TOB L6 Flashcards
Define Haematopoiesis
process by which the body produces blood cells.
Describe the sites of haematopoiesis
- Foetal blood cells form initially in yolk sac
- From the second trimester (second period of 3 mont, heamaeopoiesis takes place primarily in liver and from the third trimester (third period of 3 months), bone
- In adults, blood cell formation takes place in red marrow of sternum, pelvis, vertebrae, ribs, skull
Describe how hormones regulate mature blood cell development from progenitors
Red Blood Cells (eryhtocytes)
Erythropoietin - EPO
Platelets - Thrombopoietin (TPO)
Myeloid Cells - Granulocyte colony-stimulating factor (G-CSF) and granulocyte/macrophage colony-stimulating factor (GM-CSF);IL3
Lymphoid Cells: various interlukins
Blood Cell Statistics
Typical individual
Ranges vary between populations and laboratories
Describe the structure and function of the red blood cell membrane proteins
Band 3 proteins exchanges Cl- + HCO3-
(crucial for CO2 uptake
Spectrin - cytoskeletal protein - associates with transmembrane proteins to stabalise membranes
Glycosylated membrane proteins (such as glycophorins) contain antigenic sites - important in blood typing systems
Describe the structure, function and adaptations of red blood cells
Anucleate cells
Densely filled with haemoglobin
Flexible
Biconcave disks
Narrow diameter
Large SA for gas exchange
Deliver O2 to tissues, return CO2 to lungs
Lack of organelles make glycolysis their main source of ATP
Describe the control of erythropoiesis
Reduced pO2 (partial pressure of oxygen) is detected by interstitial peritubular cells of the kidney, stimulating them to produce EPO
EPO stimulates maturation of nucleated precursors (erythroblasts) in bine marrow + release of mature RBCs into circulation
A rise in RBCs is accompanied by rise in pO2, therefore EPO production falls (positive feedback?)
Describe the structure of haemoglobin
Tetramer - two pairs of globin chains, each with its own haem group
Haemoglobin exists in two configurations
Oxyhaemoglobin
Deoxyhaemoglobin
Diagram of Oxygen-Haemoglobin Dissociation Curve
RBC / Haemoglobin deficiencies - Anaemia
Blood loss (e.g. trauma)
Decreased RBC production (iron or Vitamin B12 deficiency
Reduced haemoglobin / increased RBC destruction
Thalassemia - inherited mutations in alpha and beta haemoglobin chains
Sickle cell anemia
Outline different causes of anaemia
RBC / Haemoglobin Deficienceis anaemia: General category where no of red blood cells / amount of haemoglobin within them is lower than normal. Due to nutritional deficiencies, chronic disease etc
- Blood loss (e.g. trauma): significant blood loss due to trauma (surgery, gastrointestinal bleeding). Losing large vol of blood reduces overall rbc in circualtion
- Decreased RBC production (Iron / Vit b12 deficiency): reduced production of rbc caused by nutritional deficiencies includng iron deficiency anemia (inadequate iron for haemoglobin production) or vitamin B12 deficiency anemia (insufficient vit b12 for RBC maturation)
- Increased RBC destruction/ recduced Hb: blood cells prematurely destroyed / issue with haemoglobin within RBC. This can be due to conditions such as:
- THALASSEMIA: inherited genetic disorder
mutation to genes responsible for producing alpha + beta Hb chains. Mutations result in abnormal haemaglibin - leads to anemia - SICKLE CELL ANEMIA: inherited genetic disorder
mutation in beta Hb chain
Cuases RBC to take on sickle shape when they release oxygen - leads to anemia
Describe patterns of haemoglobin synthesis
Describe sickle cell aneamia
A single nucleotide polymorphism (SNP) in the haemoglobin beta chains leads to polymerisation of the HbS. under low oxygen conditions the RBC will take on this sickle shape, resulting in the loss of cell flexibility and increased fragility.
As a result, sufferers cannot carry as much oxygen. This can result in ischemia…
Describe how damaged RBCs are removed by reticuloendothelial system (RES)
- RBC live 120 days
- No nucleus/other organelles, therefore unable to synthesise new compounds to replace damaged ones
- Damaged RBCs destroyed by fixed phagocytic macrophages in spleen + liver
- Break down products are then recycled + waste is excreted
What is the reticuloendothelial system composed of?
