Ong Material Flashcards
1
Q
Composition of Human Blood (What does human blood do; overview of components)
A
- Transports substances to tissues:
- O2, nutrients, hormones, leukocytes, red cells, platelets, antibodies
- Carbon dioxide and nitrogenous waste products of cell metabolism to the excretory organs of the body
- Volume of blood: about 5 quarts, but varies by individual
- Half of blood is cellular components suspended in plasma
2
Q
Composition of Human Blood (cellular elements)
A
- CBC= Complete Blood Count
- Cellular elements are:
- RBC: for oxygen delivery
- WBC: for immune defense
- Platelets: clotting
- RBCs: WBCs: Platelets ~=600:1:15
- 2-3x1013 RBC in the body at any time
- About 2x1011 new RBCs are made each day
3
Q
Composition of Human Blood (hemoglobin)
A
- RBCs are filled with hemoglobin (>90% dry weight)
- Hemoglobin binds heme (porphyrin) groups that are complexed with iron (oxygen binding)…can chelate ions
- Hemoglobin A (adult) is a tetramer of 2 alpha, 2 beta
- Hemoglobin F (fetus) is a tetramer of 2 alpha, 2 gamma
- Fetus needs to take oxygen away from maternal blood stream, gamma has higher affinity than beta for oxygen
4
Q
Anemia (Definition, Most common cause)
A
- Deficiency of RBC or hemoglobin blood. Never normal/always sign of a disease
- Most common cause is an insufficient supply of iron, B12/cobalamin or folate
5
Q
Kinetic approach to classifying anemia
A
- Decreased RBC production
- Lack nutrients
- Bone marrow disorders/suppression
- Low levels of trophic hormones (EPO)
- Increased RBC destruction
- Bone marrow unable to keep up with replacing 5% of RBC mass/day
- Blood loss
6
Q
Morphologic approach to classifying anemia
A
- Macrocytic (large RBC) anemia
- Folate or B12 deficiency
- Lack of intrinsic factor (glycoprotein that binds B12 for adsorption in ileum) in autoimmune disease, pernicious anemia
- Drugs that interfere with DNA synthesis (hydroxyurea, zidovudine)
- Microcytic (small RBC) anemia
- Decreased hemoglobin content within the RBC
- Iron deficiency (hypochromic microcytic anemia) most common
- Disorders of heme biosynthesis
- Reduced hemoglobin production: thalassemia
- Normocytic anemia
- Renal disease, cancer
7
Q
Sites of iron, B12 and folic acid absorption in SI
A
- Iron=duodenum
- Folic acid=jejunum
- Cobalamin/B12+intrinsic factor=ileum
8
Q
Iron Absorption
A
- Iron absorption in intestine
- Inorganic iron via DMT1
- Heme iron via HCP1
- Transported to blood by ferroportin or complexed with apoferritin and stored as ferritin
- Iron transported to erythroid precursors for synthesis of hemoglobin
- via transferrin
- transferrin-iron complex binds to transferrin receptors in erythroid precursors and hepatocytes and is internalized
- Release iron and recycled to plasma membrane
- transferrin then released from receptor
- Release iron and recycled to plasma membrane
- Iron storage in liver
- stored as ferritin
- Iron reclaimed from RBC
- By macrophages
- Export it or store it as ferritin
- Heme converted to bilirubin and excreted in bile
- Take up iron and store it as ferritin via ferroxidase
- By macrophages
9
Q
Folate and B12 Metabolism
A
- Folates in diet are polyglutamates
- Enzymatically converted into folate monoglutamates (via folate reductase in jejunum)
- Folic acid is absorbed two-fold better than folates
- Folate needed for synthesis of TMP
- Folate for neural tube development
- B12 methyl donor to convert homocysteine to methionine
- activated to make SAM, which methylates DNA, proteins, metabolites
- B12 released via HCl and proteases in stomach
- Free B12 combines with intrinsic factor (a glycoprotein from stomach’s parietal cells) and results in complex that undergoes absorption within the distal ileum of small intestine
- Pernicious anemia=immune destruction intrinsic factor
- Liver main storage site B12. Can store 3 yrs worth.
10
Q
Hemolytic Anemia
A
Hereditary
- Abnormal shape: hereditary spherocytosis
- Abnormal hemoglobin: hemoglobin S replace A (sickle-cell anemia)
- Defective hemoglobin synthesis: thalassemia minor and major; globulin chains are normal but synthesis is defective
- Enzyme defects: G6PD deficiency predispose to acute episodes of hemolysis (allergy to sulfa, fava, anti-malarial)
- Variation in population; some mild and others severe
11
Q
Sites of hematopoiesis
A
- Fetus:
- Starts in yolk sac and liver
- Adult:
- Primarily in bone marrow
12
Q
Sustaining Hematopoiesis
A
- Sustained by multipotent hematopoietic stem cells
- Stem cells self-renew or commit to one or another hematopoietic lineage by proliferating and differentiating, under the control of cytokines, growth factors, and TF
- Single multipotent SC can repopulate entire hematopoietic system
13
Q
Sequential steps of blood cell development are directed by cytokines
A
Committed stem cell→Cytokine A→Cytokine B→Cytokine C→Differentiated and Functional blood cell
14
Q
The development of T-lymphocytes and red cells
A
- IL=interleukine (general name for hematopoietic growth factors)
- SDF-1 (stromal cell Derived factor)
- FLT-3 Ligand
- SCF (stem cell factor) effects both neural crest and hematopoietic cell development. Binds C0kit tyrosine kinase receptor, mutation of which has near identical phenotype as SCF mutations
- Tpo (thrombopoietin)
- Epo (Erythropoietin)
- GM-CSF (granulocyte macrophage stimulating factor [sargramostim])
- G-CSF (granulocyte stimulating factor [filgrastim])
- Interleukin-11
15
Q
Erythropoietin (EPO)
A
- Stimulates erythroid proliferation and differentiation in red cell progenitors in bone marrow
- Feedback control of RBC production is through EPO
- Necessary to prevent death and promote proliferation of committed precursor
- Shifts non-committed progenitor cells into the erythroid lineage
- Feedback control targets CFU-Es by upregulating their production as well as stabilizing these cells
16
Q
HIF-1 control of EPO expression in response to O2 levels
A
- HIF-1 is a heterodimeric TF that binds hypoxia-response elements (HREs) that are associated with a broad range of transcriptional targets, particularly Epo
- In normoxia, hydroxylation can cause HIF-1alpha to be:
- Degraded by the proteasome
- Blocked from recruiting a transcriptional coactivator, p300
- Prolyl hydroxylase domains (PHDs) downregulate and inactivate HIF subunits
- HIF-1alpha is stabilized in hypoxia and can activate Epo production
- HIF hydroxylases are inactive, allowing transcription to be active
17
Q
JAK-STAT signaling in hematopoiesis
A
- Hematopoietic factors interact with membrane receptors of the cytokine receptor super family
- Binding of cytokines (like EPO) to their receptors (like EPOR) phosphorylates and activates JAK
- Activated JAKs phosphorylates STAT proteins, which dimerize and translocate to the nucleus
- STATs are transcription factors that bind to regulatory elements in the genome to activate gene transcription
-
JAK-STAT pathway negatively regulated by:
- SOCS (suppressor of cytokine signaling) proteins
- Protein tyrosine phosphatases
- SH2 domain containing PTP1, SHP2, CD45 and T-cell PTP (TCPTP)
- Ubiquination and degradation of JAK
- PIAS (protein inhibitor of activated STAT)
18
Q
Therapeutic Uses of Erythropoietin
A
- Treat anemia caused by chronic kidney disease
- Target hematocrit 30-36%
-
Used previously to treat anemia caused by cancer treatments
- Since 2008, studies shown increased risk of death/tumor growth. Not enough evidence for clinical benefit
-
Used previously to treat anemia in critically ill patients
- Didn’t change the # of blood transfusions needed
- Benefit must be weight against the 50% increase in thrombosis
19
Q
Blood Doping
A
- Use in endurance sports
- Pro athletes are already optimized; might not actually see a benefit in them
20
Q
Adverse effects of erythropoietin
A
- Increased risk of HTN in pts with kidney disease if used to rapidly increase Hb to above 13.0 g/dl
- Often to treat anemia in chronic kidney disease, only when Hb levels <10 g/dl
-
Recommended caution in using EPO in cancer patients
- Risk of stroke and increased death related to malignancy may outweigh any potential benefits of erythropoietin or darbopoietin in absence of severe anemia
21
Q
Myeloid Growth-Factors: GM-CSF & G-CSF
A
- GM-CSF stimulates the proliferation/differentiation of myeloid cell lineages
- Monocytes, macrophages, neutrophils, eosinophil
- Secreted by macrophages, T-cells, mast cells, endothelial, and fibroblasts
- Recombinant GM-CSF (sargarmostim) is produced in yeast.
