Cytokines and hematopoiesis (Heck) Flashcards
Describe the components of blood in a test tube with an anti-coagulant present
clear/liquid portion: plasma consisting of proteins (albumin, fibrinogen), hormones, antibodies, vitamins and salts
buffy coat: white blood cells and platelets
cellular: RBCs
Describe the components of blood in a test tube in absence of fibrinogen
liquid: Serum
blood clot at base
What percent of the blood is RBCs
45
what does thrombopoiesis stand for
formation of platelets
What are colony forming units
committed precursor cells for hematopoiesis
lymphoid cells
will differentiate into B cells and T cells (lymphocytes)
myeloid cells
differentiate into every but lymphocytes
When does hematopoiesis begin in development and where?
in the yolk sac around 3 weeks. formation on hemangioblasts
What is the big transformation of RBC formation in 7th month of development?
Switch to hematopoiesis being done in the bone marrow
general trends in hematopoiesis
cell size decrease, cytoplasm becomes less basophilic, changes in nuclear:cytoplasmic ratio,
changes in nuclear condensation rxns (euchromatin and heterochromatin)
2 characteristics of Hematopoietic Stem Cells HSCs
pleuripotent–> give rise to many cell types
self renewing–> divide to maintain own population
Stem cell factor/ c-kit ligand is produced where?
bone marrow in stromal cells and in fetal tissue during development
C-kit R is expressed by what and what type of R
HSCs
tyrosine kinase R–> (MAPK, JAK/STAT, IP-3)
what type of mutation in c kit R leads to cancer
gain of function
protooncogene–>oncogene
how is c kit ligand used clinically?
used in marrow transplant cases–> to determine which RBS are HSC based on whether they have C-kit ligand (acts as a marker)
Imatinib (drug) does what?
Inhibitor of tyrosine kinase activity
reducing differentiation of HSCs
used for chronic myeloid anemia
Linear Restricted Progenitor cells
arise from HSCs, multipotent
differentiate into lymphoid or myeloid cells.
These do NOT renew themselves
3 categories of blood elements
erthyrocytes RBCs
leukocytes WBCs
platelets
2 types of leukocytes
granulocytes and agranulocytes
Anatomy of RBCs
biconcave Anucleate lack of organelles PM unique cytoskeleton contains hemoglobin contain glycolytic enzymes
how long do RBCs stay in circulation
120 days.
ABO blood groups are what?
assemblies on cell surface.. glycoproteins
O antigen
lacking functional enzymes
(default)
no sugars
A antigen
N- acelylgalactosamine on O structure
B antigen
galactose transferase enzyme to add galactose O antigen
What cytokines affect erthyropoiesis?
IL-3 IL-4 and erythropoietin
What is the common progenitor type for erythrocytes
myeloid progenitor cells
order of erythropoiesis
Megakaryocyte/Erythrocyte progenitor-> Erythrocyte-ommited progenitor->Proerythroblast->Basophilic Erythroblast->Polychromatophilic Erythroblast->Normoblast->Reticulocyte-> Erythrocyte
what accounts for blue appearance in early erythrocytes?
synthesis of hemoglobin on ribosomes
What state in erythropoiesis does the appearance of nucleus change?
normoblast, nucleus gets more dense
no longer capable of dividing
At what stage in erythropoiesis does the RBC no longer have a nucleus
reticulocyte
how do we use reticulocytes clinically?
Measured in blood to calculate how much erythropoiesis is going on. Only circulate 1-2 days before they fully mature
What GF stimulate erythropoiesis and through what R cascade? Where is it produced?
Erythropoietin, produced in kidnerys. tyrosine-kinase JAK STAT signaling cascade
EPO is produced in response to what signal?
Hif-1 (hypoxia)
True or false. The activation of EPO R is anti-apoptotic
True! less apoptosis when EPO is circulating and being taken up by those committed erythroid progenitor cells
Where is recombinant EPO used?
blood doping
Clinically: treat chronic kidney diseases
chemotherapy to promote regeneration of RBCs depleted by treatment
What method can we detect recomb-EPO in an athlete’s blood?
electrophoresis. because isoelectric point of recombinant is different
What is the basic structure of platelets
Small, membrane bound cytoplasmic fragments that are anucleate.
