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IHL Waddup! Exam 1 > Cytokines of Hematopoesis 8/22 > Flashcards

Cytokines of Hematopoesis 8/22 Flashcards

1
Q

Hematopoesis in tissues during development

A
  1. Yolk-Sac Phase: 3rd week of gestation
  2. Hepatic Phase: in liver and spleen - during second trimester
  3. Bone Marrow Beginning the 2nd trimester, becomes the only location in adulthood
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2
Q

Stem Cell Factor (C-Kit Ligand)

A
  • produced by bone marrow stromal cells
  • HSC has c-Kit (tyrosine kinase) receptors where it binds SCF (through MAPK, jak/stat pathway)
  • Proto-Oncogene
  • Signaling of SCF induces self-reneewal and differentiation (directed by probability and environment along with synergistic signals)
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3
Q

Imatnib

A

an inhibitor of tyrosine kinases with effects in the treatment of chronic myeloid leukemia
- in the presence of imatinib (bound intracellularly to the ATP binding site) a protein substrate is not phosphorylated and signaling cascade is inhabited.

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4
Q

Lineage Restricted Progenitor Cells

A

Descends of HSC’s in bone marrow

  • multipotent, non-renewing
  • two types: common myeloid progenitor cells (CMP) and common leymphoid progenitor cells (CLP)
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5
Q

Cellular Elements of blood

A

all descend from myeloid stem cells

  • erythrocytes
  • leukocytes
  • granulocytes
  • agranulocytes
  • platelets
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6
Q

Erythrocytes

A
  • RBC’s
    Anatomy: Anucleate, biconcave, lacks organelles
    Contains: PM, CS, Hemoglobin, Glycolytic Enzymes
    Lifespane = 120 days
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7
Q

ABO Blood Groups

A
  • products of glycosylation
  • O antigen (default): lacking functional enzyme, no extra sugar
  • A Antigen: N-acelylygalactosamine adds an additional N-acetylgalactosamine
  • B Antigen: Galactose transferase adds an additional galactose
  • AB Blood- group has both enzymes
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8
Q

Erythropoiesis

A

Location: Bone Marrow, erythrocytes mature in blood stream (last step)

  • 10 step process: starts with the Common Myeloid Progenitor (CMP)
  • under the influence of cytokines: Erythropoietin (EPO), IL-3 and IL-4
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9
Q

10 steps of erythropoesis (see pictures of staining changes through this process)

A
  1. Megakaryocyte/Erythrocyte Progenitor (MEP: bipotential stem cell
  2. Erythrocyte-committed Progenitor (ErP)- monopotent stem cell)
  3. Proerthroblast: large nucleus, basophilic staining due to free ribosomes synthesizing hemoglobin
  4. Basophilic Erythroblast: Large nucleus, basophilic due to free ribosomes
  5. Polychomatophilic Erythroblast: Large Nucleus, basophilic b/c of ribosomes and also acidophilic (eosin staining) due to hemoglobin produced
  6. Normoblast: orthochromatophilic erythroblast, dense nucleus, eosinophilic b/c of hemoblobin, no longer capable of dividing
  7. Reticulocyte: polychomatophilic erthrycotye, anucleate, eosinophilic b/c of hemoglobin, more basophilic than erythrocytes due to some ribosomes still. Reticulocytes remain in marrow for 1-2 days arnd are released into blood stream where they mature into
  8. erythrocyte
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10
Q

Erythropoietin (EPO)

A
  • stimulates the early stages of the erythroid colony-forming unit (CFU) to proliferate and differentiate into polychomatophilic and orthochromatic erythroblasts.
  • produces in the kidneys in response to hypoxia: HIF-1
  • when EPO is present there is less apoptosis
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11
Q

EPO Receptor

A

Expressed by committed erythroid progenitors

  • activation is antiapoptotic: normally these cells undergo large amounts of apoptosis
  • expressed by proerythroblasts and normoblasts and induces proliferation
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12
Q

Erythropoietin and JAK-STAT Pathway

A
  1. EPO produced by IS cells in the renal cortex and is transported to the bone marrow by blood.
  2. In bone marrow, EPO binds to EPO receptor and induces binding of cystolic STAT 5 protein to JAK2
  3. the inactive form of STAT5 contains an SH2 domain. STAT5 is recreuited by JAK2 and binds to it, and becomes homodimerized
  4. Phosphorylated STAT5 translocates to nucleus.
  5. after binding DNA, the phosphorylated STAT 5 activates the transcription of specific genes required for erythropoeisis.
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13
Q