Monocytes
Macrophages of lymph nodes, spleen, liver (kupfer cells)
State which lymphoid organ surveils the blood
spleen is the only lymphoid organ that surveils the blood
Describe the process of haemoglobin catabolism
- Macrophages in the spleen, liver or red bone marrow phagocytose damaged RBCs
- The globin and the heme portions of haemoglobin are split apart in the reticuloendothelial system
- Globin is broken down into amino acids which can be reused to synthesise sother proteins
- The iron is removed from the heme and transferred to the bone marrow via transferrin, leaving biliverdin (non-iron portion of the haem). It is a green pigment
- Biliverdin reduced to bilirubin (yellow pigment)
- Bilirubin enters blood + transported to liver, where it forms component of bile
- In the large intestine, gut commensal bacteria converty bilirubin to urobilinogen
- Urobilinogen is ultimately excreted in faeces in form of brown pigment - called stercobillin - gives faeces brown colour
- Some urobilinogen absorbed back into blood and then converted to a tellow pigment called urobilin and is excreted in urine
State the role of the spleen
spleen is the only lymphoid organ that surveils the blood
site for antibody production and lymphocyte activation
It provides a reservoir for platelets
State the function of transferrin
It is a plasma protein that transports iron in the blood.
Diagram of Haemoglobin Catabolism
Describe the structure, function and adaptation of platelets
Small, round particles produced from cytoplasm of megakarocytes in bone marrow
- Anucleate
- Stored in spleen
3 Principal inflammatory mediator released by platelets - Serotonin - Derived from bone marrow megakarocytes
- Platelets cytoplasm cntains alpha granules + dense granules
Alpha granules: contain fibrinogen, von Willebrand’s factor and other large molecules
Dense granules: contain small molecules such as ADP and calcium, important in platelet adhesion
Appear blue with Wright’s / Giemsa stain
What colour do platelets appear to be with Wright’s / Giemsa stain?
BLUE
Define thrombopoiesis
Formation of platelets in bone marrow
Describe the control of thrombopoiesis
Controlled by hormone thrmbopoietin
Produced constitutively (released constantly all the time) by liver + kideys
Under influence of of thrombopoietin, myeloid stem cells develop into megakarocyte colony forming cells that develop into precursor cells called megakaryroblasts
Megakaryoblasts transform into magakaryocytes
TPO acts in bone marrow to stimulate megakaryocytes to increase in size by undergoing DNA replication without dividing. Platelets bud off / ligate from enlarged cells
How do we stop thrombopoeisis from happening / switch it off?
Thrombopoietin is primary regulator of platelet production
TPO can bind to receptors on platelets
Upon binding to plateletsm hormone is removed from circulation + destroyed
This reduces bioavailability of hormone in blood as platelet number rise (-ve feedback) platelet destroys the hormone which prevents further formation of platelets
Define thrombocytopenia
Abnormally low platelet levels
Describe the process of clotting
- Following damage to blood vessel walls, the exposure of platelets to underlying collagen activates the intrinsic pathway (contact activation pathway)
Extrinsic pathway (tissue factor pathway) stimulated by trauma, requires a thrombin “burst”
Rupture of vessels exposes tissue factor (found in subendotheloial tissue) to Factor VII, which becomes activated
These factors intersect in the common pathway.
Activated Factor X (Factor Xa) converts prothrombin to thrombin, which in turn converts fibrinogen to fibrin
Describe the process of primary haemostasis
- Platelets weakly adhere to exposed collagens via glycoprotein (GP) la/lla receptors. Stronger adhesion (to collagen) occurs via binding of von Willebrand factor (vWF) to the platelet GP Ib/IX.V heterotrimeric receptors
- GP IIB/IIIa receptors on activated platelets act to increase platelet aggregation
Compare the binding in strong and weak adhesion
Weak adhesion to collagen fibres = binding to GP la/lla
Strong adhesion to collagen fibres = binding of von Willebrand factor (vWF) to platelet GP Ib/IX/V heterotrimeric receptors
Describe the process of secondary haemostasis
Secondary haemostasis leads to polymersiation of fibrin which traps platelets and RBCs, forming a clot
by clotting cascade
Describe the clotting cascade in secondary haemostasis
- Intrinsic pathway is activated by damage to endothelium
Exposure to collagen activates FXII which activates FXI - The extrinsic pathway is activated when blood escapes from vascular system
Tissue Factor (expressed by smooth muscle + fibroblasts) binds to
and activates circulating FVII - These processes both activate FX, initiating the common pathway, leading to fibrin-cross linking
Describe the retraction and removal of the clot
Contraction of platelet actin and myosin filaments reduce the size of the clot
As the damaged endothelium is repaired, the clot is dissolved by plasmin (Fibrinolysis)
Define coagulation
Process of blood clotting
State disorders of coagulation
Haemophillia A - results from mutations / deletions in Factor VIII gene
Von Wilebrand disease - common inherited bleeding disorder involving vWF. Severity of bleeding varies between different types
Vitamin K: important co-factor in formation of clotting factors. Deficiencies lead to bruising + uncontrolled bleeds.
