Quiz #7 (12/2-12/7)

Question 1

Functions of blood

Answer 1

Functions to transport substances to tissues including oxygen, nutrients, hormones, leukocytes, red cells and platelets. Also functions to remove waste from the body including carbon dioxide and nitrogenous waste products

Question 2

RBCs

Answer 2

for oxygen delivery. There are between 2-3 X10^13 RBC in the body and about 2X10^11 new RBC are made each day

Hemoglobin are > 90% of RBC weight

Hemoglobin binds heme (porphyrin) groups that are complexed with iron (oxygen binding)

Hemoglobin A (adult) is a tetramer of 2 alpha, and 2 beta subunits

Hemoglobin F (fetal) is a tetramer of 2 alpha and 2 gamma subunits. Fetal hemoglobin has a higher binding affinity for oxygen because fetus needs oxygen from mother

Question 3

RBC:WBC: platelets

Answer 3

should be close to 600:1:15

Question 4

Anemia

Answer 4

deficiency of red blood cells or hemoglobin in blood. Never is normal and is generally a major sign of disease. Most common cause is an insufficient supply of iron, vitamin B12/cobalamin or folate

Question 5

Kinetic approach to anemia

Answer 5

1. Decreased RBC production: lack of nutrients, bone marrow disorders or suppressions (drugs, chemotherapy, etc), or low levels of trophic hormones (EPO)
2. Increased RBC destruction: Anemia occurs when the bone marrow is unable to keep up with the need to replace more than about 5% of the RBC mass per day
3. Blood loss: surgery, ulcer, cancer, internal bleeding and excessive blood draws

Question 6

Morphologic approach to anemia

Answer 6

Based on cell size

1. Macrocytic (large RBC) anemia: Can be caused by folate and/or vitamin B12 deficiency, lack of intrinsic factor or by drugs that interfere with DNA synthesis
2. Microcytic (small RBC) anemia: Is a decreased hemoglobin content within the RBC. Can be caused by iron deficiency (most common), disorders of heme biosynthesis or reduced hemoglobin production (thalassemias)
3. Normocytic (normal RBC) anemia: Can be caused by renal disease or cancer

Question 7

Iron

Answer 7

absorbed in the duodenum

Once in blood stream is carried by transferrin to erythroid precursors for synthesis of hemoglobin

Iron storage is in the liver

Iron can also be reclaimed from RBC

Question 8

Folic acid

Answer 8

: absorbed in jejunum. Involved in DNA synthesis

Question 9

B/12 and intrinsic factor

Answer 9

: absorbed in ileum. Important in SAM formation which donates methyl groups and causes DNA methylation which controls gene expression.

Question 10

Hereditary hemolytic anemia causes

Answer 10

has a genetic link

1. Abnormal shape: hereditary spherocytosis
2. Abnormal hemoglobin: hemoglobin S replaces hemoglobin A (sickle hemoglobin in sickle-cell anemia)

3 .Defective hemoglobin synthesis: thalassemia minor and major; globin chains are normal but synthesis is defective

4 .Enzyme defects: glucose-6-phosphate dehydrogenase (G6PD) deficiency predisposes to episodes of acute hemolysis, allergy to sulfa drugs, fava beans. Variable in society

Question 11

Sites of hematopoiesis

Answer 11

Prenatal: yolk sac, liver and bone marrow (later right before birth)

Postnatal: skeleton. vertebral and pelvis are the major then sternum and ribs

Question 12

Blood development lineages

Answer 12

Lymphoid lineages: Plasma cells, CTL and helper T cells. IL-7 is a common cytokine

Myeloid lineages: Erythrocytes (EPO), Platelets (IL-11 and Tpo), basophils, eosinophils (GM-CSF), neutrophils (G-CSF and GM-CSF) and macrophages (GM-CSF)

Question 13

Erythropoietin (Epo)

Answer 13

Stimulates erythroid proliferation and differentiation in red cell progenitors in bone marrow.

Feedback control of RBC production is through Epo. This is necessary to prevent death and promote proliferation of committed precursors. Feedback shifts non-committed progenitor cells into the erythroid lineage. Feedback targets CFU-Es by upregulating their production as well as stabilizing these cells.

