P: White blood cells & haemostasis Flashcards
Innate response
general processes against infectious agents
Adaptive response
directed response against specific infectious agents.
Leukocytes
4-10 x 10^9 cells/L
Nucleated cells with 5 subtypes:
- Neutrophils (phagocytosis)
- Eosinophils (phagocytosis)
- Monocytes (phagocytosis)
- Basophils (released hydrolytic enzymes from cytoplasmic granules + histamine)
- Lymphocytes
Granulocytes
- Neutrophils, eosinophils, basophils
- Granules visible in cytoplasm
- Called polymorphonuclear leukocytes. (PMN or PML)
- Multiple nuclei of varying shapes
- Originate from bone marrow precursor cells: myelocytes
Genesis of myelocytes
- Under cytokine control
- 6-10 days in bone marrow/circulation
- 4-5 days in tissues
- Large numbers held in marrow as reserve pool
- Marrow has 10x as many myeloid cells as erythroid cells
- Neutrophils - most common white cell (40-75%)
- Eosinophils - 1-6% circulating cells
- Basophils - least common circulating cell (<1% in adult)
Neutrophils
- Participate in phagocytosis in blood + tissues
- Circulate in blood and migrate into tissues by squeezing through pores via diapedesis
- Numbers increase dramatically during infection.
- Constitute about 50-80% of all leukocytes.
Eosinophils
- Constitute 1-4% of all leukocytes
- Weakly phagocytic: mainly attack infecting parasites too large to be engulfed by attaching to parasite and secrete hydrolytic enzymes from cytoplasmic granules
- Can reverse tissue damage during allergic reactions: phagocytose allergen-antibody complexes & inflammation inducing substances.
Basophils
- Least common circulating leukocyte <1%
- Non-phagocytic, act like eosinophils to release hydrolytic enzymes from cytoplasmic granules
- Release chemicals that contribute to allergic reactions: histamine, bradykinin, serotonin, heparin, slow-reacting substance of anaphylaxis, lysosomal enzymes.
Monocytes
- Largest of leukocytes - 2-4%
- Circulate in blood for a few hours before migrating into tissues: increase in size by factor 5-10 and develop into tissue macrophages where they phagocytose infectious agents + abnormal/ dying cells including RBCs only in tissues.
Monocyte –> macrophage cell system:
- Monocytes enter tissues + become macrophages
- Attach to tissues indefinitely + can be recruited into tissues if required
- Reticuloendothelial system
Macrophages prominent in:
- Lymph nodes
- Lung alveolar walls
- Liver sinusoidal capillaries
- Red pulp of spleen
Chemotaxis
Neutrophils & macrophages are recruited to tissue inflammation
Inflammation
- Large number of neutrophils recruited by chemotaxis + enter by margination
- Activated macrophages secrete factors which promote granulocyte + monocyte production.
Natural killer cells (innate immunity)
- Produced from lymphoid lineage
- Specifically target tumour cells + virus infected cells
- Induce programmed cell death (apoptosis) via release of contents of cytoplasmic granule
- Activated in response to interferons/ macrophage-derived cytokines.
Lymphocytes (acquired immunity)
- 20-40% of leukocytes
- 3 main subtypes:
1. B lymphocytes: mature into plasma cells which secrete antibodies
2. T lymphocytes: helper T cells secrete cytokines which activate other leukocytes.
Cytotoxic T cells secrete factors that kill virus-infected cells + tumour cells
3. Natural killer cells: also secrete factors that kill virus-infected cells + tumour cells.
Genesis of lymphocytes
Produced + stored in lymphoid tissue.
- Lymph glands, spleen, thymus, tonsils, bone marrow & peyers patches in intestinal epithelium
- Positioned to intercept invading organisms/ toxins
- Various cytokines drive growth + differentiation
Lymphocyte processing
- Pro-T cells migrate to + process in thymus gland
- Pro-B cells processed in liver + bone marrow
- Both divide rapidly, surface receptors on individual cells develop specificity for thousands and millions of different antigens.
