
- Best activator of classical pathway
- Isohemagglutinins

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Summary of thymic events

1. Expression of CD2
2. Somatic recombination of beta chain
3. Expression of pre-TCR-CD3 complex (CD3, preTa, and B chain; requires prior somatic recombination of beta chain)
4. Expression of both CD4 and CD8 on the same cell
5. Somatic recombination of alpha chain
6. Expression of TCR-CD3 complex
7. SELECTION-SCREENING (positive, negative, death by neglect)
8. Lineage selection
9. Cross into medulla
10. Negative selection (this time, APCs are from bm, not thymus)
11. Exit to periphery
12. Effector cells that exit include CD4+ Thp, CD8+ pCTL

39

Characteristics of membrane immunoglobulin (B cell antigen recognizing receptor)

mIg associated with CD79 a + B (Ig a + B) heterodimer. 2 light chains - k or l and 2 heavy chains - m or d

40

Armamentarium of NK cells

Lytic granules containing perforin and granzymes

41

DAMPs examples

MSU - monosodium urate crystals, chol crystals, skin irritants/UVB radiation, gluc-derived ROS/elevated extracellular gluc, FFAs, silica dust

42

Endogenous antigen processing

Class I MHC!!!

1. Microorganisms present in cytoplasm, but not enclosed within vacuole degraded by proteosome
2. Peptide fragments from proteosome bind to transporter of antigen processing (TAP) proteins
3. TAP brings fragments to ER
4. In ER, fragments come into contact with class I MHC molecules -> form complex
5. Complexes are released from Golgi into vesicle that fuse with cell membranes
6. Ag peptide/class I MHC is displayed on cell surface

43

Factor I in classical complement pathway

Cleaves C4b, needs cofactor. Soluble!

44

NALP3 inflammasome cleavage cascade

1. Process pro-caspase-1 zymogen to active caspase-1/IL-1B converting enzyme -> cleavage of:
2. Pro-IL-1B and pro-IL-18 to active forms

45

Role of nTregs (CD 4+, CD25+, FOXP3)

Separate T cell lineage, exit to periphery, and control self-reacting T cells. Responsible for peripheral tolerance. Also negatively regulate immune response to allo/non-self -> better immune response without nTregs

46

Polyclonal activators (mitogens) for B and T cells

B cells - pokeweed mitogen (PWM), high conc of LPS

T cells - PWM, concavalin A (Con A), phytohemagglutinin (PHA)

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Macrophage recs

IFNy, TNF, IL-10, IL-4, TGFB, IL-1, MCP-1, FcyR, CRP-R, CR1

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Clinical manifestation of FOXP3 mutation

IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) - autoimmune diseases inflammation -> watery diarrhea, eczema, DM I

49

Cytokines that activate NADPH oxidase

IFNy and TNF

50

DAF in alternative complement pathway

Binds/competes with C3b on autologous cells -> prevents Factor B binding. Membrane!

51

Cross presentation of exogenous antigens and presentation by class I MHC

Exogenous lysosomes normally processed in phagolysosomes and presented on cell surface are instead presented by class I MHC. X-presentation normally by dendritic cells. X-priming for CD8+ T cells

Ags in endosome may escape to cytosol -> proteosome degradation. Common with Rickettsia rickettsia bc they lyse endosomal membrane

52

1. Amount of time needed to produce response after exposure to antigen
2. Characteristics of response to second exposure to antigen

1. 10 days
2. No lag time! Produce higher antibody titer because of memory cells

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DAF in classical complement pathway

Binds/competes with C4b

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Factor I in alternative complement pathway

Cleaves C3b, needs cofactor. Soluble!

55

Cytokines secreted by activated macrophages

IL-1, IL-6, IL-12, TNF

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Ligand for CR-2

C3bi

57

Factors that affect interactive avidity in T cells

1. Intrinsic affinity of T cells for self-MHC
2. Density of TCRs* RLS
3. Density of self-antigen MHC in thymic cortex* RLS
4. Density of antagonistic peptide complexes
5. Influence of adhesion molecules and accessory molecules

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Hematopoietic chart

.

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Epstein Barr virus (EBV)/HHV-4

Inhibits proteosome activity -> can't get peptide fragments of necessary size in MHC I

60

BLyS

For B selection and survival. First a cell surface protein, then cleaved and released as soluble protein. Secreted by macs/monos, dens, and some lymphocytes. Ligand that binds to BR3*, BCMA, TACI. With BR3, no apoptosis.

