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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
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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
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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
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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
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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
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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
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7
Q

Sites of iron, B12 and folic acid absorption in SI

A
  • Iron=duodenum
  • Folic acid=jejunum
  • Cobalamin/B12+intrinsic factor=ileum
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8
Q

Iron Absorption

A
  1. 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
  2. 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
  3. Iron storage in liver
    • stored as ferritin
  4. 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
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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.
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10
Q

Hemolytic Anemia

A

Hereditary

  1. Abnormal shape: hereditary spherocytosis
  2. Abnormal hemoglobin: hemoglobin S replace A (sickle-cell anemia)
  3. Defective hemoglobin synthesis: thalassemia minor and major; globulin chains are normal but synthesis is defective
  4. Enzyme defects: G6PD deficiency predispose to acute episodes of hemolysis (allergy to sulfa, fava, anti-malarial)
  • Variation in population; some mild and others severe
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11
Q

Sites of hematopoiesis

A
  • Fetus:
    • Starts in yolk sac and liver
  • Adult:
    • Primarily in bone marrow
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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
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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

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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
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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
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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:
    1. Degraded by the proteasome
    2. 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
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17
Q

JAK-STAT signaling in hematopoiesis

A
  1. Hematopoietic factors interact with membrane receptors of the cytokine receptor super family
  2. Binding of cytokines (like EPO) to their receptors (like EPOR) phosphorylates and activates JAK
  3. Activated JAKs phosphorylates STAT proteins, which dimerize and translocate to the nucleus
  4. 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)
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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
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19
Q

Blood Doping

A
  • Use in endurance sports
  • Pro athletes are already optimized; might not actually see a benefit in them
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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
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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
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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
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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
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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
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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)
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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
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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
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28
Q

Summary table of common hematopoietic growth factor in clinic

A
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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
  • Inflammation is signaled by mast cells
    • Release histamine
      • Fluids collects around an injury to dilute toxins
      • Swelling
      • Increased temp to kill temperature-sensitive microbes.
  • 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
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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
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31
Q

Cells of the immune system

A
  • Lymphocytes
    • B cell
      • Antibodies
    • T Cell
      • Cytokines
    • Large granular lymphocyte
      • Cytokines
  • Phagocytes
    • Mononuclear phagocytes
      • Cytokines
      • Complement
    • Neutrophil
    • Eosinophil
  • Auxiliary Cells
    • Basophil
      • Inflammatory mediators
    • Mast Cell
      • Inflammatory mediators
    • Platelets
      • Inflammatory mediators
  • Other
    • Tissue Cells
      • Interferon
      • Cytokines
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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
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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

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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
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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)
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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
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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)
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38
Q

Complement Cascade: Membrane Modification

A
  • Complement fragments deposit on unwanted materials
  • In <5min, millions C3b fragments coat
    • Opsonization
  • MAC
39
Q

Complement Cascade: Promotion of Inflammation

A
  • Release peptides known as anaphylatoxins
    • Directed movement of motile cells (chemotaxis and chemokinesis)
    • Release of mediators, such as histamine from mast cells
    • Activation of cells like epithelial and endothelial cells
    • Contraction of smooth muscle
    • Dilation of blood vessels
    • Exudation of plasma and cells
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
48
Q

MHC Class I

A
  • Present cytoplasm-derived peptides that are representative of the normal components for the same cell or of intraceullar parasites (viruses)
    • Degraded in proteasome, peptide transferred to ER, assembled MHC/antigen complex transported to cell surface
  • MHC-1 present to CD8 cytotoxic T-cell
    • Induce apoptosis or release cytotoxic proteins
  • Since virus attack any cell, MHC-1 on al cell (except RBC)
    • High levels on APC (dendritic cells, macrophages, B lymphocytes, vascular endothelial)
49
Q

