Term
| What are the different actions of Interferon alpha, beta and gamma? What do they all have in common? |
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Definition
All 3 use JAK/STAT, by binding to type II cytokine receptors (Type 1, hematopoietic receptors also utilize JAK/STAT)
1) IFN-a and IFN-b activate pathways that block protein synthesis and increase poly RNA degradation (decrease virus production). They up-regulate MHC-I expression.
2) IFN-y regulates Th1 cells, macrophages and NK cells. It up-regulates MHC-I and MHC-II expression. |
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Term
| Which cytokines use JAK/STAT? |
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Definition
| Type 1 "hematopoietin" family (including IL-6, IL-2) and Type II/Interferon family (all IFNs) |
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Term
| What are the main functions of IL-2? |
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Definition
Pleiotropic!
SHORT- T/B/NK and tolerance.
1) T cell growth factor released by TREGS
2) NK growth factor
3) Induces Ab production in B-cells
4) Induces Tolerance (prevent autoimmunity) |
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Term
| How does IL-2 act on T-cells in the body |
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Definition
SHORT- T cell needs ALL 3 receptors to bind to IL-2 with high affinity.
1) IL-2 has 3 side-chains (alpha, beta and gamma), but naive T-cell only has beta and gamma receptors (IL-2Rb and IL-2Ry have too low an affinity to bind physiological levels of IL-2)
2) Activation of TCR by MHC+Antigen causes IL-2R-a to be expressed, increasing affinity 100X
**IL-2 receptor subunits are shared by other receptors such as IL-4R, IL-7R, IL-9R, IL-15R, IL-21R, IL-15R, IL-13R ** |
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Term
| Explain the molecular basis for the immunodeficiency syndrome often called "Bubble Boy" |
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Definition
This is also called X-linked Severe Combined Immunodeficiency Syndrome (X-linked SCID)
X-linked SCID arises from mutation in IL-2Ry, which prevent activation of T-cell proliferation by IL-2, leading to severe immunodeficiency. |
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Term
| How does IL-17 act in the body? |
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Definition
Bridges innate and adaptive immunity (found elevated in autoimmune disorders)!
1) Released by Th-17 cells (immunity to extracellular organisms, autoimmunity)
2) Induces innate signals such as PMNs, Acute Phase Responses (TNF-a, IL-1, IL-6) and anti-microbial peptides.
2) Synergiezes with TNF-a |
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Term
| What are the 4 major subsets of Th cells, the developmental cytokines which induce T-cells to release them, and their cytokine products? |
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Definition
1) Th1- immunity to intracellular organisms (viruses and bacteria)
Developmental-IL-12 (via STAT4) released from macrophages to induce T-cells
Main- IFNy (cell-mediated immunity) released by T-cells to activate macrophages
2) Th2 (immunity to helminthes (worms), allergy)
Developmental- IL-4 (via STAT6) causes IgE expression by B cells
Main- IL-4, IL-5 (Humoral Immunity, Allergy)
3) Th17 (immunity to extracellular organisms, autoimmunity)
Developmental- TGF-b, IL-1, IL-6 (via STAT 3)
Main- IL-15, IL-17F, IL-22 and IL-23 (feedback) (Inflammation & Autoimmunity)
4) TREGS (immune suppression, prevention of immunopathology, tolerance)
Developmental- TGFB, IL-2, via (STAT5)
Main- IL-10, TGFB (immune suppression) |
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Term
A patient presents with severe infections and you discover that they are derived from worms that have entered her skin on a previous trip.
What type of T cell is not doing its job and what cytokines are lacking. |
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Definition
| Th2 cells are not releasing IL-4 or IL-5 |
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Term
A patient presents with several viral infections simultaneously.
What type of T cell is not doing its job and what cytokines are lacking. |
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Definition
| Th1 cells are not producing enough IFN-y |
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Term
A patient presents with Rheumatoid Arthritis and Diabetes, and well a number of exogenous bacterial infection, but otherwise is physiologically normal.
What type of T cell is not doing its job and what cytokines are lacking. |
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Definition
These are autoimmune conditions and extracellular bacterial infections, so a good guess would be Th17 cells.
These cells release IL-17, IL-17F and IL-22, and are involves in immunity to extracellular organisms as well as autoimmunity. |
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Term
| What major signaling pathway is involved in developmental cytokines associated with all 4 T helper subsets. |
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Definition
JAK/STAT
STAT3= Th17....TGF-b, IL-1, IL-6
STAT4= Th1......IL-12
STAT5= TREGS..TGF-b, IL-2
STAT6= Th2......IL-4 |
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Term
How does EBV mimic cytokine/cytokine receptor activity to evade the immune system?
Vaccinia?
CMV?
Leporipoxvirus? |
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Definition
EBV- IL-10 homolog for immune suppression (usually released by TREGS)
Vaccinia- Soluble IL-1b receptor
CMV- chemokine receptor homologs (bind RANTES, MCP-1 and MIP-1a)
Poxvirus- Soluble IFN-y receptor |
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Term
| What cytokine might you give as a therapeutic treatment for anemia (also taken by Olympic hopefuls)? |
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Definition
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Term
| What cytokine might you give as a therapeutic treatment Neutropenia? |
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Definition
G-CSF increases neutrophil production
Recall, CSF is induced in the bone marrow in response to acute phase reactants (IL-1, IL-6 and TNF-a), in order to maintain an acute inflammatory response! |
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Term
| What cytokine might you give as a therapeutic treatment for malignant melanoma and renal cancer? |
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Definition
IL-2
Recall, IL-2 incudes progenitor T-cells to become TREGS, which release IL-10 and TGFB in order suppress the immune system.