Ag binds BCR -> upreg of BR3 -> enhanced expression of BLyS and cleavage -> BLyS binds BR3 on activated B cells -> B cell differentiation to plasma cells -> downreg of B cells via FcyR via ITIM sending signal to downreg B cells. FcyR linked to apoptotic pathway

Trigger for membrane release of BLyS is x-linking of FcyR by IgG

Elevated BLyS -> RA, SLE, MS bc autoreactive cells survive

61

Factors that affect antibody specificity

1. Multiple germline genes
2. Combinatorial association
3. Junctional diversity
4. Random selection of light and heavy chains

62

Factor H in alternative complement pathway

Binds/competes with C3b. Soluble!

63

Clinical manifestations of AIRE mutation

APECED/APS-1 (autoimmune polyendocrinopathy candiasis ectodermal dystrophy/autoimmune polyglandular syndrome type 1) - autoimmune dz that primarily affects endocrine system. Chronic mucocutaneous candiasis, hypoparathyroidism, autoimmune adrenal insufficiency

64

Stages of B cell development

1. Pro B cell - transcription of RAG 1, 2, CD19, Tdt, CD79
2. Pre-B cell - expression of pre-BCR with CD79a/b. Pre-BCR signaling -> proliferation and differentiation of B cells. Start CD20 and go throughout. Somatic recombination happens. Allelic exclusion
3. Immature B cell - tolerance induction. Somatic rearranged light and heavy chains with CD79a, b goes to surface, downregulation of pre-BCR. Autoreactive mIgs undergo apoptosis or anergy
4. Mature, naive B cell - alternative splicing at hnRNA level -> coexpression of sIgM and sIgD. Mature cells leave marrow, enter blood, go to periph lymphoid tissues, and recirc if no Ag encountered there. CD40 expressed!

Activated B cell - somatic mutation, affinity maturation, isotype switching

65

Inactivation mechanism of C3b on autologous cells

Sialic acid on autologous cells preferentially binds Factor H instead of C3b -> no complement activation, no opsonization

66

Role of RAG-1 and 2 and Tdt

RAG 1, 2 - recombinases for V, D, J of heavy and light chains.

Tdt - incorporates nucleotides at junctions to maintain open reading frame, generates junctional diversity

67

Btk

Kinase from pro-B to pre-B that plays important role in B cell act, diff, prolif. Mutation only affects at pre-B, not before! Results in defective B cell pop that fails to mature and enter circ. XLA (Bruton's) - low amount of B cells in blood, very low Ig of ALL classes

68

Cytomegalovirus (CMV)/HHV-5

CMV proteins redirect newly made MHC I from ER back to cytosol where they are degraded by proteosome

No sx's in immunocompetent people. Immunocompromised -> encephalitis, pneumonia, hepatitis, retinitis, blindness.

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Herpes simplex virus (HSV)/HHV 1,2

Little MHC I in neurons. HSV has early protein that binds cytosolic part of TAP -> can't go to ER, can't form Ag peptide/MHC I complex, can't detect infxn

70

Cytokines for activation and downregulation of iNOS

Activation: TNF, then IFNy. (Mycobacteria, Leishmania, gram-neg organisms, IFNy)

Downreg: IL-10, IL-4, and/or TGFB

71

Pathway of processing exogenous protein Ag

Class II MHC!

1. Endocytosis by APC
2. Fusion of endocytotic vesicle with lysosomes
3. Newly formed vesicle fuses with endosome containing class II MHC -> chimeric endosome
4. Class II MHC/Ii comples exposed to lysosomal enzymes -> Ii is degraded and antigenic peptide binds newly exposed groove of class II MHC via another MHC-encoded molecule (DM)
5. Chimeric endosome goes to and fuses with cell membrane so that antigen peptide/class II MHC is displayed on APC surface
6. When complexes are recognized by TCRs on CD4+ T cells, T cell secretes cytokines

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Process of AB feedback in negative reg of B cells using FcyR

IgG x-links mem-bound ABs of same spec with low affinity FcyR -> secreted IgG is neg feedback to inhib further activation of naive cells of that spec and subsequent secretion of ABs