Recombinant EPO (rHuEPO)

A
  • in chronic kidney disease- reduced EPO production leads to anemia
  • chemotherapy- promotes regeneration of RBCs depleted by treatment
  • blood doping: can be detected because rHuEPO has a different isolectric point because itis a different isoform
  • EPO acts here to induce formation of proerythroblast, primitive/mature progenitor and erythroid CFU
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14
Q

Thrombocytes and their 4 zones

A
  • platelets = small membrane bound cytoplasmic fragments, anucleate
    4 zones:
  • Peripheral Zone: Cell membrane and Glycocalyx (integral membrane glycoporteins, coagulation factors, glycosaminoglycans)
  • Structural Zone: cytoskeleton
  • Organelle Zone: Mitochondria, peroxisomes, glycogen, granules
  • Membrane Zone: Open Canalicular system (OCS, contains remnants of membrane channels that subdivided the precursor megakaryocyte into platelets); Dense Tubular System (storage for calcium ions, originates from RER of precursor)
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15
Q

Thrombopoiesis- Six steps

A

Location: Bone Marrow
6 steps of platelet Generation:
1) CMP: under influence of cytokines: granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-3
2. Megakaryocyte/Erythrocyte Progenitor (MEP)- biopotent stem cell
3. Megakayrocyte- Committed progenitor cell (MKP): monopotent stem cell
4. Megakaryoblast: large cell, non-lobed, endomitosis (chromosomes replicate but cell does not divide), under the influences of cytokines (thrombopoietin)
5. Megakaryocyte: Large cell, complex, multi-loved nucleus, scattered azurophilic granules, Karyokinesis (division of nucleus), Cytokinesis
6. Platlets

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16
Q

Thrombopoietin (TPO)

A
  • regulator of platelet production
  • produced primarily by liver and also kidneys and bone marrow
  • prevents apoptosis of megakaryocytes (MKs)
  • promotes MK maturation
  • promotes proliferation of MKP
  • synergistic affect with platelet agonists - promotes thrombosis
  • acts on c-Mpl receptor (expressed on platelets, megakaryocytes and precursors)
17
Q

Clinical Relevance of TPO: Thrombocythemia, Thrombocytosis, Thrombocytopenia

A

Liver Failure –> insufficient in producing TPO

  • Thrombocythemia: inherited, activating mutations in TPO. Results in too many platelets, abnormal clotting.
  • Thrombocytosis= inherited, too many platelets due to a secondary mechanism- not at platelet level of production
  • Thrombocytopenia= bleeding disorder b/c not enough platelets
18
Q

Leukopoiesis

A

= a form of hematopoiesis in which white blood cells (WBC, or leukocytes) are formed in bone marrow- formation of neutrophils, macrophages, eosinophil, basophils

  • Granulocytes vs. Agranulocytes: based on the presence of granules: granules have secretory vesicles filled with cytotoxic enzymes and peptides released via degranulation
  • Azurophilic (nonspecific) granules: filled with enzymes that function in phagocytosis - stains darkly
19
Q

Granulocytes vs. Agranulocytes

A
  • Granulocytes: have grainy cytoplasmic type of staining. Cells contain specific granules: neutrophils, eosinophils, basophils
  • Agranulocytes: Cells without specific granules: Lymphocytes (T cells, B cells, NK cells), Monocytes/macrophages
20
Q

Myeloid Lineage

  • basophilic = blue = lots of ribosomes = + environment
  • azurophilic= magenta = acidic
A
  1. Myeoblast: nucleus is round and uncondensed chomatin visible in nucleolus. Cytoplasm is granule free (As cell progresses, nucleus becomes indented, then segmented then chromatin increases in condensation.)
  2. Promyelocyte: Larger, has a large nucleus with uncondensed chromatin, and nucleoli. Primary granules (azurophilic) stain magenta. Cytoplasm is basophilic due to presence of rER (stains blue)
  3. Myelocyte: cell shrinks, basophilic cytopalasm contains granules - last stage capable of mitosis
  4. Metamyelocyte: smaller diameter, the bean-shaped nucleus contains some condensed chromasome, the specific granules outnumber primary
  5. Band Form: cell is smaller, Nucleus is U-Shaped
    (don’t need to know the specifics of this card….)
21
Q

