WBC Function

Overview of Leukocyte Function

Definition: Leukocytes (white blood cells) are essential components of the immune system, responsible for defending the body against infection, inflammation, and other threats
Classification:
- Granulocytes: Neutrophils, eosinophils, and basophils
- Monocytes
- Lymphocytes: T lymphocytes (T cells), B lymphocytes (B cells), and natural killer (NK) cells
General Functions:
- Innate Immunity: Immediate, non-specific defense mechanisms (e.g., phagocytosis, inflammation)
- Adaptive Immunity: Slower, antigen-specific immune responses mediated by lymphocytes

Granulocytes

Neutrophils:
- Function: Primary role in defense against bacterial and fungal infections
- Mechanisms of Action:
  - Phagocytosis: Engulfing and destroying pathogens and debris
  - Degranulation: Releasing antimicrobial substances from granules:
    - Lysozyme: Breaks down bacterial cell walls
    - Myeloperoxidase (MPO): Generates reactive oxygen species (ROS) to kill pathogens
    - Defensins: Antimicrobial peptides
    - Elastase: Degrades bacterial proteins
  - Oxidative Burst: Production of reactive oxygen species (ROS) to kill phagocytosed pathogens:
    - NADPH oxidase: Enzyme responsible for generating superoxide (O2-)
    - Superoxide dismutase (SOD): Converts superoxide to hydrogen peroxide (H2O2)
    - Myeloperoxidase (MPO): Uses H2O2 and chloride ions to produce hypochlorous acid (HOCl, bleach)
  - Neutrophil Extracellular Traps (NETs): Extruding a meshwork of DNA, histones, and antimicrobial proteins to trap and kill bacteria extracellularly
- Chemotaxis: Migration of neutrophils to sites of infection or inflammation in response to chemical signals (chemokines)
- Clinical Significance:
  - Neutrophilia: Increased neutrophils, often seen in bacterial infections, inflammation, or stress
  - Neutropenia: Decreased neutrophils, increasing susceptibility to infections
    - Agranulocytosis: Severe neutropenia (ANC < 200 cells/μL)
Eosinophils:
- Function: Primarily involved in defense against parasitic infections and allergic reactions
- Mechanisms of Action:
  - Degranulation: Releasing substances from granules to kill parasites and modulate allergic responses:
    - Major basic protein (MBP): Toxic to parasites
    - Eosinophil peroxidase (EPO): Generates reactive oxygen species
    - Eosinophil cationic protein (ECP): Toxic to parasites and causes mast cell degranulation
    - Eosinophil-derived neurotoxin (EDN): Involved in nerve damage in some parasitic infections
  - Phagocytosis: Engulfing antigen-antibody complexes and other debris
  - Modulation of Allergic Reactions:
    - Releasing enzymes that degrade mediators released by mast cells and basophils (e.g., histaminase, arylsulfatase)
- Clinical Significance:
  - Eosinophilia: Increased eosinophils, often seen in parasitic infections, allergic reactions, asthma, and certain malignancies
  - Eosinopenia: Decreased eosinophils, can occur in acute infections or corticosteroid use
Basophils:
- Function: Primarily involved in allergic reactions and inflammation
- Mechanisms of Action:
  - Degranulation: Releasing substances from granules that mediate allergic and inflammatory responses:
    - Histamine: Increases vascular permeability and causes smooth muscle contraction
    - Heparin: Anticoagulant
    - Leukotrienes: Promote inflammation and bronchoconstriction
  - IgE Receptors: Basophils express high-affinity IgE receptors, which bind to IgE antibodies
    - Crosslinking of IgE receptors by antigens triggers basophil degranulation
- Clinical Significance:
  - Basophilia: Increased basophils, seen in myeloproliferative neoplasms, allergic reactions, and certain infections
  - Basopenia: Decreased basophils, difficult to detect due to the normally low number of basophils in the blood

