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IMS: Microanatomy > Blood > Flashcards

Blood Flashcards

1
Q

Blood

Composition

A
  • Cells
    • Erythrocytes (RBC) - most abundant
    • Leukocytes (WBC) - most diverse
    • Thrombocytes (platelets)
  • All cells derived from a pluripotent hematopoietic stem cell in the bone marrow via hematopoiesis
  • Cells suspended in a liquid extracellular matrix = plasma
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2
Q

Leukocyte

Cell Distribution

A
  • Neutrophils most abundant WBC in adults
  • Lymphocytes most abundant WBC in children
  • -cytosis or -philia = too many cells
  • -penia = too few cells
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3
Q

Causes of leukocytosis

A
  • Neutrophilia - bacterial infection
  • Lymphocytosis - infectious mononucleosis, chronic lymphocytic leukemia
  • Eosinophila - parasitic infections, asthma, allergic reactions
  • Monocytosis - tuberculosis, malaria, monocytic leukemia
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4
Q

Causes of Leukopenia

A
  • Lymphocytopenia: aids
  • Thrombocytopenia: drug toxicity
  • Erythropenia: some anemias
  • Pancytopenia: chemotherapy, radiation therapy, bone marrow failure
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5
Q

Hematocrit

A

The percentage of blood volume occupied by packed RBC’s after centrifugation under standard conditions.

RBC’s heaviest so settles to the bottom.

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6
Q

Factors Affecting Hematocrit

A
  1. Sex
    • F < M
  2. Age
    • Children < Adult < Infant
  3. Exercise
    • Increases with regular exercise
  4. Altitude
    • More RBC’s because air is thinner
  5. Pregnancy
    • Retained water in later stages of pregnancy = lower hematocrit
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7
Q

Polycythemia Vera

A
  • Increased RBC’s
  • Hematocrit up to 70-80%
  • Blood is too viscous
  • Treated with therapeutic phlebotomy
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8
Q

Buffy Coat

A

Thin layer containing leukocytes and platelets that lies just above the RBCs after centrifugation.

~ 1% of blood volume

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9
Q

Plasma

vs

Serum

A

Plasma = the liquid phase of unclotted blood

Serum = the liquid phase that remains after blood is allowed to clot

Serum = plasma minus clotting factors

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10
Q

Blood

Functions

A
  1. Transport
    • Blood gases (O2 and CO2)
    • Absorbed nutriends
    • Metabolic wastes
    • Hormones
  2. Protective functions
    • Platelets to repair damaged vessels and mediate coagulation
    • WBCs, antibodies, complement proteins, interleukins, etc for immune & inflammatory reactions
  3. Regulation of body temperature by distribution of heat
  4. Regulation of ion balance & acid-base balance
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11
Q

Romanovsky Stains

A

Mixtures of dyes used to stain blood smears.

  • Methylene blue: stains nuclei, ribosomes, and basophil specific granules purple
  • Azure dyes: stains aurophilic granules (lysosomes) of leukocytes reddish purple
  • Eosin: stains RBCs salmon pink & specific granules of eosinophils red
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12
Q

Erythrocytes

Structure & Function

A
  • Transports respiratory gases (O2 and CO2) bound to seperate parts of the hemoglobin molecule
  • Biconcave disc = increased surface area to volume
  • No nucleus or cytoplasmic organelles
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13
Q

Erythrocyte

Lifecycle

A
  1. Released into the blood as immature reticulocytes
    • Anucleate but still contains a few residual polysomes
    • Special stains causes polysomes to clump forming a dark-staining reticulum visible by LM
    • Increased # indicates increased rate of RBC production
  2. Mature RBCs nonmotile & flexible
  3. When RBC loses flexibility they are destroyed
    • Mainly in the spleen but also in bone marrow and liver
  4. Average lifespan = 120 days
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14
Q

Poikilocytosis

A

Abnormally shaped RBC.

Causes:

  • Defects in the spectrin cytoskeleton or its anchoring to the plasma membrane
    • Hereditary spherocytosis
    • Hereditary elliptocytosis
  • Defects in hemoglobin
    • Sickle Cell Anemia
      • HbS polymerizes into long rods under low oxygen tension
      • Deforms the RBC which blocks capillaries
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15
Q

Anisocytosis

A

Abnormalities in erythrocyte size.

  • Macrocytes: abnormally large
    • Vit B12 or folate deficiency
  • Microcytes: abnormally small
    • Iron deficiency
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16
Q

Hemoglobin Content

Abnormalities

A
  • Hyperchromic = contains more Hb than normal
    • Very rare
  • Hypochromic = contains less Hb than normal
    • Seen in some anemias
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17
Q

Anemia

A

A decrease in the oxygen carrying capacity of the blood.

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18
Q

Platelet

Functions

A

Limit bleeding after injury to a blood vessel.

Promote vessel repair.

Required for maintenance of an intact endothelium.