Question 14

HIF-1

Answer 14

is a heterodimeric transcription factor that binds hypoxia-response elements that are associated with a broad range of transcriptional targets, particularly Epo.

Question 15

HIF-1 control of EPO

Answer 15

Normal oxygen levels (normoxia): HIF-1 isn’t needed. hydroxylation causes HIF-1alpha to be either degraded by the proteasome or can be blocked from recruiting a transcriptional coactivator, p300.

Hypoxia (lack of oxygen): HIF-1alpha is stabilized and can activate Epo production. Epo increases production of RBC

Question 16

MOA EPO

Answer 16

1. hemaopoietic 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. In the nucleus, STATS act as transcription factors to bind to regulatory elements in the genome to activate gene transcription.
5. Regulation: SOCS (suppressor of cytokine signaling) proteins, protein phosphatases, ubiquitination and degradation of JAK, and PIAS (protein inhibitor of activated STAT)

Question 17

Therapeutic Uses of Epo

Answer 17

1. Anemia caused by chronic kidney disease: Target hematocrit range is 30-36%
2. Anemia caused by cancer treatment: Used previously but recent studies have shown an increased risk of death and tumor growth in chemo patients taking anti-anemia drugs
3. Anemia in critically ill patients: Not used anymore because recent studies have found no benefit and high risk of thrombosis associated with use.

Question 18

Blood doping

Answer 18

history of abuse in endurance sports including cycling, rowing, distance running, and cross country skiing. Some studies show there is lack of evidence for efficacy because your oxygen transport is already optimized. Epo has not been shown to boost RBC in these people.

Question 19

Adverse effects of EPO

Answer 19

Associated with an increased risk of hypertension in patients with kidney disease

Caution in cancer patients receiving chemotherapy because the risk of stroke and increased death related to malignancy may outweigh any potential benefit of erythropoietin in the absence of severe anemia.

Question 20

GM-CSF

Answer 20

stimulates the proliferation and differentiation of myeloid cell lineages including monocytes, macrophages, neutrophils and eosinophils. It is secreted by macrophages, T cells, mast cells, endothelial cells and fibroblasts

Question 21

Sargramostim

Answer 21

recombinant GM-CSF

Question 22

G-CSF

Answer 22

enhances phagocytic and cytotoxic activities of neutrophils, with little effect on monocytes, macrophages and eosinophils. More selectivity, better tolerated. Produced by endothelial cells, macrophages, and a number of other immune cells.

Question 23

Filgrastim

Answer 23

recombinant C-CSF

Question 24

Therapeutic uses of G-CSF and GM-CSF

Answer 24

1. Treat neutropenia, which is an abnormally low number of neutrophils.
2. Neutropenia is common in cancer patients after chemotherapy, AIDS patient and bone marrow transplantation patients.
3. Also used in autologous stem cell transplantation with patients that undergoing high-dose chemotherapy with extreme myelosuppression. Before chemotherapy, hematopoietic stem cells are mobilized from bone marrow into peripheral blood by treatment with G-CSF, GM-CSF and collected with apheresis. Myelosuppression is counteracted by re-infusion of patient’s own HSC after chemotherapy

Question 25

Side effects of G-CSF and GM-CSF

Answer 25

GM-CSF: fevers, malaise, arthralgias (joint pain), myalgias, and capillary leak syndrome characterized by peripheral edema and pleural or pericardial effusions. Allergic reactions can also occur G-CSF: bone pain which clears upon discontinuation. Much better tolerated

Question 26

IL-11

Answer 26

stimulates the proliferation and differentiation of megakaryocytes and platelets.

Question 27

Oprelvekin

Answer 27

Recombinant IL-11

Question 28

Thrombopoetin (Tpo)

Answer 28

stimulates the proliferation and differentiation of megakaryocytes and regulates downstream production of platelets.

Question 29

Romiplostim

Answer 29

IgG fusion with tpo fragment. Recombinant Tpo is not approved for therapeutic use.

