INTS 2: The Haematopoietic System Flashcards
(82 cards)
1
Q
Define embryonic development
A
- the beginning of cell and tissue development during embryonic life which covers the period from conception to birth
- this is 21 days in mice and 9 months in humans.
- embryonic development refers more precisely to the initial stages of development in the uterus while we use the term ‘fetal’ development when organs are formed.
2
Q
Define stem cells
A
- undifferentiatied cells that can differentiate into specialised cells but also maintain the ability to divide (through mitosis) to produce more stem cells
- found in multicellular organisms
3
Q
Define bone marrow
A
- where haemopoietic (haematopoietic) tissue and cells develop
- located in the cavity of some bones, particularly large bones
- e.g. femur and pelvic bones
4
Q
Define peripheral blood
A
- the fluid circulating in veins and arteries which carries the main cells that take care of:
- oxygen distribution (red blood cells)
- immunity (lymphocytes)
- antibacterial defence (granulocytes)
- a variety of proteins
- fluids (water) distribution
5
Q
Define lymphocytes
A
- cells orginating from the bone marrow, but leave when it reaches maturity and is transferred to the lymphoid tissues
- thymus
- spleen
- lymph nodes
- lymphocytes are counted in their thousands per 100 ml (deciliter) of blood and a normal count is between 1000 and 2500 per 100ml of blood in normal individuals
- they represent 20-30% of the circulating cells in the body
6
Q
Define lymphocytosis
A
- an excessive-high number of lymphocytes in the blood
7
Q
Define lymphocytopenia
A
- an abnormally low number of lymphocytes in the blood
8
Q
Define granulocytes
A
- granule-carrying cells are the primary cell type involved in bacterial and parasite defense
- granulocytes are counted in their thousands per 100 ml (deciliter) of blood and a normal count is between 3000 and 7500 (per 100ml) of blood in normal individuals
- they represent 60-70% of the circulating cells in the body.
9
Q
Define granulocytosis
A
- an increased number of granulocytes in peripheral blood
10
Q
Define granulocytopenia
A
- a reduced number of granulocytes in peripheral blood
11
Q
What are the three stages of the development of the haemopoietic system (haematopoiesis)?
A
- The haematopoietic stem cells originate in the yolk sac and the dorsal aorta
- known as ‘primitive haematopoiesis’ - The liver is then colonised through circulation of cells from 1
- Finally, the bone marrow is established as the definitive site of haemotopoiesis
- Steps 2 and 3 are known as ‘definitive haematopoiesis’
12
Q
What are the three layers of cells in the developing embryo?
What kind of tissues are derived from each ‘derm’?
A
- the ectoderm
- the mesoderm
- the endoderm
- study the image to see derived tissues
13
Q
Describe stage 1 of the development of the haematopoietic system (and the role of the yolk sac)
A
- the system is derived from the mesoderm layer
- the original pool of haematopoietic stem cells (HSCs) is formed during embryogenesis in a complex process starting in the yolk sac
- then the precursor cells (of endothelial origin) migrate to the dorsal aorta region, then to the placenta and to the foetal liver
- HSCs colonise the bone marrow around the time of birth
14
Q
Explain how it is evident that the haematopoietic system originated from the yolk sac and later migrate to dorsal aorta etc?
A
- by looking at the expression of some myelopoietic (bone marrow) genes like RUNX1 (AML1) and NOTCH1
- RUNX1 was expressed in cells in the yolk sac and ventral part of the dorsal aorta
15
Q
As well as haematopoietic markers, what else is expressed in HSCs?
A
- they also express endothelial markers
- particularly CD34 (a precursor cell of the haematopoietic lineage) and CD45 (expressed in all nucleated cells)
- these are cluster of differentiation (CD), used to identify the antigens on the surface of cells
16
Q
Why do HSCs only migrate to the bone marrow around birth and not earlier?
A
- it requires the bone to be formed
- this involves the differentiation of osteoblasts (bone-forming cells) and chondrocytes (cartilage cells) to help form the supporting structure of the bone marrow
17
Q
Describe stage 2 of the development of the haematopoietic system: the role of the fetal liver
- Does this stage happen after embryonic development?