MHC Class II

A
  • Noncovalently associated heterodimer of alpha-beta chain
  • Bind peptides from exogenous proteins
    • Endocytosed, fragmented, and put on cell surface
  • Present to CD4 helper T-cell
  • Expressed constitutively only on the surface of interstitial dendritic cells, macrophages, and B cells
    • Epithelial/vascular endothelial cell MHC-2 upregulated by proinflammatory cytokines (IL-2, IFN-gamma)
50
Q

MHC and HLA

A
  • Major histocompatibility complex
    • Human leukocyte antigen is human version
  • HLA important in immune system
    • Involved in the processes of identifying self and non-self
    • Very variable, barcode for self
    • Responsible for tissue rejection in organ transplants
    • Genetic inheritance, basis for autoimmune disease
    • Certain subtypes associated with disease
    • Certain subtypes impact drug efficacy
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)
  • If the second signal is absent, T-cell either stops responding (anergic) or undergoes apoptosis
54
Q

Cell mediated and humoral immunity

55
Q

Immunopathology

A
  • Hypersensitivity: allergic reaction to harmless antigens
  • Immunodeficiency: unable to stop an infection
  • Autoimmune disorder: immune system targets self-antigens
56
Q

Immunosuppression

A
  • Immunosuppressive drugs are used to
    • Prevent organ rejection
      • Activated T cells are main mediators of immunologic rejection, attack donor organ
  • 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
  • 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
  • Used in place of azathioprine
  • Used in three compound regiment
    • Calcineurin inhibitor (cyclosporine or tacrolimus)
    • Corticosteroid (prednisone)
61
Q

Corticosteroids

A
  • Endogenous steroid hormone
    • Cortisol/corticosterone
  • Drugs
    • Prednisone, hydrocortisone, fluticasone propionate
  • Widely prescribed
    • Autoimmune
    • Severe allergies
    • Arthritis
    • Atopic dermatitis
  • Long term use associated with osteoporosis, metabolic disease and cardiovascular disease
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
63
Q

Calcineurin Inhibitors

A
  • Cyclosporine and Tacrolimus
  • Macrolide rings
  • Bind with immunophilins
    • Proteins that have cis-trans peptidyl-prolyl isomerase activities
  • Act primarily on T-helper cells
  • Cyclosporine:
    • Shift TH1 to TH2 response in RA
    • Increase TGF-beta, causing renal fibrosis
  • Tacrolimus:
    • Interferes with IgE mediated histamine/serotonin release
  • Minimal effects upon amplification of immune response following activation
  • Lack myelosuppressive activity
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.
65
Q

mTOR inhibitors

A
  • Kinase
  • Sirolimus (Rapamycin) and Everolimus
  • Sirolimus and Everolimus inhibit IL-2 mediated signaling and results in cell cycle arrest at G1-S, blocking activation of T and B cells by cytokines
    • Contrast: tacrolimus inhibit synthesis/secretion of the cytokine IL-2
  • Sirolimus also binds FK (like tacrolimus), inhibits mTOR by directly bind to mTOR Complex 1
66
Q

mTOR inhibitors MOA

A
  • Bind to FK binding protein and modulate activity of mTOR
  • mTOR inhibits IL-2-mediated signaling transduction, resulting in cell-cycle arrest in G1-S phase
  • Block the response of T and B cell activation by cytokines
    • Prevents cell-cycle progression and proliferation
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
68
Q

Anti-IL2R antibodies (daclizumab and basiliximab)

A
  • Daclizumab is humanized monoclonal Ab to alpha chain of IL-2 receptor
    • Roles in T cell activation/proliferation
  • Kidney transplant rejection
  • Higher specificity than anti-lymphocyte Ab drugs
  • Dose sparing regimens to lower doses of steroids/CNIs
    • Children who receive these are at increased risk for growth impairement, HTN, hyperlipidemia, lymphoproliferative disorders, DM, cosmetic changes
69
Q

