Leukopoiesis PDF

Leukopoiesis Matthew LAU (Scientific Officer) MLS 3009SEF (2025 Spring term)  Area to cover Leukopoiesis Structure and morphology of normal leukocytes Function of normal leukocytes  What are leukocytes? Leukocytes protect host...

Leukopoiesis Matthew LAU (Scientific Officer) MLS 3009SEF (2025 Spring term)  Area to cover Leukopoiesis Structure and morphology of normal leukocytes Function of normal leukocytes  What are leukocytes? Leukocytes protect host from infectious agents or pathogens Develop from hematopoietic stem cells in the BM, then undergo differentiation and maturation Morphology: polymorphonuclear vs mononuclear Function: innate vs adaptive immune response Classification Romanowsky stained blood smear under light microscope Surface markers (Cluster of Differentiation, CD) Number of circulating leukocytes varies Sex, age, activity, time of day, ethnicity etc Stress, disorders, production in BM Adult WBC count: 4 - 10 x 109/L Clinical hematology Atlas  What is leukopoiesis? Leukopoiesis is the process by which white blood cells (leukocytes) are produced in the bone marrow. This process is crucial for maintaining a healthy immune system and homeostasis. Overview of stages 1. Stem Cells: It all starts with hematopoietic stem cells (HSCs) in the bone marrow. These multipotent cells can differentiate into various types of blood cells. 2. Differentiation: HSCs differentiate into two main progenitor cells: myeloid progenitor cells and lymphoid progenitor cells. Myeloid Progenitor Cells: Give rise to granulocytes (neutrophils, eosinophils, basophils) and monocytes. Lymphoid Progenitor Cells: Develops into lymphocytes (B cells, T cells, and natural killer cells). 3. Maturation: The progenitor cells undergo several stages of maturation, influenced by various growth factors and cytokines, until they become fully functional white blood cells. 4. Release: Once mature, these white blood cells are released into the bloodstream to perform their immune functions, such as fighting infections and protecting the body against foreign invaders Comparative Anatomy and Histology. DOI: http://dx.doi.org/10.1016/B978-0-12-802900-8.00019-1  Sites of leukopoiesis Primarily occurs in the BM, but there are several specific sites within the body where different stages of leukocyte development and maturation take place Bone Marrow: Primary site for the production and maturation of most WBCs, including granulocytes (neutrophils, eosinophils, basophils) and monocytes. HSCs in the BM differentiate into various types of leukocytes. Thymus: This gland is crucial for the maturation of T lymphocytes (T cells). Immature T cells, produced in the BM, migrate to the thymus where they undergo further development and selection processes to become functional T cells. Lymph Nodes: These are secondary lymphoid organs where lymphocytes, particularly B cells and T cells, can further mature and proliferate in response to antigens. Lymph nodes also serve as sites for immune responses. Spleen: The spleen acts as a site for the proliferation and maturation of lymphocytes, especially B cells. It also filters the blood and helps in the removal of old or damaged blood cells. Peripheral Blood: Once mature, leukocytes are released into the bloodstream where they circulate and perform their immune functions.  Granulopoiesis Granulopoiesis (or granulocytopoiesis) is the process by which granulocytes are produced in the BM. Granulocytes include neutrophils, eosinophils, and basophils. Overview of stages 1. Myeloid Progenitor Cells: HSCs differentiate into myeloid progenitor cells, which are the precursors to granulocytes. 2. Granulocyte-Macrophage Progenitor Cells (GMPs): Myeloid progenitor cells further differentiate into GMPs, which can give rise to both granulocytes and monocytes. 3. Lineage Commitment: GMPs commit to the granulocyte lineage and differentiate into specific granulocyte precursors: Myeloblasts: The earliest recognizable precursors of granulocytes. Promyelocytes: These cells contain primary granules and are the next stage in development. Myelocytes: At this stage, cells begin to show specific granules characteristic of neutrophils, eosinophils, or basophils. Metamyelocytes: These cells have indented nuclei and further maturation of granules. Band Cells: These are immature granulocytes with a band-shaped nucleus, particularly seen in neutrophil development. 