Monocytes and Macrophages

Monocytes:
- Function: Circulate in the blood and then migrate into tissues, where they differentiate into macrophages or dendritic cells
- Mechanisms of Action:
  - Phagocytosis: Engulfing pathogens, debris, and dead cells
  - Cytokine Production: Secreting cytokines that regulate inflammation and immune responses (e.g., TNF-α, IL-1, IL-6)
  - Antigen Presentation: Presenting antigens to T lymphocytes to initiate adaptive immune responses
Macrophages:
- Function: Tissue-resident phagocytes that play a critical role in innate and adaptive immunity, tissue remodeling, and wound healing
- Types of Macrophages:
  - Kupffer cells (liver)
  - Alveolar macrophages (lungs)
  - Histiocytes (connective tissue)
  - Microglia (brain)
  - Osteoclasts (bone)
  - Splenic macrophages (spleen)
- Mechanisms of Action:
  - Phagocytosis: Engulfing pathogens, debris, and dead cells
  - Antigen Presentation: Processing and presenting antigens to T lymphocytes
  - Cytokine Production: Secreting cytokines that regulate inflammation and immune responses
- Clinical Significance:
  - Monocytosis: Increased monocytes, seen in chronic infections, inflammation, and certain malignancies
  - Monocytopenia: Decreased monocytes, can occur in severe infections or bone marrow disorders
Differentiation of Macrophages: Macrophages can differentiate into functionally distinct populations:
- M1 Macrophages (classically activated): Promote inflammation and kill pathogens
- M2 Macrophages (alternatively activated): Promote tissue repair and suppress inflammation

Lymphocytes

T Lymphocytes (T Cells):
- Function: Mediate cell-mediated immunity, recognize antigens presented by antigen-presenting cells (APCs)
- Types of T Cells:
  - Helper T Cells (CD4+ T Cells):
    - Recognize antigens presented on MHC class II molecules
    - Secrete cytokines that activate other immune cells (e.g., B cells, cytotoxic T cells, macrophages)
    - Essential for coordinating adaptive immune responses
    - Subsets:
      - Th1 cells: Promote cell-mediated immunity and defense against intracellular pathogens
      - Th2 cells: Promote humoral immunity and defense against extracellular parasites
      - Th17 cells: Involved in inflammation and defense against extracellular bacteria and fungi
      - Treg cells: Suppress immune responses and maintain tolerance
  - Cytotoxic T Cells (CD8+ T Cells):
    - Recognize antigens presented on MHC class I molecules
    - Kill infected or cancerous cells by releasing cytotoxic granules containing perforin and granzymes
- Mechanisms of Action:
  - T Cell Receptor (TCR): Recognizes specific antigens presented on MHC molecules
  - Cytokine Production: Secreting cytokines that regulate immune responses
  - Cytotoxicity: Killing target cells through direct cell-to-cell contact
B Lymphocytes (B Cells):
- Function: Mediate humoral immunity, produce antibodies
- Mechanisms of Action:
  - Antibody Production:
    - B cells recognize antigens via their B cell receptor (BCR), which is a membrane-bound antibody
    - Upon activation, B cells differentiate into plasma cells, which secrete large amounts of antibodies
  - Antibody Functions:
    - Neutralization: Binding to pathogens to prevent them from infecting cells
    - Opsonization: Coating pathogens to enhance phagocytosis
    - Complement Activation: Triggering the classical pathway of complement activation
    - Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): Targeting infected cells for destruction by NK cells or other immune cells
- Memory B Cells:
  - Long-lived B cells that provide long-term immunity
  - Upon re-exposure to an antigen, memory B cells rapidly differentiate into plasma cells and produce antibodies
Natural Killer (NK) Cells:
- Function: Part of the innate immune system, kill infected or cancerous cells without prior sensitization
- Mechanisms of Action:
  - Release of Cytotoxic Granules: Perforin and granzymes
  - Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC): Recognize and kill antibody-coated cells
  - Release of Cytokines: IFN-γ and TNF-α
- Activation and Inhibition: NK cell activity is regulated by a balance of activating and inhibitory receptors
  - Activating receptors: Recognize stress-induced ligands on target cells
  - Inhibitory receptors: Recognize MHC class I molecules on normal cells, preventing NK cell activation