Anti-coagulant warfarin inactivates vit k dependent clotting factors
Define innate immunity
Immediate + non specific, transient (lasting for short time perioid) response to infection
Define Adaptive immunity
LESS TRANSIENT, SLOWER
Humoral responses involve secretion of immunoglobulins (antibodies) by B cells
Cell mediated responses involving the killing of infected cells by T cells
What are leukocytes?
White blood cells
Describe the structure, function and adaptations of leukocytes
- Have nuclei + full complement of organelles
- Do not contain haemoglobin
- Classified as granular or agranular
Describe the classification of leukocytes
WBC
Describe the difference between innate and adaptive / acquired immunity
Innate immunity is an immediate, non specific, transient response to infection
Adaptive / acquired immunity is divided into two:
1. Humoral: Involves secretions of immunoglobulins by B cells into extracellular fluids
2. Cell mediated immunity - involve killing infected cells by T cells
Table comparing Neutrophils, Eosinophils, Basophils, Natural killer cells, monocytes
What is the lifespan of neutrophils?
1-4 days
How common are neutrophils
Most common (60% of WBC)
Describe the structure of the nucleus neutrophils
Multi-lobed (2-5 lobes) - sometimes called polymorphonuclear cells
State the function of neutrophils
To be recruited + migrated out of circulation to site of infection(chemotaxis) + destroy foreign material by phagocytosis
Where are nuetrophils developed?
Neutrophils develop in the bone marrow
under the control of G-CSF
Describe the lifespan of monocytes
Variable lifespan
How common are monocytes?
3-5% of WBC
Describe the nucleus of monocytes
Kidney shaped
State the function of monocytes
Differentiate into macrophages in tissues.
Respond to inflammation + act as antigen presenting cells
They are:
- Phagocytic
- Pinocytic
(pinocytosis - ingestion of small amounts of fluid)
What is the lifespan of eosinophils?
8-12 days
How common are eosinophils?
1-3% of WBC
Describe the nucleus of eosinophils
Bi-lobed
State the function of eosinophils
- Combating helminth infections (helminths - parasitic worms)
- Mediating hypersensitivity (allergic) reactions - when body exposed to allergens, eosinophils recruited to site of allergic reaction
- Phagocytosing antigen-antibody complexes
Histology of eosinophils in the colonic mucosa
What is the lifespan of basophils?
Basophils have a half-life of 2.5 days
How common are basophils?
account for
0.2-1% of circulating leucocytes.
Describe the nucleus in basophils
Bi-lobed
State the function of basophils
Important in type 1 hypersensitivity reactions (eg. exposure to allergens).
ALLERGIC REACTIONS
Describe the nucleus of natural killer cells
Large nuclei
State the function of natural killer cells
Produce rapid response to viral infection
Recognition of “stressed” cells:include those undergoing cellular stress, tumour cells, cells with DNA damage. When detecting these stressed cells, initiate a response to eliminate them
Compare natural killer cells to cytotoxic T cells
Mechanism of killing similar to cytotoxic T cells, albeit with less
specificity.
Describe how adaptive immunity is divided into two systems
- Humoral immunity: Secretion of immunoglobulins (antibodies) by B lymphocytes into extracellular fluids (humors)
- Cell mediated immunity:
T lymphocyte-mediated destruction of infected cells
Which cells are involved in adaptive immunity?
Lymphocytes
(T lymphocytes and B lymphocytes)
State an adaptation of B lymphocytes
“shuffle” DNA which encodes for immunoglobulins (antibodies) to create variety of antibodies which are able to recognise a variety of antigens
When B cell presented with foreign antigen it recognises, it proliferates (under control of T helper cells) to form plasma cells which produce antibodies specific to that antigen
State the role of memory B lymphocytes
Expand following re-exposure to antigen
State the role of B lymphocytes
- B lymphocytes are presented with foreign antigen it recognises
- Proliferates (under control of T helper cells)
- Forms plasma cells
- Plasma cells produce antibodies specific to antigen
State the origin of T lymphocytes
Bone marrow
Mature in thymus (or spleen in adults)
State the role of T helper cells
CD4+ (T helper): induce proliferation + differentiation of T cells + B cells + activate macrophages
CD8+ (T cytotoxic): -induce apoptosis (controlled cell death) in cells infected by virus
1. Release perforin (protein).
2. Punches holes (forms pores) in plasma membrane of infected cell 3. CD8+ T cells release granzymes into pores 4. Granzymes reach target cells, activate series of intracellular processes, leads to cell destruction