Question 30

Therapeutic Uses of IL-11

Answer 30

Used to treat thrombocytopenia, which is an abnormally low number of platelets. Thrombocytopenia commonly seen in vitamin B12 or folic acid deficiency, leukemia or myelodysplastic syndrome and myelosuppression associated with chemotherapy

Question 31

Side effects with IL-11

Answer 31

excessive fluid retention with edema and cardiac decompensation, renal impairment, allergic and severe reactions.

Question 32

Organs of the immune system

Answer 32

Bone marrow: source of blood cells Thymus: maturation of T cells Spleen: hematopoietic organ, site of macrophage antigen presentation and antibody response Lymph nodes and vessels: source of lymphocytes

Question 33

Cells of the immune system

Answer 33

lymphocytes: B-cells (antibody production), T-cells and large granular lymphocytes (both of these produce cytokines). phagocytes: mononuclear phagocyte (cytokine and complement production), neutrophils and eosinophils Auxiliary cells: basophils, mast cells and platelets all produce inflammatory mediators

Question 34

Innate immunity

Answer 34

Rapid response. General molecular patterns. Limited diversity of immune system, with no memory and is nonreactive to self. Barriers include skin, mucosal epithelia and blood proteins include complement. Cells include phagocytes, NKC, innate lymphoid cells

Question 35

PPRs in innate

Answer 35

Pattern recognition receptors include Toll-like receptors (TLR), C-type lectin receptors (CLRs) and nucleotide-binding oligomerization domain-like receptors (NLR)s. Expressed by tissue macrophages and dendritic cells. Used to detect PAMP (pathogen associated molecular patterns) like LPS.

Question 36

Complement in innate

Answer 36

Primary functions are chemotaxis through C3a and C5a, opsonization through C3b and cell lysis through the MAC complex

Question 37

Adaptive immunity

Answer 37

longer response. Specific for microbial and nonmicrobial antigens, can be very specific. Very large diversity of response, with memory and is nonreactive to self. Barriers contain lymphocytes and antibodies. Blood proteins are antibodies and cells are lymphocytes.

Question 38

Cell mediated adaptive immunity

Answer 38

Cell-mediated: phagocytosed microbes are displayed on macrophages. Helper T cells bind to it, recognize it and activate it to allow other T cells to come bind the same antigen

Question 39

Humoral adaptive immunity

Answer 39

Humoral: B lymphocyte responds to extracellular microbe. Antibody is excreted to block infection and eliminate extracellular microbes.

Question 40

Antibodies

Answer 40

V(D)J recombination is the mechanism for diverse binding selectivity in the B-cell receptor (antibodies) and T-cell receptors. Immunoglobulin isotypes: IgG and IgM are most important in plasma. IgG is dominant in extracellular fluid around the body. IgE is dominant in mast cells. Fetus gets mostly IgG. Brain usually has no immunoglobulins. Functions: neutralization, opsonization, sensitization for killing by NK cells, sensitization of mast cells and activation of complement

Question 41

MHC Class

Answer 41

Major histocompatibility complex. Large gene family involved in immune function. HLA complex is the human version of the MHC genes. HLA genes are involved in the process of identifying self and non-self and are responsible for tissue rejection in organ transplants Class I: present on most cells, bind endogenous antigens synthesized in a cell. Present antigen to CD8 cytotoxic T cell lymphocytes. And presence of foreign or over-abundant antigens targets cell for destruction Class II: Present only on antigen-presenting cells and binds exogenous antigens. Present antigen to CD4 helper T cell lymphocytes

Question 42

T-cell activation

Answer 42

is a 2 step process Signal 1: MHC + TCR. dendritic cell presents antigen on a MHC molecule and the T-cell receptor engages MHC + antigen complex Signal 2: co-stimulatory molecules and receptors act on T-cell to activate or negatively regulate. Examples are CD80/86 (APC) CD28 (T-cell) to activate the T-cell.

Question 43

Immunopathology

Answer 43

Hypersensitivity: allergic reactions to harmless antigens Immunodeficiency: unable to stop an infection Autoimmune disorder: immune system targets self-antigens Examples: Type 1 diabetes, RA, MS Stems from an abnormal immune response to the tissues or substances in your own body.