Major histocompatibility complex
- Macrophages + dendritic cells phagocytose microorganisms + present antigenic fragments on cell surface to nearby lymphocytes
- Binding of antigens to specific cell surface receptors on lymphocytes activates these specific cells only
- Activated lymphocytes reproduce rapidly - large numbers of a clone of lymphocytes released into circulation
- Macrophages secrete IL-1 which promotes specific clonal growth.
Helper T lymphocytes
- 75% of T-cells
- Secrete lymphokines (IL2-6)
- Promote growth of activated B cells
- Stimulation of cytotoxic + suppressor T cells
- Activation of macrophages
- Feedback stimulation of helper cells
Types of T lymphocytes
Cytotoxic T cells
Suppressor T cells
Cytotoxic T cells
- Killer cells which destroy micro-organisms containing activating antigen
- Virus infected cells, cancer cells + transplanted cells
Suppressor T cells
- Prevent damage of tissues by cytotoxic cells
- Responsible for immune tolerance
- Failure causes autoimmune diseases
Classes of antibodies
IgM, IgG, IgA, IgD, IgE.
Secondary immune response with memory cells:
- Memory B cells rapidly converted to plasma cells
- Memory T cells rapidly converted to helper, cytotoxic + suppressor T cells.
Haemostasis
- Vascular spasm (damaged blood vessel constricts)
- Platelet plug formation (platelets adhere to damaged endothelium to form platelet plug)
- Blood coagulation (formation of solid blood clot at site of platelet plug)
Vascular constriction due to trauma to blood vessels:
- Local myogenic contraction
- Local axon reflexes initiated by pain/sensory receptors at/near damaged vessels
- Local platelets in blood release a vasoconstrictor substance thromboxane A
Thrombocytes (platelets)
- Produced by megakaryocyte
- No nuclei but contain residual cell organelles
- Synthesise various factors that act on plasma proteins + local blood vessels + issue
- Lifespan of 3-4 weeks
- Eliminated from circulation by macrophages mainly in spleen
Formation of platelet plug
- Plasma protein (von Willebrand factor) triggers aggregation + adherence of platelets to one another + to sites of vascular damage
- Platelets undergo structural changes + release ADP and thromboxane A2 which act on nearby platelets triggering further aggregation/adherence
- Formation of a loose platelet plug.
Difference between extrinsic + intrinsic pathways for blood clots
Extrinsic pathway: activated by vessel/tissue trauma
Intrinsic pathway: initiated by blood factors
Coagulation cascade
- Fibrinogen is converted to fibrin by thrombin
- Loose fibrin stabilized by formation of covalent bonds catalysed by coagulation factor XIIIa which is activated by thrombin.
Vitamin K
- Needed for hepatic synthesis of clotting factors e.g. prothrombin
- Deficiencies leads to bleeding tendencies
- Synthesised by bacteria in intestinal tract
- Vitamin k deficiency caused by obstruction of bile ducts/ liver disease
- Newborns lack intestinal bacterial flora –> contain 50% of adult clotting factors so vitamin K is administered at birth.
Feedback inhibition by formation of fibrin:
- 85-90% of thrombin formed from prothrombin is absorbed to fibrin
- Antithrombin III binds + removes remaining thrombin
Cessation of clotting cascade.
- Antithrombin III binds + removes remaining thrombin
To stop contact activation of intrinsic pathway
layer of glycocalyx on endothelium + thrombomodulin binds + removes thrombin from plasma.
Heparin
activates antithrombin III, removes free thrombin + upstream factors, used as anti-clotting agent.
Aspirin
blocks production of thromboxane by inhibiting enzyme cyclooxygenase, long-term aspirin inhibits platelet aggregation
Prostacyclin
binds prostacyclin receptor on platelets, increases intracellular cAMP, blocks increase in intracellular Ca2+ caused by thromboxane receptor. Blocks platelet aggregation/adherence
Dipyridamole
inhibits thromboxane synthase + phosphodiesterase which degrades cAMP. Blocks platelet aggregation/adherence.