2 distinct regions: peripheral hylomere and center granulomere
4 zones of platelets
Peripheral zone: PM, glycocalyx
Structural zone: cytokeleton
Organelle zone: mitochondria, peroxisomes, glycogen, granules for clotting
Membrane zone: open canicular system and dense tubular system (store Ca)
order of thrombopoiesis
HSC->common myeloid progenitor cell->Megakaryote/Erythrocyte progenitor cell->megakaryote-committed progenitor cell->megakaryoblast->megakaryocyte->platelet formation
What cytokines are involved in thrombopoiesis?
Granulo-macrophage colony stimulating factor
IL-3
thrombopoietin
Endomitosis
replication of chromosomes without cytokinesis-> large cell. seen in megakaryoblast
differences between megakaryoblast vs -cyte
megakaryoCYTE has multi-lobed nucleus (karyokinesis)
has scattered azurophilic granules
What produces thrombopoietin?
liver primarily. prevents apoptosis
promotes proliferation and thrombopoiesis
What and where is the receptor for thrombopoietin
c-Mpl receptor found on platelets megakaryocytes and precursor cells
Clinical relevance of thrombopoietin
liver failure patients
thrombocythemia patients. (too many platelets because gain of function in R or thrombopoietin)
thrombocytosis is the secondary mechanism of thrombocythemia
thrombocytopenia- not enough platelets->bleeding disorder
types of granules in granulocytes
specific- secretory vesicles with cytotoxic enzymes, release via degranulation
non-specific are most common- azurophilic, filled with enzymes that function in phagocytosis
All cells from common myeloid progenitor cells have what type of granules
specific granules therefore considered granulocytes.
Granulocytes
Neutrophils, Eosinophils and basophils
Agranulocytes
Lymphocytes like B and T and NK cells
1 myeloid cell (monocytes) aka macrophages
Describe the developmental characteristics of myeloid granulocytes
myelopoiesis:
myeloblasts has nuclei (RNA production) but no granules
promyelocytes produces primary granules (azurophilic)
myelocyte produces specific granules (differences between eosinophil neutrophil and basophil)
metamyelocyte changes in nucleus, post mitosis, each type has characteristic nuclei
Neutrophil unique developmental characteristic.
band form- nucleus forms a U shape
nucleus has 2-4 lobes and heterochromatin is at periphery. cytoplasm lacks staining!
Neutrophils time spent in circulation vs tissues
hours in circulation, days in tissues
Structure unique to eosinophil
stains very dark due to specific granules- degranulation (important in parasitic reactions)
bi-lobed nucleus
Structure unique to basophil and general function
bi-lobed nucleus- usually cannot see it though because there is so much specific granules(basophilic-very blue)
allergy rxns, histamine producing
1 meyloid cell type that is an agranulocyte, and unique characteristics and functions
mononuclear phagotcytes. Largest WBC
distinct indentation in nucleus
circulates about 3 days then moves to a tissue to differentiate into local tissue macrophage and sometimes osteoclasts
When are monocytes mobilized into tissues?
they circulate in peripheral circulation until encounter signals on endothelial cells.
move through tissue and differentiate into tissue-specific macrophages
eg microglia, langerhans etc..
Granulopoiesis location
subtype of myelopoiesis
occurs in bone marrow with final differentiation in tissues
Order of granulopoiesis
common myeloid progenitor-> granulocyte/monocyte progenitor-> granulocyte progenitors (1 for each type)->myeloblast->promyelocyte->myelocyte->metamyelocyte->mature granulocyte
* before mature granulocyte, neutrophils become band cells
IL-3
expansion of immature marrow progenitors into all types of mature hematopoietic cells, and mast cells
produced by CD4+ T cells
GM CSF Granulocyte-macrophage, colonystimulatingfactor
major roles in granulocyte maturation
produced at cell injury or infection.
Lymphocytes are distinguishable because?
majority are very small, same size as RBC.
nucleus slightly indented. azurophilic staining(normal cell)
change in size based on activation increase cytoplasm:nuclear ratio
B cells, function and location of maturation
ab producing. live long time.
Mature in bone marrow
T cells, function and location of maturation
extremely long lived. Cell-immediated immunity
final differentiation in thymus
Natural Killer cell, function and location of maturation
activated lymphocyte with kidney shaped nucleus. more intense staining due to larger granules
Mature in peripheral tissues
Lymphopoiesis activated by what signal which is produced where
stromal cells in bone marrow and other tissues produce IL-7 to stimulate expansion of immature T and B cells
X linked severe combined immunodeficiency
marked dec in T cells. increase in B cells. Lack of IL7 signaling
