Section 2: White Blood Cells – Types and Roles

Hematopoiesis:  Formation of Blood Cells

Hematopoiesis is the formation of blood cells.  Production begins at day 7 of the embryonic life in the yolk sac, migrates to the liver and spleen at week 7, and moves to the bone marrow at ~week 20.  The pluripotent stem cells giving rise to all blood cell types are called hemocytoblasts.  Their daughter cells differentiate into erythrocytes (RBCs), megakaryocytes (platelet precursors), and leukocytes (WBCs).

Red Blood Cells (Erythrocytes) 

Erythropoiesis is the production of RBCs.  Developing erythroblasts become increasingly packed with hemoglobin.  At the normoblast stage, they lose their nucleus, become reticulocytes, enter the bloodstream 2-3 days later and mature into erythrocytes over the following 2 days.  Main function:  use hemoglobin to transport 98.5% of the oxygen and ~23% of the carbon dioxide in blood.  Lifespan ~120 days; aged cells are recycled by macrophages in the liver, bone marrow, and spleen.

Erythropoiesis is regulated by erythropoietin (EPO) hormone, secreted by the kidneys in response to low blood-oxygen levels, growth hormone (GH), thyroxine, and testosterone.  In an adult, 2-3 million RBCs are produced per second and RBC production requires B vitamins, folate, amino acids and iron.

Platelets (Thrombocytes) 

Megakaryocytes fragment into ~1,000 anuclear platelets (thrombocytes).  Despite lacking a nucleus, platelet contain ~300 chemicals involved in hemostasis (blood clotting) and are essential for innate defense and preventing excessive bleeding.

White Blood Cell Lineages 

WBCs are classified as either granulocytes (containing large granules, readily visible with light microscope); also called polymorphonuclear leukocytes (PMNs) or agranulocytes (containing smaller granules).  Granulocytes include: neutrophils, eosinophils, mast cells, and basophils.  Agranulocytes include: monocytes, macrophages, dendritic cells, Natural Killer lymphocytes (NK cells), T lymphocytes (T cells), and B lymphocytes (B cells).  All WBCs perform amoeboid movement and diapedesis (emigration from blood vessels into tissue – also termed extravasation or transmigration.

Granulocytes (Polymorphonuclear Leukocytes, PMNs)

*ROS = Reactive Oxygen Species, such as superoxide, O₂^•− and hydroxyl radical HO^• are free radicals with unpaired electrons that damage DNA, lipids and proteins.

Agranulocytes: Monocytes, Macrophages, and Dendritic Cells

Monocytes are immature macrophages that mature within 1-3 days into fixed macrophages, free macrophages, or dendritic cells.  Despite being immature, monocytes can phagocytose bacteria, secrete cytokines, and act as Antigen Presenting Cells (APCs).

Agranulocytes play important roles in phagocytosing bacteria, as well as secreting cytokines (glycoprotein messengers) to induce inflammation and recruit immune cells to the infected or damaged area.  Additionally they release growth factors to promote tissue repair.

Steps of Phagocytosis

Phagocytes (neutrophils, monocytes, macrophages, dendritic cells, eosinophils) remove cellular debris and are able to provide non-specific defence by destroying pathogens through seven ordered steps:

• Activation:  Pro-inflammatory cytokines activate the phagocyte, enabling pathogen recognition and production of antimicrobial ROS.
• Chemotaxis:  Activated phagocytes follow chemokine gradients to the site of infection or injury.
• Recognition and Adherence:  Opsonins (antibodies, lectin, complement proteins) coating the pathogen facilitate phagocyte binding when direct adherence is blocked (e.g., by a bacterial slime capsule).
• Ingestion:  The phagocyte extends pseudopods that encircle the pathogen, forming an internal vesicle called a phagosome.  
• Killing and Recycling:  The phagosome fuses with a lysosome → phagolysosome.  Lytic enzymes kill the pathogen and digest its components for recycling, display, or expulsion.
• Antigen Display:  Pathogen antigens are coupled to MHC (Major Histocompatibility Complex) molecules and displayed on the phagocyte’s surface to activate T and B cells.
• Expulsion:  Undigested components are expelled from the cell as waste via exocytosis.

Agranulocytes: Natural Killer (NK) Cells

Natural Killer (NK ) cells are lymphocytes providing non-specific defense.  NK lymphocytes are cytotoxic (able to kill other cells) and make up 5-20% of lymphocytes.  NK cells recognize and destroy damaged, abnormal, cancerous, virally-or bacterially-infected cells, and extracellular pathogens.

NK cells contain granules of perforin (pore-forming proteins) and granzymes (proteases) that are degranulated near a target cell.  Perforin creates portals in the target membrane that if released in high concentration without granzyme can cause a cell to leak in fluid and lyse; though often granzyme are released at the same time and quickly enter the pores and induce apoptosis.  Crucially, NK cells prefer inducing apoptosis in virally-infected cells rather than lysing them – preventing newly formed virions from escaping into surrounding tissue.

NK cells also release alpha-defensins (damaging bacterial cell walls, fungi, and enveloped viruses) and pro-inflammatory cytokines to activate other WBCs.  Together with macrophages, NK cells recycle senescent cells (cells that have stopped replicating and are at risk of DNA damage due to age).