4. Mature Granulocytes: The final stage involves the maturation of band cells into fully functional granulocytes: Neutrophils: The most abundant type of granulocyte, crucial for phagocytosing bacteria and fungi. Eosinophils: Important for combating parasitic infections and involved in allergic reactions. Basophils: Play a role in inflammatory responses and release histamine during allergic reactions. Comparative Anatomy and Histology. DOI: http://dx.doi.org/10.1016/B978-0-12-802900-8.00019-1  Stem cell pool: self-renewal and differentiation Proliferation pool: dividing and maturation. Myeloblasts, promyelocytes, and myelocytes. CMP = common myeloid progenitor; GMP = granulocyte-macrophage progenitor; CSF = colony stimulating factor; Maturation pool: maturation. Metamyelocytes, bands, and segmented neutrophils.  Neutrophil Development Derived from granulocyte-monocyte progenitor in BM GM-CSF, IL-3 and G-CSF are cytokines responsible for growth and differentiation Six stages: myeloblast, promyelocyte, myelocyte, metamyelocyte, band and neutrophil Myeloblast takes 3 to 6 days to develop into myelocyte, another 5 to 7 days in the maturation pool, then release to the peripheral blood Average lifespan 6 to 10 hours in PB; several days once they migrate into tissues Mature neutrophils Storage pool in BM Circulating pool and marginating pool in PB Neutrophil Characteristics (myeloblast to myelocyte)  Neutrophil Characteristics (metamyelocyte to segmented neutrophils)  https://www.frontiersin.org/journals/physiology/articles/10.3389/fphys.2018.00113/full Neutrophil Functions Phagocytosis: Neutrophils are highly effective at engulfing and digesting pathogens such as bacteria and fungi. They recognize, ingest and destroy these invaders through a process called phagocytosis. Degranulation: Neutrophils contain granules filled with enzymes and antimicrobial proteins. When they encounter pathogens, they release these granules to kill and digest the microbes. Formation of Neutrophil Extracellular Traps (NETs): Neutrophils can release web-like structures called NETs, which trap and kill pathogens. NETs are composed of DNA and antimicrobial proteins, providing a physical barrier to contain infections. Chemotaxis: Neutrophils are attracted to sites of infection or inflammation by chemical signals (chemokines). They migrate quickly to these areas to respond to the infection. Inflammatory Response: Neutrophils are among the first responders to infection and injury. They release signaling molecules that help recruit other immune cells to the site, amplifying the inflammatory response. Interaction with Other Immune Cells: Neutrophils interact with other immune cells, such as macrophages and lymphocytes, to coordinate a more effective immune response  Neutrophil Granules Primary granules (azurophilic, non-specific) Promyelocyte Myeloperoxidase (MPO), lysozyme, hydrolases, bacterial permeability-increasing protein (BPI) Secondary granules (specific) Myelocyte and metamyelocyte forms Contain lactoferrin, lysozyme, collagenase Tertiary granules Metamyelocyte and band forms Contain lysozyme, collagenase Secretory granules (secretory vesicles) Band and segmented neutrophils Alkaline phosphatase Myeloblast w/o granules; Myeloblast w/ granules; Promyelocyte; Myelocyte (early); Myelocyte (late); Metamyelocyte; Band neutrophil; Segmented neutrophil  Eosinophil Development Derived from eosinophil-basophil progenitor GM-CSF, IL-3 and IL-5 are cytokines responsible for the growth and differentiation of eosinophils IL-5 is critical for eosinophil growth and survival Eosinophil myelocyte is the first maturation phase that can be identified as eosinophilic under light microscope by Romanowsky staining Average half-life of an eosinophil is around 18 hours in circulation, and 2 to 5 days in tissues  Eosinophil Characteristics (myelocyte to mature eosinophil) https://www.researchgate.net/publication/359092180_Eosinophilic_airway_diseases_basic_science_clinical_manifestations_and_future_challenges/figures?lo=1 Eosinophil Functions Parasitic Infections: Eosinophils are especially effective against parasitic worms (helminths). They release toxic granules containing enzymes and proteins, such as major basic protein (MBP) and eosinophil cationic protein (ECP), which can damage and kill parasites. Allergic Reactions: Eosinophils are involved in the body's response to allergens. They release inflammatory mediators, such as histamine and leukotrienes, which contribute to the symptoms of allergies, like asthma and hay fever. Modulating Inflammation: Eosinophils help regulate inflammation by releasing cytokines and chemokines. These signaling molecules can attract other immune cells to the site of infection or inflammation and modulate the immune response. Tissue Repair: Eosinophils can contribute to tissue repair and remodeling. They release growth factors that promote healing and repair of damaged tissues. Antigen Presentation: Eosinophils can act as antigen-presenting cells (APCs), processing and presenting antigens to T cells, which helps in the activation and regulation of adaptive immune responses. Interaction with Other Immune Cells: Eosinophils interact with other immune cells, such as mast cells, basophils, and T cells, to coordinate a more effective immune response.  Basophil Development Derived from eosinophil-basophil progenitor Requires cytokines IL-3, IL-5, and GM-CSF for development Transforming growth factor-β suppresses eosinophil differentiation and enhances basophil differentiation Basophils and mast cells are morphologic and functional similar Basophils are leukocytes where mature in BM and circulate in blood Mast cells precursors leave BM, use blood as a transit system and mature in tissues Average lifespan of a basophil is around 4 days in circulation Mature Basophil Characteristics  Raap, U., Sumbayev, V.V. & Gibbs, B.F. The role of basophils in allergic inflammation. Allergo J 24, 28–33 (2015). https://doi.org/10.1007/s15007-015-0883-y Basophil Functions Allergic Reactions: Basophils are involved in the body's response to allergens. They release histamine, which is a compound that causes blood vessels to dilate and become more permeable, leading to symptoms like itching, swelling, and redness. Inflammatory Response: Basophils release various inflammatory mediators, such as leukotrienes and cytokines, which help to amplify the inflammatory response. This is important for recruiting other immune cells to the site of infection or injury. Defense Against Parasites: Similar to eosinophils, basophils play a role in defending against parasitic infections. They release toxic granules that can damage and kill parasites. Interaction with Other Immune Cells: Basophils interact with other immune cells, such as mast cells and eosinophils to coordinate a more effective immune response. They can also influence the activity of T cells and B cells. Regulation of Blood Clotting: Basophils release heparin which helps to prevent blood clotting. This is important for maintaining proper blood flow and preventing clots that could block blood vessels. Comparative Anatomy and Histology. DOI: http://dx.doi.org/10.1016/B978-0-12-802900-8.00019-1  Monopoiesis (Monocyte Development) Monopoiesis (or monocytopoiesis) is the process by which monocytes are developed in the BM. Derived from granulocyte-monocyte progenitor GM-CSF, IL-3 and M-CSF are cytokines responsible for the growth and differentiation Three stages: monoblast, promonocyte and monocyte Average lifespan 20 to 40 hours in PB, then goes to tissues for maturation and specific function Marginal and circulating pool in PB, no storage pool of mature monocytes in BM  Monocyte Characteristics (monoblast to mature monocyte)  Planchon, M. S., Fishman, J. A., & El Khoury, J. (2024). Modulation of Monocyte Effector Functions and Gene Expression by Human Cytomegalovirus Infection. Viruses, 16(12), 1809. https://doi.org/10.3390/v16121809 Monocyte Functions Phagocytosis: Monocytes are highly effective at engulfing and digesting pathogens, dead cells and debris. This process helps to clear infections and remove damaged tissue. Differentiation into Macrophages and Dendritic Cells: Once they migrate