- Identical to endogenous GM-CSF except for glycosylation at leucine position 23
- G-CSF enhances phagocytic and cytotoxic activities of neutrophils but has little effect on monocytes, macrophages, and eosinophil
- More specific than GM-CSF and is therefore better tolerated
- Produced by endothelial cells, macrophages, and a number of other immune cells
- Recombinant G-CSF (filgrastim) is produce in E. coli
- Not glycosylated and carries an extra N-terminal methionine
22
Q
Therapeutic Uses of GM-CSF, G-CSF
A
- Primarily used to treat neutropenia
- Low number neutrophils (normally 50-70% circulating WBC)
- Neutropenia observed in:
- Cancer patient after chemo
- AIDS
- Bone marrow transplant
- Used in preparation for autologous stem cell transplant
- Before chemo, HSC are mobilized from bone marrow into peripheral blood by treatment with GM-CSF/G-CSF and collected with apheresis
- Re-infuse HSC after chemo
23
Q
Adverse effects of GM-CSF, G-CSF
A
- GM-CSF can cause fevers, malaise, arthralgias, myalgias, and a capillary leak syndrome characterized by peripheral edema and pleural or pericardial effusions.
- Allergic reaction
- G-CSF is more frequently used because it is more specific than GM-CSF (better tolerated)
- G-CSF can cause bone pain, but this clears when the drug is discontinued
24
Q
Megakaryocyte Growth Factors: IL-11
A
- IL-11 stimulates the proliferation and differentiation of megakaryocyte and platelets
- Modulates antigen/antibody responses
- Recombinant IL-11 (oprelvekin) is produced in E. coli
- Not glycosylated like endogenous form, short by one AA
25
Q
Megakaryocyte Growth Factors: Tpo
A
- Thrombopoietin stimulates the proliferation and differentiation of megakaryocytes
- Also regulates downstream production of platelets
- Recombinant is not approved for therapeutic usage
- Alternatives: Romiplostim (IgG fusion with thrombopoietin fragment), Eltrombopag (Tpo receptor agonist)
26
Q
Therapeutic uses of IL-11
A
- Treatment of thrombocytopenia
- Normal: 150,000-450,000 per mm3
- <100,000
- Have a high risk of hemorrhaging
- Thrombocytopenia is often observed in
- VitB12 or folic acid deficiency
- Leukemia or myelodysplastic syndrome
- Liver failure resulting in Tpo loss
- Dengue fever resulting in infection of megakaryocyte
- Sepsis/systemic viral or bacterial infection
- Myelosuppresion induced by chemotherapy agents
- Idiopathic thrombocytopenia purpura
27
Q
Adverse Effects of IL-11
A
- Platelet transfusion is commonly used to treat thrombocytopenia
- Some patients fail to reach the expected increase in platelet count
- Often a high frequency of fever and anaphylactic reactions
- Recombinant IL-11 can cause:
- Excessive fluid retention with edema and cardiac decompensation
- Renal impairment
- Allergic reactions
28
Q
Summary table of common hematopoietic growth factor in clinic
A
29
Q
What happens upon infection?
A
- Integumentary system (skin, mucus membranes, mucus)
- First line of defense
- Physical barrier
- Dead skin cells are constantly sloughed off; makes it hard for invading bacteria to colonize
- Sweat and oils contain anti-microbial chemicals, including some antibiotics.