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19
Q

Thrombocytopenia

A
  • Abnormally low platelet count
    • < 150,000/microliter
  • Characterized by:
    • Easy bruising
    • Nose bleeds
    • Petechial rash
    • Spontaneous bleeding
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20
Q

Idiopathic Thrombocytopenic Purpura

(ITP)

A

Autoimmune disease where anti-platelet antibodies destroy platelets.

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21
Q

Platelet

Lifecycle

A
  • Derived from bone marrow cells called megakaryocytes
  • Lifespan ~ 8-10 days
  • Removed by sleen or via clotting process
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22
Q

Platelet

Morphology

A

Hyalomere

  • Clear outer region
  • Contains a bundle of microtubules
    • Helps maintain discoid shape
  • Contains actin & myosin
    • Involved in shape change of activated platelets

Granulomere

  • Central region with basophilic stippling
  • Contains usual cytoplasmic organelles
  • Contains at least 3 types of granules
    • Alpha, Delta, and Lambda

2 systems of membrane bound channels:

  • Open canalicular system
    • Invaginations of the plasma membrane
    • Facilitates rapid exocytosis of granules
  • Dense tubular system
    • Stores Ca2+ needed for exocytosis
    • Not continuous with the plasma membrane
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23
Q

Platelet Granules

A
  • Alpha granules (α) :
    • Platelet-derived growth factor (PDGF) : mitogen for vessel repair
    • von Willebrand Factor (vWF) : mediates platelet adhesion to endothelium (collagen and laminin)
  • Delta granules (δ):
    • Ca2+, ATP, ADP: all enhance platelet aggregation
    • Serotonin: vasoconstriction
      • Picked up by platelets in circulation
  • Lambda granules (λ):
    • Lysosomal enzymes: clot resorption
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24
Q

Vessel Repair Process

A

Adhesion

  • vWF binds to components of the damaged basement membrane (collagen, laminin)
    • vWF can be secreted by many cells including platelets
  • vWF attracts platelets which have surface receptor for vWF causing a single layer to form

Aggregation

  • Platelets secrete fibrinogen
  • Other platelets attracted to the site via cell surface receptors for fibrinogen
  • Forms a multilayered primary hemostatic plug which fills the defect in the vessel wall
  • Fibrinogen links the platelets together

Activation

  • Results in:
    • Secretion of mediators stored in granules
    • Synthesis and release of new mediators derived from membrane lipids (aracidonic acid)
      • Thromboxane A2 (TXA2)
    • ​Change of platelet shape
  • Released mediators cause:
    • Further platelet aggregation
      • TXA2, serotonin, and Ca2+
    • Vasoconstriction (limits bleeding)
      • Serotonin and TXA2
    • Blood coagulation
      • Platelets release several coagulating factors from alpha granules
      • Meshwork of fibrin formed which stabilizes the platelet plug forming the secondary hemostatic plug

Clot Retraction

  • After ~ 1 hr platelets contract due to actin-myosin interaction
    • Platelet plug decreases in size & flattens against vessel wall
    • Helps to re-establish smooth blood flow

Clot Resorption

  • Mediated partially by lysosomal enzymes from λ-granules

Vessel Repair

  • Mediated by platelet-derived growth factor (PDGF) from alpha granules
  • PDGF is strongly mitogenic for cells needed to rebuild the vessel wall including:
    • Endothelial cells
    • Fibroblasts
    • Smooth muscle
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25
Q

Platelet Activation

Regulation

A
  • Platelets activated upon binding to collagen and laminin of damaged basement membrane
    • These are not exposed in healthy vessels
  • Healthy endothelial cells produce factors that inhibit platelet aggregation
    • Ex. Prostacyclin (PGI2) from arachidonic acid
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26
Q

Aspirin

A

Inhibits cyclooxygenase activity.

  • Decreases platelet function
  • Prolongs bleeding times
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27
Q

Von Willebrand’s

Disease

A
  • Most common bleeding disorder
  • Caused by deficiency of von Willebrand’s factor
  • Results in abnormal platelet adhesion
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28
Q

Bernard-Soulier

Syndrome

A
  • Due to deficiency of platelet receptor for von Willebrand’s factor
  • Results in abnormal platelet adhesion
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29
Q

Glanzmann’s Thrombasthenia

A
  • Due to deficiency of platelet receptor for fibrinogen
  • Results in decreased of platelet aggregation
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30
Q

Granulocytes

A

Neutrophils, eosinophils, and basophils.

Characterized by:

  • Abundant cytoplasmic granules of 2 types:
    • Azurophilic granules (primary)
      • small specialized lysosomes
    • Specific granules (secondary)
      • non-lysosomal secretory granules
  • Lobulated heterochromatic nucleus
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31
Q

Agranulocytes

A

Lymphocytes and Monocytes

Characterized by:

  • Few azurophilic granules
  • No specific granules
  • Non-lobulated nucleus
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32
Q

Diapedesis

A
  • Process by which leukocytes leave the blood vessels by passing between endothelial cells
  • Requires specific interactions between molecules on plasma membrane of leukocyte and endothelium
  • Rate increases with inflammation
    • