Immunology midterm Flashcards
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IL-2
Source - Thp, Th0, Th1
- Growth factor for T cells
- Enhances NK cell cytotoxicity
- Plays a role in pCTL to CTL differentiation
IL-1 and TNF (synergistic)
Source: IL-1 - MAC
TNF - MAC, Th1
- Play an important role in inflammation
- Activate (or enhance activation of) macrophages to secrete cytokines (IL-1, 6, 12, TNF) and chemokines (IL-8 and MCP-1)
- 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
- Systemically, IL-1 and TNF act on hypothalamus to induce fever and play a key role in lowering of blood pressure leading to shock
IL-3
Source - T cells
- Hematopoiesis - important for both myeloid and lymphoid progenitor cell development
IL-4
Source - mast, Th0, Th2
- Required to isotype switch to IgE
- Downregulation of Th1 cytokine production
- Downregulation of iNOS (not as effective as TGFB)
- Shifts Th0 response to Th2 phenotype
IL-5
Source - mast, Th2
- Hematopoiesis - differentiation of eosinophils
- Chemotactic for eosinophils; recruiting eosinophils to tissues
- Activation of eosinophils
IL-6
Source - MAC, Th2
- Stimulus for the secretion of C-reactive protein from hepatocytes (inflammation)
- In the presence of TGFB, IL-6 plays a role in the differentiation of Thp cells to Th17
IL-7
Source - BMS
- Hematopoiesis - role for B and T cell differentiation. Bone marrow and thymus
IL-8 (CXCL8)
Source - mac, endothelial cells
Chemotactic for neutrophils
IL-10
- Downregulates IL-12 secretion by dendritic cells and macrophages (leads to downregulation of Th1 cytokines)
- Downregulates iNOS but not as effective as TGFB
- Inhibitory molecule
IL-12
Source - MAC, den
- Activates NK cells to secrete IFNy (enhanced if either IL-15 or IL-18 is present)
IL-13
Source - Th2
- In lung, mediator of allergic asthma
- Plays a role in helminth infections (nematodes - round worms)
IL-15
Source - MAC, den
- Plays a role (along with IL-12) in inducing NK cells to secrete IFNy
- Shares many in vitro biological activities with IL-2
- Role in inflammation
- Chemo attractant for T cells, NK cells, and neutrophils
IL-17
Source - Th17
- 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)
- Autoimmune disorders if Th17 cells specific for self antigen
- IL-17 is chemotactic for neutrophils
- Plays a key role in fungal infections and in extracellular bacterial infections
IL-21
Source - Th17
- Growth factor (amplification) of Th17 cells
IL-22
Source - Th17
- Proinflammatory - has been shown to be elevated in several inflammatory conditions (eg rheumatoid arthritis and psoriasis)
IL-23
Source - den
- Role in differentiation of Thp cells to Th17 in the presence of TGFB and IL-6 or IL-1
- Proinflammatory cytokine that is composed of two subunits (p19 and p40). The p40 subunit is common to both IL-12 and IL-23
- Elevated in multiple sclerosis, psoriasis, and Crohn’s disease
IL-33
Source - mast, other
- Activates mast cells
- IL-33 is upregulated in intestinal parasite infection
- Th2 cells have receptors for IL-33. Fxn???
- 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.