A
- the foetal liver is the primary haematopoietic organ and the main site of HSCs expansion and differentiation during foetal development
- these cells come from the yolk sac
- the liver (along with the spleen) would not necessarily be able to ‘recover’ its ability to produce haematopoietic cells unless it is under stress or in the event of leukaemia
18
Q
Describe stage 3 of the development of the haematopoietic system: the role of the bone marrow
A
- this is a very late stage in the HSC development because the bones need to develop before the bone marrow can populate them
- specialised niches formed in the bones will accommodate the HSCs
- their progeny (descendants) will undergo lineage differentiation to develop red blood cells, myeloid and lymphoid progenitors
- all this occurs through the vascular invasion into the developing bones
- facilitating circulation and the seeding of haematopoietic progenitor cells
19
Q
Is the fetal liver equivalent of bone marrow in adult life?
A
- yes
20
Q
How are endothelial cells important players in helping to establish HSCs?
A
- HSCs are derived from niches of cells derived from endothelial cells of the dorsal aorta
21
Q
Where is the main site of haematopoietic cell production after birth?
A
- the bone marrow
- because it contains haematopoietic stem cells (HSCs)
22
Q
What are the two characteristics unique to stem cells?
A
- they have the pluripotent capacity to differentiate into a variety of cell lineages
- and they can do so while retaining a ‘self-renewal’ ability
23
Q
What cells can haematopoietic stem cells (HSCs) differentiate to?
A
- white blood cells (leukocytes)
- red blood cells (erythrocytes)
- platelets (thrombocytes)
24
Q
Describe the structure and anatomy of the bone marrow
A
- it is a highly vascularized tissue with a complex spongy structure
- the blood vessels are the pathway used by HSCs to migrate from the liver during foetal life to populate this tissue
25
What other types of cells present in the bone marrow apart from the haematopoietic cells and their precursors?
- stomal cells
- adipocytes
- bone matrix
- endothelial cells (forming the blood vessels)
26
What procedure would you perform to analyse the different cellular components of bone marrow?
- bone marrow aspiration
27
Briefly describe how bone marrow aspiration is performed
- where
- how
- it is taken from large bones, such as the iliac crest
- other sites with a lot of BM may not be easily accessible or be close to nerves, muscles etc
- adults usually undergo local anaesthetic and children under general
28
Describe the bone marrow aspirate
- what cells are present?
- there is a mixture of immature and mature cells if the main lineages
- immature cells are generally referred to as X-blasts
- mature cells are referred to as X-cytes
29
Observe the main lineages of cell maturation in the bone marrow
30
Which is normal and which is leukaemic bone marrow aspirate?
- in leukaemic bone, all cells look exactly the same
31
What hormones control haematopoiesis?
- a variety of growth hormones specific for each lineage:
1. Erythropoietin (EPO):
- a hormone secreted by the kidneys that increase the production of red blood cells
- acts in response to falling blood oxygen levels or haemorrhages
2. Granulocyte-colony stimulating factor (GCSF), also known as colony-stimulating factor 3:
- it is a glycoprotein that stimulates the bone marrow to produce granulocytes and myeloid stem cells and release them into the bloodstream
- G-CSF is produced by the endothelium, macrophages and a number of other immune cells
3. Thrombopoietin (TPO):
- a glycoprotein hormone made by the liver and kidneys
- stimulates the production and differentiation of megakaryocytes, which are the bone marrow cells that bud off large number of platelets
32
How is lymphocyte production controlled?
- instead of a hormone, lymphocytes receive stimulatory signals from other cells
- so they are the most difficult cells to 'push' to grow
- they can only develop from precursor lymphoid cells
33
Briefly describe red blood cells
- its relative abundance in the blood
- normal red blood count in men and women
- life expectancy
- protein in red blood cells
- red blood cells are the most numerous cells in the blood
- normal RBC in men: 4.7 to 6.1 million cells per microlitre (cells/mcL)
- normal RBC in women: 4.2 to 5.4 million cells per microlitre (cells/mcL)
- they have an average life of 90-120 days
- red blood cells contains mainly one protein: haemoglobin
34
How many molecules of haemoglobin does each red blood cell carry?
- 270, 000, 000 molecules
35
Describe the structure of haemoglobin
- it is formed by heme and globin
- heme:
- one attached to each of the globin tetrameters
- carries an iron (Fe) molecule, where 2 molecules of oxygen attach itself to be transported from the lung to the tissues
- each heme carries 1 Fe and 2 oxygen molecules
- globin:
- a tetramer made of two types of protein chains
- acts as a scaffolding for the heme
36
What happens to haemoglobin at the end of their life?
- they are removed by phagocytic cells called macrophages
- macrophages form a part of the lining of blood vessels in the spleen, liver and bone marrow (mainly first two)
- the body will try to recover as much as possible from the different components of red blood cells
- proteins and iron are recovered and recycled
- heme is metabolised to bilirubin for excretion
37
Describe in detail how haemoglobin is metabolised for excretion
1. Globin is broken down
- the amino acids are transported through the plasma to be used in the synthesis of new protein in different tissues/cells including the bone marrow
2. Iron is removed from the heme
- and it is passed back into the plasma, bound to proteins to be transported to the bone marrow
- there, it is used in the synthesis of new haemoglobin in newly forming red cells
3. the Heme is recycled through the liver
- it is converted to bilirubin, which gives the usual colour to faeces
- it must be removed to avoid toxic effects
38
Describe granulocytes
- life span
- types of cells generated
- brief function
- cell death
- inactivated human granulocyte lifespan: 5-90 hours
- its life is controlled by G-CSF production
- constantly generated in the bone marrow
- 60% produced are neutrophils
- eosinophil, basophil usually do not exceed 3% of the total myeloid mature cells
- 100 billion granulocytes are produced daily
- they are involved in controlling bacterial and parasitic infection and are primary players of 'innate immunity'
- cell death is generally via apoptosis
- this programmed type ensure the cellular membrane remains intact, so cellular toxins are retained within
- the dying cell signals for tissue macrophages to target the dead granulocyte and engulfed
39
Briefly describe platelets
- number in the blood
- where it is made from and from what
- function
- life span
- between 150,000 - 300,000 platelets per microliter of blood
- derived from the 'explosion' of megakaryocytes
- formed in the bone marrow
- essential for clotting and protects against haemorrhages
- 8-9 day life span
- old platelets are destroyed by phagocytosis in the spleen and liver
40
Briefly describe lymphocytes
- number in blood
- lifespan
- types of lymphocytes and function
- approx 4,000 - 11,000 lymphocytes per microliter of blood
- average lifespan of 5-7 days up to a few months, but a few live for a few years (especially T cells)
- two primary types:
- B lymphocytes (B cells)
- T lymphocytes (T cells)
- involved in combating viral infection and have a function in cancer immunity
41
Do lymphocytes grow more in response to G-CSF?
- no
- Lymphocytes are not stimulated by Colony Stimulating Factor; Granulocyte-Colony stimulating factor (GCSF) stimulates the proliferation of granulocytes cells.
42
What are the shortest-lived cells in the blood?
- granulocytes
- from a few hours to a few days
43
What is haematocrit?
- the total percentage amount of red cells when blood is centrifuged
44
Describe mature red blood cells
- structure
- lifespan
- contains no nucleus
- contains mainly haemoglobin (Hb)
- has a lifespan of 90-120 days
45
What are the normal levels of haemoglobin in men and women?
What does a low haemoglobin level mean?
46
Observe the stages of red cell maturation
47
Which cells in the stages of red cell maturation can be found in a normal peripheral blood sample?
Why can't the earlier stages be detected?
- the final stages: anucleated red cells and maybe reticulocytes
- all the earlier stages are only present in the bone marrow
48
What is the process of producing red blood cells (erythrocytes) called?
- erythropoiesis
- from Greek 'erythro' meaning "red" and 'poiesis' meaning "to make"
49
What stimulates erythropoiesis?
- it is stimulated by reduced O2 in the circulation because of:
1. reduced level of total red cells due to haemorrhage
2. reduced production of Hb in the red cells due to poor or limited synthesis of Hb genes
- e.g. thalassaemia
3. increased requirements
- e.g. low oxygen availability at high altitude
50
Describe the process of erythropoiesis
- the kidney observes the abnormal level of O2 (under the conditions noted in previous flashcard)
- so the production of erythropoietin is stimulated
- this hormone stimulates the proliferation and differentiation of red cell precursors in the BM
- it activates erythropoiesis in the haematopoietic tissues (BM, even the liver or the spleen)
- these are the site of fetal haematopoiesis which can be triggered again during adult life under special conditions
51
When in human life does erythropoiesis occur at the embryonic yolk sac?
- it ceases by the end of the first trimester
- and it produces predominantly immature blood cells called megaloblasts
52
Where does erythropoiesis occur during the second trimester?
- it occurs in the liver (hepatic erythropoiesis)
- stops until the beginning of the third trimester
53
Where does erythropoiesis occur in the last stages of foetal life?
- bone marrow erythropoiesis begins
- but hepatic erythropoiesis continues until a few days after birth
54
Which bones in the body are erythrocytes produced at these ages?
- before five years old
- by 25
- throughout life
- until 5 years:
- bone marrow from all bones
- by 25:
- tibia and femur stop being sites of haematopoiesis
- whole life:
- vertebrae
- sternum
- pelvis
- ribs
- cranial bones
55
Where is erythropoietin produced and what is its function?
- it is produced mainly in the kidneys and in the liver
- in response to low oxygen levels, such as anaemia
- it stimulates the production of red cells in bone marrow
56
What is 'blood doping' and how does it relate to erythropoietin?
- it refers to increasing the number of red blood cells in a person's circulatory system
- this enhances the delivery of oxygen in muscles
- which may help muscles perform better
- erythropoietin (EPO) could be used for this
57
Which cells in the blood are nucleated?
- granulocytes
- lymphocytes
58
Observe the micrograph of red blood cells and white blood cells
59
Why are granulocytes named granulocytes?
What is its other name and why?
- they are characterised by the presence of granules in their cytoplasm
- their subtype depends on what colour they stain
- they are also called polymorpho-nuclear leukocytes (PMNL) or polymorphonucleated cells or polymorph nuclear leucocytes (PMN, PML)
- due to their varying nucleus shapes
- it is usually lobulated into 2 or 3 segments
60
What types of granulocytes are there?
Do they have alternative names?
Describe their abundance
- neutrophil granulocytes
- also called polymorphonuclear leukocyte
- most abundant type
- eosinophils
- basophils
- mast cells
61
Through what process are granulocytes produced and where?
- They are produced via granulopoiesis
- in the bone marrow
62
What colour do neutrophils, basophils and eosinophils granules stain when using Wright's stain?
See images too
- neutrophils: granules stain neutral
- basophils: granules stain blue
- eosinophils: granules stain orange
63
Describe neutrophil granulocytes:
- abundance
- size
- structure of mature neutrophils
- normally found in the bloodstream
- the most abundant type of phagocyte:
- 50-60% of the total circulating white blood cells (remaining are lymphocytes)
- over 90% of granulocytes are neutrophils
- 1ml of human blood contains 5,000 neutrophils
- they are 12-15 um in diameter
- mature neutrophils are smaller than neutrophils and have a segmented nucleus with 2-5 segments
- each section is connected by chromatin filaments
64
How and when do neutrophils go to the specific site of infection/damage?
- they are very mobile and can adhere to capillaries and pass through very small gaps in endothelial cells to go to a specific site
- once they have received the appropriate signals, it takes them about 30 mins to leave the blood and reach the site of infection
- they do not return to the blood: they stay at infection site, turn into pus cells and die
65
Explain why it is abnormal to see precursor neutrophil cells in PB (peripheral blood) when there is no active infection
- neutrophils normally do not exit the bone marrow until they are mature
- unless an infection where precursors, myelocytes and promyelocytes, are released
- could be a sign of leukaemia
66
Describe the three strategies neutrophils adopt to directly attack micro-organisms
1. Phagocytosis:
- they are phagocytes
- they rapidly engulf invaders coated with antibodies and complement proteins, including damaged cells or cellular debris
2. Release of Soluble Anti-Microbials (including granule proteins) Molecules
3. Production of Neutrophil Extracellular Traps (NETs)
- these are comprised of a web of fibres composed of chromatin (DNA) from neutrophils and proteins from primary and secondary granules
- they can also secrete products that activate monocytes and macrophages
- these increase phagocytosis
- the formation of reactive oxygen compounds result in intracellular microbial killing
67
What are the three types of granules in neutrophils?
Describe what maturity of neutrophil it is found in and the different granules there are
1. Primary (azurophilic) Granules:
- found in young cells
- contains:
- cationic proteins used to kill bacteria
- proteolytic enzymes
- cathepsin G to break down bacterial proteins
- lysozymes to break down bacterial cell walls
- myeloperoxidase: to generate toxic bacteria-killing substances
2. Secondary (Specific) Granules:
- found more in mature cells
- involved in the formation of:
- toxic oxygen compounds
- lysozyme
- and lactoferrin (used to take essential iron from bacteria
3. Tertiary Granules:
- phosphatases or metalloproteinases
- the latter aiding movement through connective tissue
68
Describe the structure of eosinophils
- nuclei structure
- granule number
- they have kidney-shaped lobed nuclei
- 2- 4 lobes
- the number of granules vary because they tend to degranulate while in the blood stream
69
What is the normal range of eosinophil number?
How much of the WBC do they represent?
- the normal range is usually between 30-350 per microliter of blood
- more than 500 cells is usually considered eosinophilia
- they represent 1-3% of total WBC population
70
Describe the functions of eosinophils
| (there are many)
- killing parasites:
- their granules contain a unique toxic protein
- receptors that bind to Immunoglobulin E (IgE) are used to help with this
- they have limited ability to participate in phagocytosis
- they are antigen-presenting cells
- they regulate other immune cell function
- they destroy tumour cells
- they promote the repair of damaged tissue
- upon activation, they predominately produce:
- peroxidase
- elastase
- a variety of cytokines
- they are a mediator of allergic response and asthma pathogenesis
- they fight worm colonization
- responsible for tissue damage and inflammation in many diseases:
- e.g. asthma
- high levels of interleukin-5 up-regulate the expression of adhesion molecules
- this then facilitate the adhesion of eosinophils to endothelial cells
- causing inflammation and tissue damage
- an accumulation of eosinophils in nasal mucosa is considered a major diagnostic criterion for allergic rhinitis (nasal allergies)
71
Describe the structure and abundance of basophils
- they are one of the least abundant cells in the bone marrow and blood (less than 2% of all of these cells)
- they represent 0.5% to 1% of circulating white blood cells
- they are the largest type of granulocyte
- they predominantly have only two-lobed nuclei
- the chromatin filaments that connect them are not very visible
- they have receptors that can bind antibodies and histamine
- the cytoplasm of basophils contain a varied number of granules
- these can partially conceal the nucleus which is a feature distinguishing basophils from eosinophils and neutrophils
72
Describe the function of basophils
- they have receptors that can bind antibodies and histamine
- responsible for inflammatory reactions during an immune response
- present in the formation of acute and chronic allergic diseases
- e.g. anaphylaxis, asthma, atopic dermatitis, hay fever
- produce compounds that co-ordinate immune responses
- e.g. histamine (increasing blood flow)
- serotonin that induces inflammation
- heparin that prevents blood clotting too quickly
- hence they facilitate the influx of other cells required to fight infection and are responsible for the inflammation component of a septic event
73
Briefly describe what lymphocyte is
- structure
- abundance in blood
- size
- it is a form of small leukocyte (white blood cell) with a small, round nucleus
- found especially in the lymphatic system
- they are protective, pathogen-destroying cells that are transported in all parts of the body in the blood or lymph
- much less numerous than red blood cells and granulocytes
- around 1,000 - 4,000 cells per millilitre of blood
- approx the size of a red blood cell
- this is important as immature lymphocytes are much larger than red cells
74
What colour and shape do lymphocyte nuclei stain?
- dark blue to purple
- generally spherical and accounts for most of the cell mass
- the sparse cytoplasm appears as a thin pale blueish rim around the nucleus
75
What are the two main population of lymphocytes?