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CD1 (a->e)

Glycoproteins that preset lipids and glycolipid Ags to subsets of T cells. Similar to MHC I in that they complex with B2 microglobulin, but mech and cell surface presentation is similar to MHC II

All types on dens

74

Overall structure of TCR complex

1 heavy, 1 light chain a/B TCR with 5 CD3 molecules that link Ag binding of T cell with signal pathway. CD3 needed to have TCRs on surface

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Molecular interaction - CD80/86 aka B7-1/B7-2 (APC)

CD28 (T cell). Costimulatory for increased IL-2 transcription, stabilize IL-2 mRNA

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Molecular interaction - CD40 (APC)

CD40L (CD154) (T cell)

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Molecular interaction - LFA-3 (APC), adhesion

CD2 (T cell)

78

Molecular interaction that is absolutely necessary for isotype switching

CD40 (B cell) to CD40L (CD154) (T cell)

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Molecular interaction - Class II MHC peptide

TCR

80

Molecular interaction - ICAM 1,2,3 (APC), adhesion

LFA-1 (T cell)

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Molecular interaction - Class II MHC (APC)

CD4 (T cell)

82

CD 80/86 (APC)

Also interacts with CD152. Downregulation of T cells

83

Thymocytes that exit thymus

CD 4+ nTreg, CD8+ pCTL, CD4+ Thp

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P-selectin

On activated vascular endothelium. Histamine-induced. Causes rolling

85

E-selectin

On activated vascular endothelium. TNF and IL-1 induced. Causes rolling

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VLA-4 (CD49d and CD29) integrin. On lymphocytes, monocytes, and eosinophils

Binds VCAM-1 on activated vascular endothelium. TNF and IL-1 induced. Causes firm adhesion

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LFA-1 (CD11a and CD18) integrin. On lymphocytes, monocytes, and eosinophils

Binds ICAM-1 (TNF and IL-1 induced) and ICAM-2 on activated vascular endothelium. Causes firm adhesion

88

PECAM on lymphocytes, monocytes, and eosinophils

PECAM on activated vascular endothelium. Causes adhesion for transmigration

89

Process after Ag-induced B cell activation -> different heavy chain constant region

Isotype switching

90

Responsible for leukocyte rolling, a weak adhesion process

Selections

91

Firm adhesion

Integrins

92

Leads to expression of IgM and IgG

Alternative splicing

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Uses adhesion to move B cells through HEV; not in memory cells

L-selectin

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Pan market for B cells

CD19

95

Binds C8 to prevent MAC

CD59 (HRF20)

96

Products of pepsin antibody degradation

F(ab)2 and degraded Fc

97

Products of papain antibody degradation

2Fab and Fc

98

Results in different variable regions after antigen-induced B cell activation

Somatic mutation

99

B cell receptor that leads to inhibition with x-linked mIg receptor by IgG

Low affinity FcyR (FcyRIIB)

100

Binds C5bC6C7 to block formation of MAC

S-protein

101

Critical signal for T cell activation

Binding of CD28 and B7 (CD80/86); stabilization of IL-2 mRNA

102

Bound or associated with CD25

IL-2

103

Molecular interactions chart

.

104

Summary of T cell development

1. CD2 expression
2. PreTCR - CD3 expressed now and throughout. Somatic recombination of beta chain (RAG-1,2, Tdt), preTalpha, CD3, beta chain
3. PreTCR - CD4, CD8 expression start -> double positive
4. TCR - somatic recombination of alpha chain. Downregulation of preTCR. SELECTION/SCREENING - 1st pass, central tolerance
5. TCR - LINEAGE COMMITMENT -> downregulation of CD4 or CD8
6. Go to medulla, further negative selection via AIRE - 2nd pass, central tolerance
7. Exit to periphery

105

Criteria for screening/selection on DP thymocytes

Based in interactive avidity!
- Intrinsic avidity of TCR for self peptide-self MHC RL!
- Density of TCRs RL!
- Density of self peptide-self MHC on the thymic epithelium
- Density of antagonistic peptide complexes
- Influence of adhesion molecules and accessory molecules

106

CD25+

Constitutively expressed in CD4+ nTreg. Is high affinity IL-2 receptor chain needed for polyclonal expansion

107

Aitregs ntregs

.

108

CRP

.