from the bloodstream into tissues, monocytes can differentiate into macrophages or dendritic cells: Macrophages: These cells are long-lived and reside in tissues, where they continue to phagocytose pathogens and debris. They also play a role in tissue repair and remodeling. Dendritic Cells: These cells are important for antigen presentation. They capture antigens and present them to T cells, initiating and regulating adaptive immune responses. Cytokine Production: Monocytes produce and release various cytokines, which are signaling molecules that help regulate the immune response. These cytokines can attract other immune cells to the site of infection or inflammation and modulate their activity. Inflammatory Response: Monocytes are involved in the inflammatory response. They migrate to sites of infection or injury, where they help to coordinate the immune response by releasing inflammatory mediators and recruiting other immune cells. Antigen Presentation: Monocytes can present antigens to T cells, although this function is more prominent in their differentiated forms (macrophages and dendritic cells). This helps to activate and regulate the adaptive immune response. Comparative Anatomy and Histology. DOI: http://dx.doi.org/10.1016/B978-0-12-802900-8.00019-1  Lymphopoiesis Lymphocyte Development Lymphopoiesis ( or lymphocytopoiesis) is the process by which lymphocytes are developed in BM from common lymphoid progenitor Unique features are able to generate antigenic specificity and immunological memory Participate in adaptive immunity, also assist phagocytes in defense of the body against infection and other foreign invasion Three type of lymphocytes: T , B lymphocytes and natural killer (NK) cells T-and B-lymphocytes participate in adaptive immune response NK-cells are effector cells in innate immunity Two types of adaptive immune response: humoral immunity and cell-mediated immunity Two types of lymphoid organs for development Primary lymphoid organ: BM and thymus Secondary lymphoid organs: spleen, lymph nodes, lymphoid tissues of alimentary and respiratory tracts  Lymphocyte Characteristics 1 (lymphoblast to mature large/small lymphocyte)  Lymphocyte Characteristics 2 (Large lymphocyte and plasma cell) Activation of B Cells There are two main types of large granular lymphocytes: Cytotoxic T cells: These cells target and kill infected or cancerous cells. NK cells: These cells can destroy a wide range of infected or abnormal cells without prior sensitization  Lymphocyte Functions Lymphocytes plays a central role in both adaptive and innate immune response. B Lymphocytes (B Cells): Antibody Production: B cells are responsible for producing antibodies that specifically target and neutralize pathogens such as bacteria and viruses. Memory B Cells: After an infection, some B cells become memory B cells, which remain in the body and provide long-term immunity by quickly responding to future infections by the same pathogen. T Lymphocytes (T Cells): Helper T Cells (CD4+ T Cells): Help activate other immune cells, including B cells and cytotoxic T cells, by releasing signaling molecules called cytokines. Cytotoxic T Cells (CD8+ T Cells): Directly kill infected or cancerous cells by recognizing specific antigens presented on their surface. Regulatory T Cells (Tregs): Help regulate and suppress the immune response to prevent excessive inflammation and autoimmunity. Natural Killer (NK) Cells: Killing Infected and Tumor Cells: NK cells can recognize and kill cells that are infected with viruses or have become cancerous, without the need for prior sensitization to specific antigens. Immune Surveillance: NK cells constantly patrol the body, identifying and eliminating abnormal cells to maintain overall health.  Further reading Hoffbrand AV and Moss PAH. (2016). Hoffbrand’s Essential Hematology, 7thed. Chichester: Wiley-Blackwell. Turgeon ML. (2018). Clinical Hematology: theory & procedures, 6thed. Philadelphia: Wolters Kluwer. Keohane EM, Otto CN, & Walenga JM. (2020). Rodak’s Hematology: Clinical Principles and Applications. 6th Edition. St Louis: Elsevier. Bernadette F Rodak & Jacqueline H Carr. (2017). Clinical Hematology Atlas, 5thedition. St Louis; Elsevier