- Physiological changes in environment
- Regulated pH and temperature (Fever)
- Mucus contains lysozymes
- Destroy bacterial cell walls
- Flow of mucus washes
- Cilia mucus out of the lungs
- Phagocytes are several types of white blood cells
- Macrophages and neutrophils
- Seek and destroy invaders/damaged cell
- Phagocytes attracted by inflammatory response of damaged cells
- Macrophages and neutrophils
- Inflammation is signaled by mast cells
- Release histamine
- Fluids collects around an injury to dilute toxins
- Swelling
- Increased temp to kill temperature-sensitive microbes.
- Release histamine
- Fever
- Destroy many types of microbes
- Helps fight viral infections by increasing interferon production
- High fevers can be dangerous
- Some doctors recommend letting low fevers run their course
30
Q
Organs of the immune system
A
- Bone marrow
- Source of blood meeting
- Thymus
- Maturation of T cell
- Spleen
- Upper left of abdomen
- Hematopoietic organ, site of macrophage antigen presentation, antibody response
- Splenic macrophages remove old RBC and acts a reservoir for platelets
- Lymph nodes and vessels
- Lymphatic system is the source of lymphocytes (NK, T/Bcells)
- Clumps of lymphoid tissue especially in gateways to body
- Tonsils, adenoids, and appendix
- Lymphatic vessels closely parallels body’s veins/arteries
- Cells/fluid are exchanged between blood and lymph
31
Q
Cells of the immune system
A
- Lymphocytes
- B cell
- Antibodies
- T Cell
- Cytokines
- Large granular lymphocyte
- Cytokines
- B cell
- Phagocytes
- Mononuclear phagocytes
- Cytokines
- Complement
- Neutrophil
- Eosinophil
- Mononuclear phagocytes
- Auxiliary Cells
- Basophil
- Inflammatory mediators
- Mast Cell
- Inflammatory mediators
- Platelets
- Inflammatory mediators
- Basophil
- Other
- Tissue Cells
- Interferon
- Cytokines
- Tissue Cells
32
Q
Innate vs. Adaptive Immunity
A
- Innate Immunity
- Epithelial barriers
- Phagocytes
- Dendritic cells
- Complement
- NK cells, ILCs
- 0-12 hours
- Adaptive Immunity
- B lymphocytes to make Ab
- Start on Day 1, takes about 7 days
- T lymphocytes to effector T-cells
- Start on Day 1, takes about 7 days
- B lymphocytes to make Ab
33
Q
Comparing Innate vs. Adaptive Immunity (Summary Table)
- Specificity
- Diversity
- Memory
- Noreactivity to self
- Cellular and chemical barriers
- Blood proteins
- Cells
A
NK T cells and T cells are cytotoxic lymphocytes that straddle the interface of innate and adaptive immunity
34
Q
Innate Immunity:
A
- Detection of microorganisms and first-line defense
- Physical barriers
- Pattern recognition receptors (TLR)
- Regulation of inflammation
- Swelling, redness, heat and pain
- Serum proteins: Complement system, C-reactive protein, lectins such as mannose-binding lectin and ficolins
- Activation and instruction of adaptive immune response
- Phagocytes (neutrophils, monocytes, macrophage) use lysozyme
- Macrophage, mast cell, NK cells release cytokines and inflammatory mediators
35
Q
Adaptive Immunity:
A
- Specifically respond to variety of antigens
- Discriminate between foreign antigens and self antigens
- Response to a previously encountered antigen in a learned way by initiating a vigorous memory response
- Causes production of antibodies (humoral immunity), activation of T-cells (cell-mediated immunity)
36
Q
PRRs recognize PAMPs (Innate Immunity)
A
- Tissue macrophage and dendritic cells express:
-
Pattern Recognition Receptors
- TLRs
- C-type lectin receptors (CLRs)
- Nucleotide-binding Oligomerization Domain-like receptors (NLRs)
- To detect:
-
Pathogen Associated Molecular Patterns (evolutionarily conserved)
- Unmethylated CpG DNA
- Flagellin
- Double-stranded RNA
- Peptidoglycans
- LPS from membranes (used to assay for sepsis/infections)
