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Foundations of Disease > Exam 1: Leukocytes > Flashcards

Exam 1: Leukocytes Flashcards

1
Q

Leukocyte

Types

A
  • Granulocytes
    • Neutrophils
    • Eosinophils
    • Basophils
  • Agranulocytes (“Mononuclear leukocytes”)
    • Lymphocytes
    • Monocytes
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2
Q

All leukocytes contain…

A

azurophilic granules

  • “Primary granules”
    • Produced first during differentiation
  • Specialized lysosomes
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3
Q

Only granulocytes contain…

A

specific granules

  • “Secondary granules”
    • Produced later during differentiation
  • Non-lysosomal secretory vacuoles
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4
Q

Granulocyte

Morphology

A

3 types of granulocytes

Distinguished by LM based on:

  1. Nuclear lobulation ⇒ neutrophil > eosinophil > basophil
  2. Size and staining affinity of specific granules
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5
Q

Neutrophil

Morphology

A
  • Nucleus ⇒ 2-5 lobes connected by thin strands
    • # and shape of lobes ∆ over time
    • Inactivated X chromosome forms a drumstick appendage visible in some nuclei
    • > 5 lobes ⇒ hypersegmented
  • Small, poorly staining specific granules
    • Cytoplasm with “pebbly” appearance
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6
Q

Neutrophil azurophilic granules contain…

A

myeloperoxidase

(Used for detection during automated flow cytometry)

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7
Q

Neutrophil

Functions

A
  • Highly phagocytic
    • Especially good at killing bacteria
  • First leukocyte to arrive at site of acute infection or inflammation
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8
Q

Neutrophil

Recognition

A

Membrane receptors bind to material to be phagocytized ⇒ enhances specificity and rate of phagocytosis

  • Some receptors bind directly to target e.g. bacteria
    • Toll-like receptors (TLRs) or “Pattern recognition receptors (PRRs)
      • Binds to highly conserved molecular sequences common to many pathogens and endotoxins ⇒ Pathogen-associated molecular patterns (PAMPs)
  • Some receptors bind indirectly to target via opsonins
    • Only recognizes bound form of opsonin
    • Ex: Neutrophil Fc receptors for IgG
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9
Q

Neutrophil

Effector Mechanisms

A

Neutrophils kill via:

  1. Respiratory burst
  2. Mediators stored in azurophilic and specific granules
  3. Neutrophil extracellular traps (NETs)
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10
Q

Respiratory Burst

A

A measurable increase in oxygen consumption triggered by phagocytosis.

  • Enzyme cascades produce ROI/ROS that are antimicrobial
  • Kill by oxidizing microbial macromolecules
  • First step catalyzed by NADPH oxidase
    • Inactive subunits found on plasma membrane and in cytosol
    • Activation forms membrane-bound multimeric enzyme
      • Also found on phagosome membranes
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11
Q

Neutrophil

ROIs

A
  • Superoxide anion radical (O2·-)
    • Made by NADPH oxidase
  • Hydroxyl radical (OH·)
  • Hydrogen peroxide (H2O2)
  • Hypochlorous acid (HOCl)
    • Made from H2O2 by myeloperoxidase in azurophilic granules
    • Dissociates to form hypochlorite (OCl-)
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12
Q

Neutrophil

Azurophilic Granule Content

A
  1. Myeloperoxidase
    • H2O2 → Hypochlorous acid
  2. Bactericidal permeability-increasing protein (BPI)
    • Damages cell membrane of gram-negative bacteria
  3. Lysozyme
    • Attacks cell walls of bacteria, esp. gram-positive
  4. Defensins
    • Small cationic proteins that permeabilize bacterial membranes
  5. Neutrophil elastase
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13
Q

Neutrophil

Specific Granule Content

A
  1. Lysozyme
    • Attack bacterial cell walls
  2. Lactoferrin
    • Competes for iron and copper ⇒ bacteriostatic
  3. Collagenase
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14
Q

Neutrophil Extracellular Traps

(NETs)

A

Extracellular webs composed of nuclear/mitochondrial DNA bound by histones and granule proteins.