It also acts through the JAK/STAT pathway to induce Ab production by B-cells, and as a T-cell growth factor. |
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Term
| What cytokine might you give as a therapeutic treatment for multiple sclerosis? |
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Definition
Interferon-beta
Recall, IFN-beta acts through JAK/STAT to control poly RNA transcription and protein translation (it is a class 1 IFN) |
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Term
| What cytokine might you give as a therapeutic treatment for short stature? |
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Definition
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Term
| What anti-cytokine antibody might you give as a therapeutic treatment for autoimmunity? |
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Definition
Anti-TNF, Anti-IL-1, Anti-IL-6 and anti-IL-17
Recall, TNF is an acute phase reactant which can induce too much inflammation if it is auto-reactive. You might need to inhibit it to prevent too much inflammation. |
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Term
| What anti-cytokine antibody might you give as a therapeutic treatment for autoimmunity/inherited inflammatory diseases/gout? |
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Definition
Anti-IL-1
Like TNF and IL-6, IL-1 is an acute phase product, but it also treated gout and inherited inflammatory diseases.
Recall- IL-1 requires NFkB and NRL (caspase-1) for activation. |
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Term
| What is the only cytokine antibody currently in clinical trials? |
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Definition
| anti-IL-17 (Gaffan's favorite protein!) |
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Term
| Which 4 cytokines regulate hematopoiesis? |
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Definition
1) IL-7 for B and T cell development
2) IL-15 for NK development
3) G-CSF for neutrophil development
4) EPO for RBC development |
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Term
| Myeloid progenitor cells give rise to erythrocytes and platelets, Basophils, Eosinophils. Which cytokines are involved in myeloid differentiation? |
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Definition
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Term
What are the primary cytokines that regulate innate immunity?
What about adaptive immunity? |
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Definition
Innate- TNF-a, IL-1, IL-6, IL-17, INF-y
Adaptive- IL-2, IL-4, IFN-y |
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Term
| Which JAKs and STATs are associated with each Interferon type? |
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Definition
INF-a and b= STAT1 and JAK1/JAK2 (antiviral)
INF-y= STAT1/STAT2 and JAK1/TYK-2 (enhance macrophages and NK cells, and induce MHC-I and MHC-II expression). |
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Term
| What evidence exists for the role of IL-2 in autoimmunity? |
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Definition
| IL-2-/- knockout mice have autoimmune conditions (IL-2 is important for tolerance!). |
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Term
| Why do you see Immunodeficiency in X-linked SCID? |
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Definition
X-linked SCID ("bubble boy") is usually an issue with the IL-2R-y. IL-2 is important for tolerance and preventing autoimmunity, but not lymphocyte levels!
IL-7 shares the same gamma subunit, which means that it is also affected. IL-7 is important for T and B cell differentiation.
You might also see a lack of NK cells, because IL-15 R shares the same gamma chain as well! |
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Term
| What is important about the fact that IL-15R and IL-2R share the same beta and gamma subunits, but have different alpha subunits? |
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Definition
| They possess the same signaling components, but have different binding properties! |
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Term
What treatment has been tried for X-linked SCID?
What were such treatments halted? |
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Definition
Retroviral-mediated gene therapy for gamma subunit of IL-2R into the recipients bone marrow.
The gene has incorporated near oncogenes and led to rare forms of luekemia! |
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Term
| What "innate" properties are possessed by IL-17? How does it link the adaptive and innate systems? |
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Definition
1) IL-17 is released by Th-17 effector cells (adaptive) to alert elements of the innate immune system to begin inflammation
2) It induces typical innate signals (neutrophils, NF-kB, acute phase responses, anti-microbial peptides) |
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Term
| How does mutations in AIRE relate to IL-17 and APICED? |
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Definition
AIRE is an important t-factor in the medulla of the thymus that is important for deleting autoreactive T-cells and maintaining central tolerance.
Without adequate AIRE, autoimmune reacts act on IL-17, causing APECED (remember, IL-17 is important for preventing bacterial and fungal infections such as Staph) |
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Term
| How does mutations in AIRE relate to IL-17 and APICED? |
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Definition
AIRE is an important t-factor in the medulla of the thymus that is important for deleting autoreactive T-cells and maintaining central tolerance.
Without adequate AIRE, autoimmune reacts act on IL-17, causing APECED (remember, IL-17 is important for preventing bacterial and fungal infections such as Staph) |
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Term
| How can TGF-beta induce both IL-17 release from Th-17 cells and IL-10/TGF-b release from Tregs, when these cytokines have seemingly opposing effects? |
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Definition
For IL-17 signaling, TGF-b is paired with IL-6 and IL-1 (pro-inflammatory cytokines), which signal a state that requires an immune response.
For IL-10/TGF-b signaling, TGF-b is paired with IL-2 (proliferative), which signals an active immune state that needs to be suppressed. |
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Term
| What anti-cytokine antibody might you give to prevent inflammatory bowel disease? |
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Definition
| anti IL-12/23 (intracellular immunity and extracellular immunity). |
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Term
| What does HIES syndrome have to do with STAT3? |
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Definition
Hyperimmunoglobulin E syndrome is an Autosomal Dominant Negative disease that impairs STAT3 homodimer formation, and prevents IL-17 signaling.
It manifests with "cold" staph infections (can't protect against extracellular organisms) and very high IgE concentrations |
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