- Stimulate release of proinflammatory cytokines, chemokines, and interferons
- Success=ingested, degraded, and eliminated pathogen
- Bacterial endotoxins (LPS from Gram -) dangerous in drug formulations/need to be tested for
37
Q
The Complement Cascade (Innate Immunity)
A
- Modifies membranes and promotes inflammatory response
- Primary Functions:
-
Chemotaxis
- C3a/C5a act as chemoattracts to draw in macrophage and neutrophils
-
Opsonization
- C3b coats bacteria
-
Cell Lysis
- MAC complex (C5b, C6, C7, C8, C9)
-
Chemotaxis
40
Q
Two Arms of Adaptive Immunity: Humoral immunity
A
- Microbe: Extracellular microbe
- Responding lymphocytes: B lymphocytes
- Effector mechanism: Secreted antibody
- Transferred by: Serum
- Functions: Block infections and eliminate extracellular microbes
41
Q
Two Arms of Adapative Immunity: Cell-Mediated Immunity
A
- Cell mediated immunity (1)
- Microbe: phagocytosed microbes in macrophage
- Responding lymphocyte: Helper T cell
- Effector Mechanism: Bind to macrophage
- Transferred by: Cells (T lymphocytes)
- Functions: Activate macrophages to kill phagocytosed microbes
- Cell mediated immunity (2)
- Microbe: Intracellular microbes (virus) replicating w/i infected cell
- Responding lymphocyte: Cytotoxic T cell
- Effector Mechanism: Bind to infected cell
- Transferred by: Cells (T lymphocytes)
- Functions: Kill infected cells and eliminate reservoirs of infection
42
Q
Graph of Adaptive Immunity Response
A
- Primary exposure to antigen X
- Naïve B cells create a response, peaking around 2 weeks
- Created plasma cells to release serum Ab
- Generate memory B cells at end of response, around 4 weeks
- Secondary exposure to antigen X
- Get a very fast and large antibody response, creating plasma cells
- Memory B cells made at end of response
43
Q
Antibody Structure
A
- 2 heavy chain/2 light chains
- Variable region formed by V(D)J recombination
- Recognize antigen like lock/key
- Stem of Ab participates in the immune defenses
- Identical in all Ab of the same class
- 5 isotypes
44
Q
V(D)J Recombination
A
- Mechanism for diverse binding selectivity in the B-cell receptor (antibodies) and T-cell receptors
- Limited genetic info to make million of antibodies
- Genes spliced from DNA in two different chromosomes
- Heavy chain is where the binding of antigens occurs, so much genetic variation is involved in its assembly
- 1 of 400 possible variable gene segments (V)
- 1 of 15 diversity segments (D)
- 1 of 4 joining segments (J)
- 24,000 possible combination for DNA heavy chain
- Light chain is (VJ)
- Occurs in B-cell receptor/antibodies and T-cell receptor
- 107 to 109 antigenic determinant can be discriminated
45
Q
Five Immunoglobulin isotypes
A
- IgG and IgM in plasma
- IgG in extracellular fluid around body
- IgE in mast cells
- IgM activates complement system
- IgA transported across epithelium
- Fetus get IgG
- Brain has none
46
Q
The Action of Antibodies
A
- Agglutination
- Activation of complement
- Opsonization
- Marking target cells for destruction by macrophages, eosinophils, NK cells (Ab dependent cellular cytotoxicity)
- Neutralizing bacteria, virus or toxin
- Therapeutic uses (Herceptin/Trastuzumab to treat Her2+ breast cancer)
47
Q
MHC Class I and II: Comparison Table
A
- Class I
- Comprised of an MHC-encoded alpha chain and a ß2 microglobulin chain
- Present on most cells
- Bind endogenous antigens synthesized in a cell
- Present antigen to CD8 cytotoxic T cell
- Bind CD8 adhesion molecules on cytotoxic T cells
- Presence of foreign or over abundant antigens targets cell for destruction
- Class II
- Comprised of MHC-encoded alpha chain and a ß chain
- Present only on antigen-presenting cells
- Bind exogenous antigens
- Present antigen to CD4 helper T cell
- Bind CD4 adhesion molecules on helper T cells