Neutrophils

A
  • Looks light pink with granules and a purple multilobed nucleus in U-shape
  • Polymorphonuclear.
  • Larger than erythrocytes.
  • Nucleus has 2-4 lobes.
  • Heterochromatin located at periphery.
  • Cytoplasm lacks staining.
  • most common leukocyte
  • produced on demand and transitory manner
  • phagocytic and function in eliminating bacteria and parasites
22
Q

Eosinophil

A
  • looks brighter pink with larger granules and a less dramatic u shaped 2 lobed nucleus
  • Larger than erythrocytes,
  • Nucleus is bi-lobed,
  • heterochromatin are located at the periphery.
  • Eosinophilic dark staining due to presence of azurophilic granules (crystalline proteins)
  • cytoplasm contains large refractile specifi granules that appear bright red
  • responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells, they also control mechanisms associated with allergy and asthma.
23
Q

Basophil

A
  • looks purple/blue with no seen nucleus due to so many granules
  • larger than erythrocytes
  • lobed nucleus, usually obscured by intense basophilic staining due to azurophilic granules
  • heterochromatin located at periphery
  • active in allergy and hypersensitivity reactions, primary histamine producing cell type
24
Q

Monocytes

A
  • (not a granulocyte!) don’t stain for specific granules
  • looks pale gray blue (basophilic), with a nucleus with a distinct indentation - only stains (azurophilic/blue)
  • Mononuclear phagocytes
  • Largest of WBC’s
  • Cytoplasm: Golgi and centrioles located at nuclear indentation. Small dense azurophilic granules, SER and RER, mithcondria
  • Lifespan: circulates in blood for 3 days, differentiates in local tissues into Macrophages or Osteoclasts.
25
Q

Granulopoeisis (subtype of myelopoiesis) - production of neutrophils, eosinophils, and basophils

A
  • Location: bone marrow. Final differentiation in connective tissue.
    1. CMP (Common Myeloid Progenitor)
    2. GMP (Granulocyte/Monocyte Progenitor)
    3. Granuloycte progeinitors (neutrophil, eosinophil, basophil)
    4. Myeloblast: large cell, spherical nucleus, small amount of granules
    5. Promyelocyte: all azurophilic granules located here
    6. Myelocyte (this is where they differentiate): - subtypes may be distinguishable due to production of specific granules
    7. Metamyelocyte: specific granule production, nucleus expresses heterochromatin and indentations appear
    7** Band Cell (neutrophils only)- Nucleus becomes elongated and horseshoe appears
    8. Mature Granulocyte: nuclear lobes appear
    9. Differentiation in connective tissue
26
Q

IL-3

A

Interleukin 3= responsible for expansion of immature marrow progenitors into all types of mature hematopoietic cells
- produced by CD4 and T cells

27
Q

GM-CSF

A
  • granulocyte-macrophage Colony
  • promotes maturation of bone marrow cells into dendritic cells (T/Bcells, Langerhans, etc.) and monocytes
  • G-CSF produced at sites of infection to mobilize neutrophils from bone marrow
  • clinical correlation: both used to recover from cancer chemotherapy and bone marrow transplantation
28
Q

Lymphocytes

A

(Lympoid cells)

  • Small Lymphocytes: include T and B cells: distinguishable by size- small lymphocytes are not larger than erythrocytes. 90% of lymphocytes, slightly indentened intensely stained nucleus, cytoplasm is a thin pale blue rim
  • Large Lymphocytes: include NT cells: - same sized nucleus as small, but larger amount of cytoplastm. all blue.
  • all are produced in bone marrow.. b cells mature in marrow, t cells in thymus and NK cells in tissues
29
Q

B Cell

A

Small lymphocyte with variable lifespan

  • antibody production
  • matures in bone marrow
30
Q

T cell

A

Small lymphocyte with long life span

  • cell-mediated immunity
  • matures in the thymus
31
Q

Natural Killer Cell

A

Large Lymphocyte

  • kidney shaped nucleus with large cytoplasmic granules
  • functions in cell killing process
  • matures in specific tissues
32
Q

IL-7

A

Important in Lymphopoiesis

  • stimulates expansion of immature B and T cells
  • produced by stromal cells in many tissues
  • clinical correlation: X-linked SCID: decrease of T cells and increase of B cells due to lack of IL-7 signals.
33
Q

Granulocyte colony stimulating factor (G-CSF)

A
  • target cell: neutrophils
34
Q

Thrombopoietin (TPO)

A

target cells: megacaryocyte progenitors

IHL Waddup! Exam 1 (11 decks)

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