- Dysregulated IL-33 contributes to asthma, arthritis, and inflammatory bowel disorder
GM-CSF
Source - Mac, T cells
- Role in hematopoiesis; role in differentiation of myeloid progenitor to GM progenitor
- Role in mobilization and activation of dendritic cells
G-CSF
Source - mac
- Role in hematopoiesis; role in differentiation of GM progenitor to granulocyte/neutrophil
M-CSF
Source - mac
- Role in hematopoiesis; role in differentiation of GM progenitor to granulocyte/neutrophil
TGFB
Source - Th2
- Downregulation of iNOS
- Critical for differentiation of Th0 cells to a/i Tregs
- In the presence of IL-6 or IL-1 and IL-23 -> differentiation of Thp cells to Th17
IFNy
Source: NK cells, Th0, Th1
- Activate iNOS
- Enhances activation of NADPH oxidase
- Downregulates production of Th2 cytokines
- Critical for Th0 differentiation to Th1 phenotype
- Along with IL-2, promotes pCTL to CTL differentiation
- Enhances expression of Class I MHC on nucleated cells
- Enhances expression of Class II MHC on antigen-presenting cells
TNF alone
Source - MAC, Th1
- TNF enhances NADPH oxidase activity
- TNF: role in the activation of inducible nitric oxide synthase
MCP-1 (CCL2)
Source - mac, endothelial cells
Chemotactic for monocytes
Eotaxin (CCL11)
Source - epithelial cells, fibroblasts
Chemotactic for eosinophils
IFNa and IFNB
Source - virally infected cells, particularly double stranded RNA viruses
- Triggers production of enzymes (2’5’ oligoadenylate synthetase)
- Inhibition of T cell proliferation
- Increase expression of Class I MHC on nucleated cells
Cytokines and chemokines secreted by macrophages
Cyto: IL-1,6,12,18, TNF
Chemo: IL-8 (CXCL8) -> neutrophils and MCP-1 (CCL2) -> monocytes
Recall steps for B cell humoral immune response to protein antigen
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C3a
Anaphylatoxin, causes degranulation of mast cells and basophils -> histamine release, degranulation
C4bp
Binds/competes with C4b (ONLY IN CLASSICAL COMPLEMENT PATHWAY)
C5a
Anaphylatoxin. Also chemotactic for neutrophils
Properdin
Stabilizes C3 convertase in alternative complement pathway by increasing t1/2 by 6-10 fold. Enhances complement reaction
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
IgA
- Monomer, dimer, or trimer
- t1/2 = 1 week
- Located in MALT, tears, sweat, saliva
- Secreted for immuno surveillance
- Major in milk and colostrum
IgD
- Mostly membrane-bound
- Expressed on naive B cells
- Low detectable serum levels -> products of B cell death
IgE
- Monomer
- Mostly bound to FcER -> barely detected in serum
- Mast cells and basophils
- X-linking -> release histamine
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
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
Summary of thymic events
- Expression of CD2
- Somatic recombination of beta chain
- Expression of pre-TCR-CD3 complex (CD3, preTa, and B chain; requires prior somatic recombination of beta chain)
- Expression of both CD4 and CD8 on the same cell
- Somatic recombination of alpha chain
- Expression of TCR-CD3 complex
- SELECTION-SCREENING (positive, negative, death by neglect)
- Lineage selection
- Cross into medulla
- Negative selection (this time, APCs are from bm, not thymus)
- Exit to periphery
- Effector cells that exit include CD4+ Thp, CD8+ pCTL
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
Armamentarium of NK cells
Lytic granules containing perforin and granzymes
DAMPs examples
MSU - monosodium urate crystals, chol crystals, skin irritants/UVB radiation, gluc-derived ROS/elevated extracellular gluc, FFAs, silica dust
Endogenous antigen processing
Class I MHC!!!
- Microorganisms present in cytoplasm, but not enclosed within vacuole degraded by proteosome
- Peptide fragments from proteosome bind to transporter of antigen processing (TAP) proteins
- TAP brings fragments to ER
- In ER, fragments come into contact with class I MHC molecules -> form complex
- Complexes are released from Golgi into vesicle that fuse with cell membranes
- Ag peptide/class I MHC is displayed on cell surface
Factor I in classical complement pathway
Cleaves C4b, needs cofactor. Soluble!
NALP3 inflammasome cleavage cascade
- Process pro-caspase-1 zymogen to active caspase-1/IL-1B converting enzyme -> cleavage of:
- Pro-IL-1B and pro-IL-18 to active forms
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
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)
Macrophage recs
IFNy, TNF, IL-10, IL-4, TGFB, IL-1, MCP-1, FcyR, CRP-R, CR1
Clinical manifestation of FOXP3 mutation
IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) - autoimmune diseases inflammation -> watery diarrhea, eczema, DM I
Cytokines that activate NADPH oxidase
IFNy and TNF
DAF in alternative complement pathway
Binds/competes with C3b on autologous cells -> prevents Factor B binding. Membrane!
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
- Amount of time needed to produce response after exposure to antigen
- Characteristics of response to second exposure to antigen
- 10 days
2. No lag time! Produce higher antibody titer because of memory cells
DAF in classical complement pathway
Binds/competes with C4b
Factor I in alternative complement pathway
Cleaves C3b, needs cofactor. Soluble!
