INTRODUCTION

• White blood cells, also called leukocytes or leucocytes are the cells of the immune system that are involved in protecting the body against both infectious diseases and foreign invaders
• They make up approximately 1% of the total blood volume in a healthy adult, making them substantially less numerous than the red blood cells

Location

• Leukocytes are found throughout the body, including;
  • The blood; and
  • Lymphatic system Production
• All white blood cells are produced and derived from multipotent cells in the bone marrow known as haematopoietic stem cells
• Their development along different lineages is governed by external stimuli including cytokines, matrix proteins and other cellular products within the marrow environment
• The combination of specific cytokines and growth factors influence the maturation of WBC progeny along specific lineage Functions
• They have fundamental roles in defense against invading microorganisms and the recognition and destruction of neoplastic cells
• As well as critical roles in the acute inflammation
• Through their phagocytic functions, especially Neutrophils and monocytes, they are important in clearing senescent and apoptotic cells
• Hence, allowing tissue repair and remodeling

Blood Cells

CLASSIFICATION

• The leukocytes are basically divided into 2 broad groups
  • Phagocytes
  • Immunocytes

Phagocytes

• The phagocytes comprise the cells of the innate immune system which can act very quickly after an infection
• The phagocytes are further classified as;
  • Polymorphonuclear phagocytes – characterized by multilobed nucleus

 Neutrophils

 Eosinophils

 Basophils

• Mononuclear phagocytes Monocytes

 Macrophages

Immunocytes

• The immunocytes (lymphocytes) mediate the adaptive immune response which can develop immunological memory (e.g. after vaccination)
• They are;
  • Lymphocytes T-Lymphocytes

 B-Lymphocytes

• Plasma cells

CHARACTERISTICS OF PHAGOCYTES

Functions

• The phagocytes specialize in the destruction of foreign matters and thus have a fundamental role in the body’s defense against invasion by micro-organisms
• They also recognize and destroy tumor cells
• They ingest apoptotic cells, thereby aiding organ remodeling and tissue repair
• The phagocytic cells of all types modulate both cellular and humoral immunity through the synthesis and release of immuno-regulatory proteins and cytokines
• They have a major role in allergy and inflammatory processes Migration
• The phagocytes are produced in the bone marrow from a common haemopoietic stem cell
• Following maturation and storage in the marrow they are released to the circulation
• They exist in the blood in a relatively quiescent state and marginate to the endothelium before moving to the tissues
• During infection, they are rapidly recruited to specific sites and are activated to ingest and kill invading pathogens

Production, Lifespan & Elimination

• The development and activity of phagocytes are normally tightly regulated at all stages by a series of;
  • Chemostatic factors
  • Cytokines and
  • Growth factors such as IL-1, IL-3, IL-5, IL-6, IL-11, GM-CSF, G-CSF, M-CSF
• Inappropriate stimulation and failure of regulation however, leads to destruction of host tissue during inflammatory diseases
• At the end of their lifespan, phagocytes undergo an ageing process with surface changes resulting in recognition and removal by macrophages
• Cytokines can prolong the life of phagocytes by blocking this process
• The blood granulocytes and monocytes are formed in the bone marrow from common progenitor cells
• From the progenitor cells, it moves to the next stage
  • Myeloblast, promyelocyte and myelocytes from a proliferative or mitotic pool
  • While the metamyelocytes, band and segmented granulocytes, make up the post mitotic maturation compartment

Duration

• The development occurs over 14 days in the marrow where only the matured cells are released into the peripheral blood
• The differentiation stage between myeloblast and the myelocyte takes 7-8 days and is accompanied by cell division
• Thereafter, myelocyte matures to metamyelocyte, the band form and the segmented neutrophils
• This process takes 6-7 days and occur without cell division

Lifespan

• Large numbers of band and segmented neutrophils are held in the marrow as a ‘reserve pool’ or storage compartment
  • Lifespan in the marrow – 4-5 days
• Following their release, they spend few hours in the circulation before moving into the tissues where they perform their phagocytic functions
  • Lifespan in the circulation – 6-10 hours Granulocyte Populations
• 2 populations exist in circulation
  • The circulating; and
  • Marginal pools
• They are found in the blood and tissues and constitutes about 65% of circulating leukocytes in man

NEUTROPHILS (POLYMORPHS)

• Neutrophils are commonly referred to as polymorphonuclear (PMN) leukocytes
• They are the most abundant white blood cells, constituting 60-70% of the circulating leukocytes
• They include 2 functionally unequal subpopulations;
  • Neutrophil-killers and
  • Neutrophil-cagers

Morphology

• This cell has a dense nucleus consisting of 2-5 lobes
• And a pale cytoplasm with an irregular outline with many fine pink-blue (Azurophilic) granules
• The granules are divided into primary and secondary;
  • Primary – appears at promyelocytic stage and contains;

 Myeloperoxidase; and

 Other acid hydrolases

• Secondary – appears at myelocyte stage and predominantly in the mature neutrophil and contains;

 Lactoferrin

 Lysozyme; and

 Other enzymes

• Both the granules are lysosomal in origin Lifespan
• The lifespan of Neutrophils in the blood is only 6-10 hours

Development

• Neutrophils precursors do not usually appear in normal peripheral blood but are present in the marrow
• They are;
  • Myeloblast
  • Promyelocyte
  • Myelocyte
  • Metamyelocyte
  • Band form

Myeloblast

• The earliest recognizable precursor of neutrophil. A large cell with variable sizes
• It has a large nucleus and 2-5 pale-blue nucleoli and a fine chromatin meshwork with scanty basophilic cytoplasm
• There are no granules at this stage
• The bone marrow contains up to 5% of myeloblast
• The myeloblast give rise to the next cell