  • Released from activated neutrophils
  • Traps microbes ⇒ killed by high local concentration of granule contents
  • Helps prevent microbial spread
  • In sepsis, can form within blood vessels causing problems
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15
Q

Neutrophil

Damage

A
  • Mediator release into extracellular space can damage healthy tissue
    • Ex. elastase and collagenase
  • Release can occur during NET formation or phagocytosis
    • With phagocytosis, due to premature fusion of granules with phagosome
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16
Q

Activated neutrophils due by ___ forming the major component of ___ which is removed by ___.

A

apoptosis

pus

macrophages

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17
Q

Acute Inflammation

Clinical Indicators

A

Largely due to neutrophils:

  1. Leukocytosis
    • ↑ number of leukocytes in the blood
    • Due to increased number of neutrophils leaving bone marrow in response to inflammatory mediators
  2. Left shift
    • Neutrophil age distribution shifts towards less mature forms
    • Occurs when reserve of mature neutrophils in bone marrow exhausted
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18
Q

Acute Inflammation

Course

A
  • Edema
    • Occurs within a few hours
    • Due to increased vessel permeability by histamine and other mediators
  • Early phase
    • Neutrophils peak at ~ day 1 ⇒ “first wave”
      • Secrete chemotactic factors that attract monocytes
  • Late stage
    • Monocytes peak within ~ 2 days ⇒ “second wave”
    • Differentiate into macrophages
      • Phagocytize dead neutrophils, damaged tissue, and debris
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19
Q

Eosinophil

Morphology

A
  • 2-3 lobed heterochromatic nucleus
  • Large and eosinophilic specific granules
    • 30+ mediators
    • Cationic protins most abundant ⇒ important in parasitic infections
      • Ex. Major basic protein
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20
Q

Eosinophil

Functions

A
  1. Kill larvae of certain parasitic worms (helminths)
    • Binds to surface of larva and secrete damaging substances
      • Major basic protein
      • ROS from respiratory burst
  2. Phagocytize Ag-Ab complexes
  3. Modulate activity of basophils and mast cells
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21
Q

Eosinophil

Damage

A

Activity can damage host tissues:

  • Asthma exacerbation
    • Damages respiratory tract
      • Stimulates excess mucus production
      • Kills ciliated cells
      • Induces lung remodeling
        • ↑ CT and SM in airways
        • Stiffens airways and makes them hypercontractible
  • Atopic dermatitis
22
Q

Basophil

Morphology

A
  • Nucleus ⇒ usually 2 poorly defined lobes
  • Large basophilic specific granules
    • Often obscures nucleus
    • Appears homogenous or grainy
    • Can look like membrane arranged in stacks or whorls ⇒ myelin figures
23
Q

Basophil

Activation

A

IgE cross-linking:

  • IgE made following Ag exposure
  • Binds to high affinity IgE receptors on basophils ⇒ “primed”
  • Subsequent Ag exposure ⇒ Ag binds IgE on primed basophil ⇒ IgE molecules cross-linked by Ag ⇒ activation
24
Q

Basophil activation leads to…

A
  1. Degranulation ⇒ mediators released from specific granules
    • Histamine
    • Heparan sulfate
    • Eosinophil chemotactic factor (ECF)
    • Neutrophil chemotactic factor (NCF)
  2. Synthesis and secretion of cytokines
    • IL-4
    • IL-13
  3. Arachidonic acid pathway activation by phospholiases
25
Q

Basophil

Functions

A
  • Basophils & mast cells regulate blood vessels
  • More common in extravascular CT than blood
  • Important in defense against ectoparasites (e.g. ticks)
  • Mediator functions:
    1. Vasodilation & ↑ vessel permeability
      • Post-capillary venules > capillaries
      • Promotes diapedesis and Ab/complement extravascularization
    2. ↑ mucus secretion
      • Helps trap Ag
    3. Bronchoconstriction
      • ↑ airflow velocity easing transport of particles trapped in mucus
    4. Class switching ⇒ ↑ IgE production
    5. Chemotaxis of eosinophils, neutrophils, monocytes, and macrophages
    6. Pruritis
26
Q

Basophil

Damage

A

Excessive basophil/mast cell activation results in:

  • Edema
  • Excessive mucus secretion
    • Clogs bronchiolar lumens
    • Causes nasal congestion
  • Excessive bronchoconstriction
27
Q

Excessive basophil or mast cell activity can result in a…

A

Type I hypersensitivity

(Immediate hypersensitivity)

Which can manifest as:

  • Hay fever
  • Asthma
  • Urticaria
  • Anaphylaxis
28
Q

Basophils arise from a ___ when stimulated by ___ and mature in the ___.

A

myeloid progenitor

IL-4

bone marrow

29
Q

Monocyte

Morphology

A

Size and morphology highly variable:

  • Irregularly shaped nucleus
    • U or horsehoe shaped
    • Folded on itself
    • Flower petal pattern
    • Not lobulated
  • Lacy “moth-eaten” chromatin
    • Sharp boundary between euchromatin & heterochromatin
  • Nucleus and cytoplasm pale staining
  • Few azurophilic granules
  • No specific granules
  • Well-developed golgi
    • Can make azurophilic granules throughout lifespan
30
Q

Monocyte

Differentiation

A
  • Circulates in blood for up to several days before entering extravascular tissues
  • In tissues, differentiates into macrophages
  • Macrophages can be long-lived (several months)
31
Q

Resident Macrophage

Classifications

A

Macrophages in certain tissues/organs have characteristic morphology, functions, and names:

  • Histiocytes (“Ordinary” macrophages) ⇒ CT
  • Kupffer cells ⇒ liver
  • Osteoclasts ⇒ bone
  • Alveolar macrophages (“dust cells”) ⇒ lung
32
Q

Macrophage

Morphology

A
  • Larger and more irregularly shaped
  • Pale with euchromatic nucleus by LM
  • Evidence of phagocytic activity by EM
    • More phagosomes
    • More secondary lysosomes
    • Highly active plasma membrane
      • Many thin ‘pseudopods’ on cell surface
33
Q

Macrophage

Activation

A
  • Interferon-gamma is an important activator
  • Activation enhances activity and changes morphology
34
Q

Macrophage

Functions

A
  1. Phagocytosis
    • Has specialized applications that neutrophils are not good for
      • Apoptotic bodies, tissue debris, nuclei from RBCs in bone marrow, old RBCs in spleen
  2. Antigen-presenting cells (APCs)
    • Activates T helper cells
  3. Secretes products involved in many processes
  4. Walling off large particles or microorganisms
35
Q

Macrophage

Secretions

A

Secretes products involved in:

  • Inflammation ⇒ IL-1 & IL-6
  • Fever ⇒ IL-1 is a pyrogen
  • Hematopoiesis ⇒ GM-CSF
  • Wound healing ⇒ TGF-α (stimulates fibroblasts)
  • Normal turnover of ECM ⇒ proteases like elastase & collagenase
36
Q

Macrophage

Containment

A

Walls off large particles or microorganisms:

  • Occurs in chronic inflammation if macrophages unable to eliminate foreign material
  • Enlarge and congregate in groups to form histiocyte epithelioid cells
  • Fuse to form multinucleated giant cells
37
Q

Lymphocyte

Overview

A
  • Major cell type of the immune system
  • At least 3 functionally different types:
    • B cells
    • T cells
    • NK cells
  • All arise from pluripotent hematopoietic stem cells in bone marrow
  • T & B cells indistinguishable by LM/EM
  • NK cells w/ distinctive morphology
38
Q