- Presence of foreign antigens induces antibody production, and attracts immune cells to area of infection
51
Q
Antibodies and T-cell Receptors are Antigen receptors
A
- B-cell uses ab-receptor to bind matching antigen, engulfs, processes
- Becomes large plasma cell
- Cannot kill pathogen, only can mark
- Helper T-cell only recognize antigen in MHC II
- Sees antigen in MHCII on APC
- Helper T-cell confirms with CD4 protein
- Becomes activated helper T, aka commander of immune response
- Orders to increase # specific Ab-producing plasma cells and cytotoxic killer cells
- Killer T cells only recognize antigen in MHC I
- Recognizes virus fragments from macrophage
- Binding process and an activated helper T cell activate cytotoxic T-cell
- Goes around and kills diseased cells with same antigen in MHC I
52
Q
Antigen Receptors
A
- B cell receptor on outer surface and is a sample of antibody it is prepared to manufacture
- T-cell receptor only recognize antigen after is has been processed and presented in MHC
- Ensure that T-cell only act on precise targets at close range
53
Q
T-cell activation (2 required signal steps)
A
- Signal 1: MHC + TCR
- Dendritic cell present antigen on MHC
- TCR engages MHC + antigen
- Signal 2: Co-stimulatory molecules and receptor
- Activates T Cell
- CD80/86 (APC)→CD28 (T-Cell)
- CD40 (APC)→CD40L (T-Cell)
- ICAM-1 (APC)→LFA-1 (T-cell)
- Negative regulation to shut off T-cell
- CD80/86→CTLA-1 (T-cell)
- Activates T Cell
- If the second signal is absent, T-cell either stops responding (anergic) or undergoes apoptosis
54
Q
Cell mediated and humoral immunity
A
56
Q
Immunosuppression
A
- Immunosuppressive drugs are used to
- Prevent organ rejection
- Activated T cells are main mediators of immunologic rejection, attack donor organ
- Prevent organ rejection
- Treat GVHD after allogenic HCT
- Allogenic is genetically similar but could be a total stranger
- Crohn’s or RA
- Asthma
- Allergic rhinitis
- Psoriasis and eczema
57
Q
Mechanisms of action of immunosuppressive drugs
A
- Main pathways in immunoregulationT cell activation
- MHCII and B7 (CD80/86)→calcineruin→IL-2
- Target of rapamycin and cyclin-dependent kinase
- MHCII and B7 (CD80/86)→calcineruin→IL-2
- Steroids and NF-kappaB
- Ca2+ levels, Calcineurin, NFAT, IL-2 synthesis
- Autocrine stimulation by IL-2 to mTOR and cell cycle
- DNA synthesis and proliferation
58
Q
Immunosuppressant- a timeline
A
- Four stages in development strategies
- Anti-proliferative agents
- Steroid therapy
- Lymphocyte/depletion/modulation
- Disruption of cytokines
- mTOR inhibitor, calcineurin, IL-2 receptor blockade
59
Q
Azathioprine
A
- Purine analong
- Its active metabolite (6-MeMPN) blocks the enzyme amido-phosphoribosyltransferase
- Hinders DNA synthesis
- Inhibits the proliferation of cells, especially fast-growing cells without a method of nucleotide salvage
- T cells and B cells are particularly affected by the inhibition of purine synthesis
60
Q
IMP Dehydrogenase Inhibitors
A
- Mycophenolate mofetil to mycophenolic acid in liver
- MPA inhibits IMPD that control rate of de novo guanine (purine) synthesis in the proliferation of B and T cells
-
IMPDH catalysis NAD-dependent oxidation of IMP to XMP
- Committed step
-
IMPDH catalysis NAD-dependent oxidation of IMP to XMP
- Used in place of azathioprine
- Used in three compound regiment
- Calcineurin inhibitor (cyclosporine or tacrolimus)
- Corticosteroid (prednisone)
62
Q
Corticosteroids MOA
A
- Bind to glucocorticoid receptor that binds DNA GRE
- Alters expression of target genes like anti-inflammatory IkBalpha
- GC-GR also interacts with other TF like NF-kappaB, AP1, CREB, STAT to alter gene expression
-