Cytokines secreted by activated macrophages
IL-1, IL-6, IL-12, TNF
Ligand for CR-2
C3bi
Factors that affect interactive avidity in T cells
- Intrinsic affinity of T cells for self-MHC
- Density of TCRs* RLS
- Density of self-antigen MHC in thymic cortex* RLS
- Density of antagonistic peptide complexes
- Influence of adhesion molecules and accessory molecules
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
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
Factors that affect antibody specificity
- Multiple germline genes
- Combinatorial association
- Junctional diversity
- Random selection of light and heavy chains
Factor H in alternative complement pathway
Binds/competes with C3b. Soluble!
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
Stages of B cell development
- Pro B cell - transcription of RAG 1, 2, CD19, Tdt, CD79
- 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
- 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
- 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
Inactivation mechanism of C3b on autologous cells
Sialic acid on autologous cells preferentially binds Factor H instead of C3b -> no complement activation, no opsonization
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
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
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.
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
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
Pathway of processing exogenous protein Ag
Class II MHC!
- Endocytosis by APC
- Fusion of endocytotic vesicle with lysosomes
- Newly formed vesicle fuses with endosome containing class II MHC -> chimeric endosome
- 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)
- Chimeric endosome goes to and fuses with cell membrane so that antigen peptide/class II MHC is displayed on APC surface
- When complexes are recognized by TCRs on CD4+ T cells, T cell secretes cytokines
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
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
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
Molecular interaction - CD80/86 aka B7-1/B7-2 (APC)
CD28 (T cell). Costimulatory for increased IL-2 transcription, stabilize IL-2 mRNA
Molecular interaction - CD40 (APC)
CD40L (CD154) (T cell)
Molecular interaction - LFA-3 (APC), adhesion
CD2 (T cell)
Molecular interaction that is absolutely necessary for isotype switching
CD40 (B cell) to CD40L (CD154) (T cell)
Molecular interaction - Class II MHC peptide
TCR
Molecular interaction - ICAM 1,2,3 (APC), adhesion
LFA-1 (T cell)
Molecular interaction - Class II MHC (APC)
CD4 (T cell)
CD 80/86 (APC)
Also interacts with CD152. Downregulation of T cells
Thymocytes that exit thymus
CD 4+ nTreg, CD8+ pCTL, CD4+ Thp
P-selectin
On activated vascular endothelium. Histamine-induced. Causes rolling
E-selectin
On activated vascular endothelium. TNF and IL-1 induced. Causes rolling
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
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
PECAM on lymphocytes, monocytes, and eosinophils
PECAM on activated vascular endothelium. Causes adhesion for transmigration
Process after Ag-induced B cell activation -> different heavy chain constant region
Isotype switching
Responsible for leukocyte rolling, a weak adhesion process
Selections
Firm adhesion
Integrins
Leads to expression of IgM and IgG
Alternative splicing
Uses adhesion to move B cells through HEV; not in memory cells
L-selectin
Pan market for B cells
CD19
Binds C8 to prevent MAC
CD59 (HRF20)
Products of pepsin antibody degradation
F(ab)2 and degraded Fc
Products of papain antibody degradation
2Fab and Fc
Results in different variable regions after antigen-induced B cell activation
Somatic mutation
B cell receptor that leads to inhibition with x-linked mIg receptor by IgG
Low affinity FcyR (FcyRIIB)
Binds C5bC6C7 to block formation of MAC
S-protein
Critical signal for T cell activation
Binding of CD28 and B7 (CD80/86); stabilization of IL-2 mRNA
Bound or associated with CD25
IL-2
Molecular interactions chart
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Summary of T cell development
- CD2 expression
- PreTCR - CD3 expressed now and throughout. Somatic recombination of beta chain (RAG-1,2, Tdt), preTalpha, CD3, beta chain
- PreTCR - CD4, CD8 expression start -> double positive
- TCR - somatic recombination of alpha chain. Downregulation of preTCR. SELECTION/SCREENING - 1st pass, central tolerance
- TCR - LINEAGE COMMITMENT -> downregulation of CD4 or CD8
- Go to medulla, further negative selection via AIRE - 2nd pass, central tolerance
- Exit to periphery
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
CD25+
Constitutively expressed in CD4+ nTreg. Is high affinity IL-2 receptor chain needed for polyclonal expansion
Aitregs ntregs
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CRP
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