Targeting CD80/86

A
  • Belatacept (Nulojix) binds to CD80 and CD86 on APC, blocking costimulation of T cells
  • Abatacept is a recombinant fusion protein with CTLA-4 fused to IgG
    • Shuts down T-cell activity
  • Activated T lymphocytes are the prominent mediator of immunologic rejection
70
Q

Rh(D) Immune Globulin (RhoGam)

A
  • Prevents Rh hemolytic disease of the newborn
  • Rh factor is a protein on the surface of RBC. Rh+ is more common
  • A primary ab response to a foreign antigen can be blocked in specific ab to that antigen is administered passively at the time of exposure to antigen
  • Rh(D) Immune Globulin is concentrated hIgG containing more Ab against Rh(D) antigen of RBC
71
Q

Summary of Immunosuppresant Drugs

72
Q

NSAIDs and Acetaminophen

A
  • NSAIDs have antipyretic (anti-fever), analgesic (pain-relief) effects, anti-inflammatory, and anti-neoplastic properties
  • NSAIDs inhibit COX enzymes, prostaglandin-endoperoxide synthases
  • Acetaminophen acts on the same COX enzyme but blocks peroxidase
    • Doesn’t help with inflammation
    • Fever/pain relief by inhibiting prostaglandins in CNS
  • NSAIDs useful in pain caused by inflammation
  • Rapidly metabolized by liver, excreted through kidneys, some through biliary excretion
  • Most NSAID in body is bound to albumin
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
74
Q

Why should you care about Lipids?

A
  • Phospholipid membranes produce 5 levels of signaling lipid metabolites
    • Ether lipids
    • Eicosanoids (Prostanoid, Leukotrienes, Lipoxin)-inflammation
    • Endocanniboids
    • Lysophospholipids-inflammation and immune regulation
    • Free fatty acids
75
Q

Role of cytosolic phospholipase A2 in the activation of inflammation

A
  1. Phosphorylation of cytoplasmic PLA2 can occur by ligand-receptor signaling and/or increased intracellular Ca2+
  2. Calcium binding to the C2 domain of phospho-cPLA2 triggers binding to plasma membrane
  3. cPLA2 hydrolyses phospholipids to release AA and lysophospholipids
  4. AA converted to prostaglandins by COX
    • Inhibited by NSAIDs
  5. 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
77
Q

Adverse effects of NSAIDs

A
  • Cardiovascular
  • Gastrointestinal
  • Renal
  • CNS, Hematologic, Hepatic, Pulmonary, Skin
78
Q

NSAIDs Dual Insult

A
  • Primary insult: direct acid damage
  • Secondary insult: Prostaglandin inhibition
  • Causes gastric damage in about 20% of chronic users
  • Discontinue or switch to Cox-2 inhibitors
79
Q

Cox-2 Selective Inhibitors

A
  • Coxibs more selective for 2 over 1
  • Most withdrawn except for celecoxib because increased risks for thrombotic events
  • Improved GI events, but more concern for thrombotic events
80
Q

Aspirin aka Acetylsalicylic Acid

A
  • Irreversible, nonselective cox inhibitors
  • Acetylates and inhibits platelet COX (lasts 8-10 days)
  • Low dose aspirin reduces colorectal cancer risks
  • Aspirin’s effects and respective mechanisms vary with dose
    • Low doses: cardioprotective, antithrombic
    • Intermediate: pain and fever
    • High dose: anti-inflammatory
      • Rarely used because of adverse GI effects and hearing loss
81
Q

Daily Aspirin Therapy

A
  • Lowers cancer and heart attack risk?
  • Not something that you should start without MD supervision
  • Rebound effect, may have to continue on for the rest of life
82
Q

Choice of NSAIDs

A
  • All NSAIDs (including aspirin) are about equally efficacious
  • Choice depends on balancing effectiveness, toxicity, and cost
  • No single NSAID is right for all patients
83
Q

Rheumatoid Arthritis (RA)