Leukocyte Extravasation

Definition: The process by which leukocytes leave the bloodstream and migrate into tissues to reach sites of infection or inflammation
Steps:
1. Rolling: Leukocytes loosely attach to the endothelium via selectins (on endothelial cells) and their ligands (on leukocytes)
2. Activation: Chemokines activate leukocytes, increasing the affinity of integrins
3. Adhesion: Integrins (on leukocytes) bind tightly to adhesion molecules (ICAMs and VCAMs) on endothelial cells
4. Transmigration (Diapedesis): Leukocytes squeeze between endothelial cells and migrate into the tissues

Regulation of Leukocyte Function

Cytokines:
- Interleukins (ILs): A diverse group of cytokines that regulate leukocyte development, activation, and function
- Interferons (IFNs): Inhibit viral replication and modulate immune responses
- Tumor Necrosis Factor (TNF): Pro-inflammatory cytokine that activates leukocytes
- Chemokines: Attract leukocytes to sites of infection or inflammation
Complement System:
- Complement fragments (e.g., C3a, C5a) attract and activate leukocytes
Lipid Mediators:
- Leukotrienes and prostaglandins: Promote inflammation and leukocyte recruitment
Cell-Cell Interactions:
- Interactions between leukocytes and other cells (e.g., endothelial cells, fibroblasts) regulate leukocyte function

Disorders of Leukocyte Function

Quantitative Disorders:
- Leukopenia: Decreased number of WBCs
- Leukocytosis: Increased number of WBCs
Qualitative Disorders:
- Phagocytic Disorders: Impaired ability of phagocytes (neutrophils and macrophages) to engulf and kill pathogens
  - Chronic granulomatous disease (CGD): Defect in NADPH oxidase, leading to impaired production of reactive oxygen species
  - Chediak-Higashi syndrome: Defect in lysosomal trafficking, leading to impaired phagocytosis and degranulation
- Adhesion Disorders: Impaired ability of leukocytes to adhere to endothelial cells and migrate into tissues
  - Leukocyte adhesion deficiency (LAD): Defects in integrins or selectin ligands
- Other Functional Defects: Impaired chemotaxis, degranulation, or cytokine production

Laboratory Evaluation of Leukocyte Function

Complete Blood Count (CBC) with Differential:
- WBC count: Measures the total number of leukocytes
- Differential count: Determines the percentages and absolute numbers of each type of leukocyte
Peripheral Blood Smear Examination:
- Morphology: Evaluates the morphology of leukocytes (e.g., toxic granulation, Dohle bodies)
Flow Cytometry:
- Immunophenotyping: Identifies cell surface markers and classifies leukocytes
- Functional assays: Measures leukocyte activation, proliferation, and cytokine production
Functional Assays:
- Neutrophil oxidative burst assay: Measures the production of reactive oxygen species
- Chemotaxis assay: Measures the ability of leukocytes to migrate in response to chemical gradients
- Phagocytosis assay: Measures the ability of leukocytes to engulf particles
- Adhesion assay: Measures the ability of leukocytes to adhere to endothelial cells
Genetic Testing:
- Identifies mutations in genes associated with inherited leukocyte disorders

Key Terms

Leukocytes: White blood cells
Neutrophil: Most abundant WBC, involved in bacterial and fungal infections
Eosinophil: WBC involved in parasitic infections and allergic reactions
Basophil: WBC involved in allergic reactions and inflammation
Monocyte: WBC that differentiates into macrophages
Macrophage: Tissue-resident phagocyte
Lymphocyte: T cell, B cell, and NK cell
Phagocytosis: Engulfment and destruction of particles
Chemotaxis: Migration of cells in response to chemical signals
Cytokines: Signaling molecules that regulate immune responses
Extravasation: Migration of leukocytes from the bloodstream into tissues
Innate Immunity: Immediate, non-specific defense mechanisms
Adaptive Immunity: Slower, antigen-specific immune responses

WBC Production

WBC Destruction