Glucocorticoids repress transcription of many pro-inflammatory cytokines and chemokine, cell adhesion molecules and key enzymes involved in the initiation and/or maintenance of the host inflammatory response
- Modulates transcription of genes in a hormone-dependent manner through tethering to other DNA-bound TF
- Regulation of these other TF by extracellular signals
- GR ubiquitously expressed in all cells in the airway
- GC-GR can also bind negative GRE and result in repression of transcription
- GRs can recruit histone deactylases to NF-kappaB-driven proinflammatory gene transcription to decrease transcription
- Suppress production of IgG and cytokines
- Inhibit differentiation, migration and antigen-presentation of dendritic cell and activation of TH17 cells
64
Q
Calcineurin Inhibitors: MOA
A
- Bind to cyclophilins for cyclosporine, FK binding proteins for tacrolimus
- Calcinuerin is activated by intracellular Ca after stimulation of TCR
- Ca/calmodulin dependent phosphatase
- Drug-receptor complex specifically and competitively binds to and inhibits calcineurin
- Inhibits translocation of TF NF-AT (not deP) into nuclease leading to reduced transcriptional activation of early cytokines genes for IL-2, TNF-alpha, IL-3, IL-4, CD40L, GM-CSF, IFN-gamma.
67
Q
Anti-lymphocytic antibodies
A
- Muromonab-CD3 (OKT3)
- Binds TCR-CD3 complex leading to activation but then apoptosis of T cell
- Protects transplanted tissues from T cells
- Alemtuzumab (Campath, Campath-1H)
- Ab to CD52 (protein on mature lymphocytes)
- Rituximab (Rituxin)
- Ab to CD20 on surface of B cells
- ADCC
- Antibody dependent cell mediated cytotoxicity
- NK cells lyse target cell whose membrane antigens have been bound by Ab
71
Q
Summary of Immunosuppresant Drugs
A
73
Q
Several chemical classes of NSAIDs
A
- Different Cox1/2 selectivity and variable half lives in plasma
- Cox-2 inhibitors have a longer half life in plasma
- NSAIDs can be individual specific
75
Q
Role of cytosolic phospholipase A2 in the activation of inflammation
A
- Phosphorylation of cytoplasmic PLA2 can occur by ligand-receptor signaling and/or increased intracellular Ca2+
- Calcium binding to the C2 domain of phospho-cPLA2 triggers binding to plasma membrane
- cPLA2 hydrolyses phospholipids to release AA and lysophospholipids
- AA converted to prostaglandins by COX
- Inhibited by NSAIDs
- Arachidonate 5-lipoxygenase (5-LOX) converts AA to leukotriene
76
Q
Prostaglandin-endoperoxidase synthases=COX enzymes
A
- COX1 is housekeeping expressed in almost all tissues and is cytoprotective
- Maintains prostanoid levels for tissue homeostasis
- COX2 is an immediate-early response gene that is highly induced at sites of inflammation and during tumor progression by cytokines and mitogens
84
Q
Rheumatoid Arthritis Figure
A
- Monocytes attracted to joint and differentiate into macrophages/become activated
- Secrete TNF and IL-1
- TNF increases expression of adhesion molecules on endothelial cells (recruit more cells to the joint)
- Induce synovial fibroblasts to express cytokines (such as IL-6), chemokines (such as IL-8), growth factors (GM-CSF) and matrix metalloproteinases (MMPs)
- Contribute to cartilage and bone destruction
- TNF contributes to osteoclast activation and differentiation
- IL-1 mediates cartilage degradation directly by inducing the expression of MMPs by chondrocytes
- Chemokines (MCP1 and IL-8) are also secreted by macrophages and attract more cells into the joint.
86
Q
Methotrexate
A
- Lower doses in RA than in chemotherapy
- Inhibits AICAR transformylase and thymidylate synthetase
- AICAR competitively inhibits AMP deaminase, leading to accumulation of AMP
- AMP is released and converted extracellularly to adenosine, which is a potent inhibitor of inflammation
- Inflammatory functions of neutrophils, macrophages, dendritic cells, and lymphocytes are suppressed