Promyelocyte

• A large cell, bigger than the myeloblast
• With centrally located nucleolus in the nucleus
• And reddish-purple primary cytoplasmic granules
• It gives rise to↓

Myelocyte

• A cell with more abundant basophilic cytoplasm
• Nuclear chromatin is more aggregated and there are no nucleoli
• Secondary granules start at this stage
• It matures to the next stage

Metamyelocyte

• Has indented or horse-shoe nucleus
• And cytoplasm filled with primary and secondary granules

Band form

• Stab or juvenile
• It may occur in normal peripheral blood

Segmented

• Contain 2-5 lobes nucleus and fine violet-pink cytoplasmic granules Granules of the Polymorphs
• There are 5 different types of granules
  • Primary (Azurophilic) granules – contain;

 Myeloperoxidase

 Elastase

 Lysozyme

• Specific granules – contain; Collagenase
• Tertiary granules – contain; Gelatinase
• Microperoxisomes – contain; Catalase
• Organelles – contain;

 Alkaline phosphatase

Bone Marrow Nucleated Cells Composition

• Myeloblast                                                 1-4%
• Promyelocyte                                     5%
• Myelocyte                                                 12%
• Metamyelocyte                                     22%  Mature neutrophil                                            20%

Functions

• They are usually first responders to microbial infection
• They defend against bacterial or fungal infections due to their ability to ingest and kill microorganisms
• These cells are not able to renew their lysosomes (used in digesting microbes) and die after having phagocytozed a few pathogens and are found in large amount in pus
• They synthesize cytokines in response to stimulation and immunomodulation

EOSINOPHILS

• Constitute a minor species of granulocytes, comprising 1-4% of total white cells (0.04-

0.44 × 10⁹/L)

• This count fluctuates throughout the day, seasonally and during menstruation  It rises in response to;
  • Allergies
  • Parasitic infections
  • Collagen diseases and
  • Disease of the spleen and central nervous system
• They are rare in the blood, but numerous in the mucous membranes of the respiratory, digestive, lower urinary tracts and skin

Morphology

• Mature eosinophils have 2-3 lobes, and numerous coarse brownish-red granules and slightly bigger than neutrophils

Lifespan

• Blood transit time 3-8 hours

Development

• This is regulated by IL-5 and follows the neutrophil pattern Granules of the Eosinophils
• Mature eosinophils have 3 types of granules; ü Primary granules – contain;

 Eosinophil peroxidase and

 Charcot-Leyden crystal protein

• Secondary granules – contain;

 Most basic proteins – cytotoxic to mammalian cells and parasites through membrane damage

• Eosinophil cationic protein and eosinophil derived neurotoxin^[1] Function

• They enter inflammatory exudates and have a special role in;
  • Allergic responses
  • Defense against parasites and
  • Removal of fibrin formed during inflammation
• Eosinophils have less phagocytic and bactericidal activity, but have an important role in mediating hypersensitivity reactions such as;
  • Bronchial asthma and
  • Skin inflammation
• It secretes cytokines like IL-1, IL-3, IL-6, IL-8 and TNF-β
• Proteins released from eosinophils also induce histamine release from basophils and mast cells thus, amplifying the inflammatory response
• Eosinophil granular proteins are also toxic to bacteria and multicellular parasites
• It has a role in wound healing and tissue remodeling by modulating the deposition of extracellular matrix proteins
• The gelatinase secreted by eosinophil may mediate metastasis of tumors by degrading extracellular matrix proteins

BASOPHILS AND MAST CELLS

• Basophils comprise 0.2-1% of circulating leukocytes (NR^[2] – 0.01-0.1 × 10/L)
• And about 0.3% nucleated cells in the marrow
• Mast cells are predominantly located in the tissue
• There are 2 types of mast cells
  • Connective tissue mast cells – found on;

 The skin

 Intestinal mucosa

• Mucosal mast cells – residing in;

 Intestinal mucosa

 Lung alveoli

Morphology

• Mature basophils are multilobed with dark cytoplasmic granules which overlie the nucleus and contain heparin and histamine Functions
• Primary effector in allergic reactions - basophils are chiefly responsible for allergic and antigenic response by releasing the chemical histamine, causing the dilation of blood vessels
• Hypersensitivity reactions
• Chemotactic for neutrophils

MONOCYTES AND MACROPHAGES

• About 5% of leukocytes in the circulation 0.2-0.8 × 10⁹/L

Morphology

• They are larger than other peripheral blood leukocytes
• And possess a large central oval or indented nucleus with clumped chromatin  The cytoplasm is abundant and greyish-blue containing granules Lifespan
• Half-life in circulation is 17 hours
• Their extravascular lifespan after their transformation to macrophages may be as long as several months or even years

Development

• The precursors are monoblasts and promonocytes
• They migrate to the tissues at a fairly constant rate and become macrophages or dendritic cells
• In the tissue, they self replicate without replenishment from blood
• GM-CSF and M-CSF are involved in their production and activation
• They are called different names in various tissues;
  • Kidney                                     Kidney intraglomerular mesangial cells
  • Brain                                     Microglia
  • Lung                                       Alveolar macrophages
  • Liver                                       Kupffer cells
  • Spleen                                                Sinus macrophages
  • Bone marrow                         Macrophages ü Lymph node                                      Macrophages

Functions

• They have role in the control of both primary and secondary immune response
• They;
  • Scavenge debris
  • Aid wound healing
  • Sequester and detoxify injurious materials
  • Remove senescent or dying cells
• They are active in bone resorption and remodeling
• They can mediate the killing of tumor cells by antibody-dependent and independent mechanisms, as well as destroy pathogens

[1] Yh! That’s the 3^rd granules “in the material”. Ugh!

[2] Normal Range