A
  • 70% of join erosions are detectable by radiograph in first 1-2 years of disease onset
  • Increased infections, cardiovascular disease, lymphoma, shortened life expectancy
  • Cause is unknown but risk factors include:
    • Women
    • Age >60 years
    • Certain HLA II genotypes/mutations in PTPN22
    • Smoking
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.
85
Q

Disease modifying anti-rheumatic drugs

A
  • DMARDs
  • Methotrexate: First line DMARD
  • Cyclosporine
  • DNA/RNA inhibitors:
    • Azathioprine: DNA synthesis inhibitor blocks B- and T-cell proliferation, IL-2 secretion
    • Mycophenolate Mofetil: DNA synthesis inhibitor blocks B- and T-cell proliferation
    • Leflunomide: inhibits dihydrorotate dehydrogenase in pyrimidine synthesis and leads to G1 growth arrest. Leads to decreased T-cell proliferation and antibody production by B-cells
  • Antibodies/Biologics:
    • Abatacept: CTLA-4 fusion binds to CD80/86 and blocks T-cell activation
    • Rituximab: Monoclonal Ab targeting apoptosis of CD20 B cells
  • Anti-TNFalpha agents 

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
87
Q

TNF-alpha blocking agents

A
  • Second line to MTX
  • Prevent signaling to TNFR’s by binding TNF-alpha
  • TNF-alpha normally contributes to osteoclast activation and differentiation (remodeling of bone)
88
Q

Side Effects of TNF-alpha blockers

A
  • Important for macrophage activation, phagosome activation, differentiation of monocytes into macrophages, recruitment of neutrophils and macrophages, granuloma formation, and maintenance of granuloma integrity
  • Acute infusion rxn: anaphylaxis
  • Delayed infusion rxn: skin rash, joint pain
  • Neutropenia
  • Infection: emergence of latent infection (TB)
89
Q

Glucocorticoids

A
  • Like prednisone used in 60-70%
  • Into nucleus to repress gene expression of pro-inflammatory genes
  • Side effects from long term use: osteoporosis, metabolic disease, cardiovascular disease
  • Can be injected into joints
90
Q

Gout

A
  • Build up of urate crystals in joints, bones and soft-tissues
  • Urate is a poorly soluble end product of purine metabolism
  • Hyperuricema is a necessary predisposing factor for gout, but the majority of hyperuricemic patients never develop gout
  • Risk Factors:
    • Male, old age, ethnicity, obesity, meat/seafood diets, alcohol
91
Q

Pathogenesis for Gout

A
  • Uric acid crystals in joints are taken up by macrophages as a part of innate immune response to urate crystals
  • Macrophages produce IL-1beta via intracellular inflammasomes
  • IL-1beta helps recruit neutrophils from the bloodstream into the affected joint
  • Activation and degranulation of neutrophils contribute to pain associated with an acute gout flare
  • ♦♦♦♦♦♦♦♦♦♦♦♦
92
Q

Treatments for Gout

A
  • NSAIDS
    • First line treatment
  • Colchicine
    • Previous first line therapy
    • Inhibit microtubule to prevent WBC migration and phagocytosis
    • Also causes side effects: nausea, diarrhea, vomiting
    • IV admin runs risk of life-threatening SE
  • Uricosuric Agents
    • Probenecid and Sulfinpyrazone
    • Increase uric acid excretion by decreasing readsorption of uric acid in the proximal tubule
  • Allopurinol
    • Inhibit xanthine oxidase (which produces uric acid)
    • Xanthine/hypoxanthine are more soluble
    • Standard of care between episodes of gout
93
Q

NSAIDs and Colorectal Cancer

A
  • Risk reduction for colorectal cancer (especially aspirin)
    • Induces apoptosis
    • COX involved in colonic tumorgenesis
  • Potential benefits are outweighed by the risks
  • Good screening can prevent/treat colorectal cancer

Phcol 401 (10 decks)

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