Question 44

Immunosuppression

Answer 44

intentionally reducing activation or decreasing efficiency of the immune system.

Question 45

Immunosuppressive drugs

Answer 45

are used to prevent rejection of organ transplants, treat autoimmune disease, asthma, allergic rhinitis, psoriasis, eczema, or to treat graft-versus-host disease (GVHD) after allogeneic HCT. Activated T cells are the main mediators of immunologic rejection, attacking donor organ

Question 46

MOA immunosuppressives

Answer 46

Many mechanisms that act to suppress the cell cycle pathways of immunoregulation: T-cell activation; steroids and NF-kappaB; calcium levels, calcineurin, NFAT, IL-2 synthesis; autocrine stimulation by IL-2 to mTOR and cell cycle; DNA synthesis and proliferation

Question 47

Azathioprine

Answer 47

purine analog that inhibits DNA synthesis and proliferation of cells, especially fast-growing cells without a method of nucleotide savage, such as lymphocytes. T cells and B cells are particularly affected by the inhibition of purine synthesis.

Question 48

Mycophenolate

Answer 48

IMP dehydrogenase inhibitor. Metabolized in the liver to the active form mycophenolic acid (MPA) which inhibits IMPD. IMPD controls the rate of de novo guanine (purine) synthesis in the proliferation of B and T cells

Question 49

Corticosteroids

Answer 49

The endogenous steroid hormone is cortisol Examples: prednisone, hydrocortisone, fluticasone MOA: two possible processes. 1) bind to GR (nuclear) then to GRE to alter expression of target genes, increasing anti-inflammatory genes 2) To block T cell activation and reduce inflammation genes

Question 50

Calcineurin inhibitors

Answer 50

cyclosporine and tacrolimus. Both are natural products from fungus and bacteria respectively. Contain macrolide rings. They bind to and inhibit calcineurin which inhibits translocation of transcription factors NF-AT into the nucleus. This results in reduced transcriptional activation of early cytokine genes for IL-2, TNF-alpha, GM-CSF, interferons and other IL. Proliferation of lymphocytes is reduced.

Question 51

mTOR inhibitors

Answer 51

Sirolimus (Rapamycin) and Everolimus. Inhibit IL-2 mediated signaling and results in cell cycle arrest at G1-S and thereby blocks activation of T and B cells by cytokins. Macrolides.

Question 52

Anti-lymphocyte antibodies

Answer 52

ADCC: antibody-dependent cell-mediated cytotoxicity. NK cells actively lyse target cells whose membrane-surface antigens have been bound by specific antibodies Examples: Alemtuzumab (Campath) mAB to CD52 on mature lymphocytes; Muromonab-CD3 (OKT3) mAB to CD3 on T cells, Rituximab (Rituxan) mAB to CD20 on B cells

Question 53

Anti-IL2R Antibodies

Answer 53

daclizumab and basiliximab. Used in kidney transplants and have higher specificity than anti-lymphocyte antibody drugs.

Question 54

Targeting CD80/86

Answer 54

Belatacept (Nulojix) and Abatacept Effectively blocks second signal to prevent T cell from activating. : binds to CD80 and CD86 on antigen presenting cells.

Question 55

Rho(D) Immune Globulin (RhoGAM)

Answer 55

prevents Rh hemolytic disease of the newborn. Rhesus (Rh) factor is a protein on the surface of RBC. Rh + is more common. Prevents B-cell and antibody development

Question 56

Phospholipase A2 mechanism

Answer 56

1. Activated through calcium signaling or ligand-receptor signaling (ligands include serotonin, glutamate, FGF, IFN-alpha, IFN-gamma). phosphorylation of cytoplasmic PLA2 (cPLA2) 2. Calcium binding to the C2 domain of phospho-CPLA2 triggers binding to plasma membrane 3. cPLA2 hydrolyses phospholipids to release arachidonic acid AA and lysophospholipids 4. AA is converted to prostaglandins by COX enzymes which can be inhibited by NSAIDS 5. Arachidonate 5-lipoxygenase, 5-LOX converts AA to to leukotrienes