Briefly describe their functions
- B lymphocytes:
- oversee the production of antibodies (humoral, antibody-driven adaptive immunity) that are released into the blood
- represent approx 5-10% of total white blood cell population
- T lymphocytes:
- for cell-mediated, cytotoxic adaptive immunity
- play a regulatory role
- destroy grafts, tumour and virus-infected cells
- represent 20-45% of the white blood cell population
76
What do the T and B stand for in T and B cells?
- T: thymus
- B: bone marrow in humans, or bursa-derived cells in chickens
77
Describe how T and B cells/lymphocytes are major cellular components of the adaptive immune response and how that generates acquired immunity
- they recognise specific 'non-self' antigens
- during a process called antigen presentation
- once an invader is identified, the cells generate specific responses to eliminate specific pathogens or pathogen-infected cells
- B cells respond by producing large quantities of antibodies
- these neutralise foreign objects (like bacteria or viruses)
- some T cells called T helper cells, producing cytokines that direct the immune response
- other T cells, called cytotoxic T Cells, produce toxic granules that contain powerful enzymes that induce the death of pathogen-infected cells
- following activation, memory cells have a record of the antigens encountered
- which are able to remember each specific pathogen encountered
- more strong and rapid response will be produced if the same pathogen is detected again
- this is acquired immunity
78
What is the difference and relationship between innate and adaptive immune responses?
- innate immune responses:
- activated directly by pathogens
- defend all multicellular organisms against infection
- adaptive immune responses:
- in vertebrates: pathogens, together with the innate immune responses they activate, stimulate adaptive immune responses, helping to fight infections
79
Describe the role natural killer cells play in the immune system
How are they activated?
- part of the innate immune system
- play a major role in defending the host from:
- tumours
- virally infected cells
- they can differentiate from normal cells by recognising changes of a surface molecule called MHC class I
- they are activated in response to a family of cytokines called interferons
- activated natural killer cells release cytotoxic granules, destroying the altered cells
- they are called natural killer cells because they do not require prior activation in order to kill cells that are missing MHC class I
80
What are platelets made from? Where?
How do they stain?
How many are there in the blood per microliter?
What is their function?
How long do they live for?
- they are cell fragments of large multinucleate cells (megakaryocytes) formed in the bone marrow
- they appear as darkly staining, irregular shaped bodies interspersed among the blood cells
- normal platelet count: 250,000 to 300,00 per microliter
- they are instrumental in the clotting process that occurs in plasma
- they live approx 9-10 days
81
Describe the structure of platelets
Describe their staining
- blood plates do not contain a nucleus
- they are about 3µm long but appear smaller in the microscope
- because their cytoplasm is divided into two zones:
- outer hyalomere: hardly stains
- inner granulomere: bluish staining granules (though appear more homogenously blue)
- inside thrombocyte granulomere:
- diverse vesicles (the granules):
- serotonin
- compounds important for blood coagulation
- platelet-derived growth factor (PDGF)
- mitochondria
- ribosomes
- lysosomes
- endothelial reticulum
- hyalomere contains:
- cytoskeletal fibres: actin and myosin
82
What is the function of platelets?
Describe how platelets work
- they assist in haemostasis: the arrest of bleeding and clotting processes
1. Platelets release serotonin
- which adhere to the walls of damaged vessels and causes vasoconstriction (a brief and intense contraction of blood vessels)
- this is sufficient to close small arteries
2. Platelets, which come into contact with collagenous fibres in the walls of the vessel (which are not usually exposed to the blood stream), swell, become "sticky"
- they activate other platelets to undergo the same transformation
- this results in the formation of a platelet plug (or platelet thrombus)
3. Finally, activating substances are released from the damaged vessel walls and from the platelets
- These substances mediate the conversion of the plasma protein prothrombin into thrombin
- Thrombin catalyses the conversion of fibrinogen into fibrin, which polymerizes into fibrils and forms a fibrous net in the arising blood clot
- Platelets captured in the fibrin net contract leading to clot retraction, which further assists in haemostasis (a process that causes bleeding to stop)
- more detail in the second video of INTS 2 module