T-cell & B-cell

Overview

A
  • Size varies based on activation state
    • Inactive ⇒ small lymphocyte
    • Active ⇒ large lymphocyte
  • Activation ⇒ blast transformation ⇒ clonal expansion
  • Daughter cells mature into either:
    • Effector cells ⇒ participate in ongoing immune response
    • Memory cells ⇒ reserved until a subsequent immune response
39
Q

Small Lymphocyte

Morphology

A
  • ~90% of lymphocytes in blood
    • ~ 60-80% of blood lymphocytes are T-cells
  • Nucleus ⇒ round/kidney bean shaped and heterochromatic
  • Very thin rim of basophilic cytoplasm ⇒ ‘sky-blue’ color
  • Few small azurophilic granules by LM
  • No specific granules by LM or EM
  • Few organelles
40
Q

Large Lymphocyte

Morphology

A

“Immunoblasts or Lymphoblasts”

  • Develop from small lymphocytes that undergo blast transformation
  • Up to 30 microns
  • Nucleus ⇒ euchromatic w/ ‘smudged’ chromatin pattern
  • Amount of cytoplasm increases
  • Few small azurophilic granules
41
Q

Humoral Immunity

A

Immunity that can be transferred passively from an immune donor to a non-immune recipient using serum alone.

(Live cells are not required)

42
Q

B-Cells

A
  • Important in humoral immunity ⇒ Ab-mediated
  • Specific for a particular Ag
    • Ag binds BCR ⇒ activation ⇒ blast transformation ⇒ clonal expansion & affinity maturation
43
Q

Plasma Cells

A

Effector cells derived from activated B-cells.

  • Secrete Ab
  • Short-lived ⇒ 10-30 days
  • Old plasma cells may become Russell body cells
    • Contain large, distended RER cisternae ⇒ Russel bodies
      • Full of Ab and stain very eosinophilic
44
Q

Cell-Mediated Immunity

A

Immunity that can only be transferred from an immune donor to a non-immune recipient via live T-cells.

  • Live cells required because:
    • Living T-cell has to directly carry out some function
    • T-cell needed to produce constant supply of short-lived mediators
  • Important in defense against viral and fungal infections and tumor cells
45
Q

T-Cells

A
  • Essential for cell-mediated immunity
  • Specific for a particular Ag
    • Ag binds TCR ⇒ activation
  • Many different types including:
    • Cytotoxic T-cells
    • Helper T-cells
    • Regulatory (suppressor) T cells
46
Q

Cytotoxic T-cells

A
  • CD8+ surface marker
  • Kill target cells that express ‘foreign’ Ag
    • Virus infected cells
    • Tumor cells
    • Genetically different cells e.g. tissue grafts
  • Killing requires binding of T-cell to target cell
  • Kills via several mechanisms including secretion of:
    • Perforins
    • Granzymes
47
Q

Perforins

A

Proteins that aggregate to form pores in target cell membranes.

48
Q

Granzymes

A

“Fragmentins”

Proteases that enter target cells through pores and induce apoptosis.

49
Q

Helper T-Cells

A

“TH cells”

  • CD4+ surface marker
  • TCR recognizes Ag bound to MHC II of antigen-presenting cells
  • Main function to secrete cytokines
    • Helps activate cytotoxic T cells ⇒ stimulates cell-mediated immunity
    • Helps active B cells ⇒ stimulates humoral immunity
50
Q

Regulatory T-cells

A

“Suppressor T-cells”

  • Diverse group
  • Downregulates immune responses
    • Maintains tolerance to self
    • Helps prevent autoimmune diseases
51
Q

NK Cells

A
  • ~5-10% of lymphocytes in blood
  • ~ 15 microns
  • Moderate number of large azurophilic granules by LM
  • Able to kill some virus-infected cells and some tumor cells
    • Requires close contact to targets
    • Several mechanisms
      • Perforins
      • Granzymes

Foundations of Disease (46 decks)

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