Question 57

COX enzymes

Answer 57

COX-1: housekeeping enzyme expressed in almost all tissues and is cyto-protective. Constitutively expressed COX-2: immediate-early response gene that is induced at sites of inflammation and during tumor progression by cytokines and mitogens

Question 58

Adverse effects of NSAIDs

Answer 58

Cardiovascular: fluid retention, hypertension, edema and rarely myocardial infarction and CHF GI: abdominal pain, dysplasia, nausea, vomiting and rarely ulcers or bleeding "Dual insult": Primary insult is direct acid damage and secondary insult is prostaglandin inhibition (COX-1 and COX-2) Treatment is discontinuation or COX-2 inhibitors Renal: acute kidney injury, renal insufficiency, renal failure, hyperkalemia and proteinuria Other less important: CNS, hematologic, hepatic, pulmonary and skin adverse events

Question 59

Aspirin effects

Answer 59

Low doses: sufficient to irreversibly acetylate COX-1 resulting in an anti-thrombotic, cardio-protective effect. Usually have to take life-long due to rebound effect with withdrawal that may cause increased risk of heart attack, deep vein thrombosis etc... Intermediate doses: analgesic and antipyretic effects. Inhibition of COX-1 and COX-2 High doses: anti-inflammatory. Rarely used at this dose though due to adverse GI effects and other NSAIDs work better

Question 60

RA

Answer 60

Autoimmune disease affecting about 1% of the population. Involves thickening and inflammation of synovial membrane and immune response begin attacking the natural synovial cells. IL-1 activates osteoclasts and MMP to degrade the matrix of the bone. TNF-alpha also activates. 70% of joint erosions detectable by radiograph of hands and feet occur in the first two years of disease Increases risk of infections, cardiovascular disease, lymphoma, and shortened life expectancy Cause is unknown but risk factors include females, age older than 60, smoking, and certain HLA class II genotypes and mutations

Question 61

Methotrexate

Answer 61

DMARD for RA. Anti-neoplastic and anti-rheumatic drug (acts through different mechanisms). In RA inhibits AICAR transformylase leading to an accumulation of AMP. AMP is exported and extracellulary is converted to adenosine which is a potent inhibitor of inflammation.

Question 62

TNF-alpha blocking agents

Answer 62

DMARD for RA. antibodies against TNF-alpha which contributes to osteoclast activation and differentiation (remodeling of bone) Examples: Etanercept, Infliximab, Adalimumab, Certolizumab pegol, Golimumab Side effects: acute infusion reaction, delayed infusion reactions, neutropenia, and infection including TB manifestation

Question 63

Glucocorticoids

Answer 63

DMARD for RA. prednisone. Bind to glucocorticoid receptors to repress gene expression of many pro-inflammation genes.

Question 64

Gout

Answer 64

Caused by build-up of urate crystals in joints, bones and soft tissues. Urate is a poorly soluble end product of purine metabolism.

Question 65

Gout risk factors

Answer 65

risk factors include males, old age, ethnicity, obesity, diets rich in meat and seafood, and alcohol. Hyperuricemia (urate concentration > solubility of urate in extracellular fluid) is necessary to develop gout but the majority of hyperuricemia patients do not develop gout

Question 66

Gout pathogenesis

Answer 66

Uric acid crystals in the joint are taken up by macrophages as part of the innate immune response Macrophages produce IL-1-beta via intracellular inflammasomes IL-1-beta helps recruit neutrophils from the blood stream to the affected joint Activation and degranulation of neutrophils contribute to pain associated with an acute gout flare

Question 67

Gout treatment

Answer 67

NSAIDs: first line treatment Colchicine: microtubule inhibitor to block phagocytosis. Side effects are extensive and include diarrhea, nausea, vomiting. Uricosuric agents: probenecid and sulfinpyrazone increase uric acid excretion by blocking reabsorption of uric acid by kidney. Lowers levels of uric acid in joints Allopurinol: inhibits xanthine oxidase which produces uric acid. Xanthine and hypoxanthine are more soluble than uric acid and eventually are converted to uric acid. Cleared better from body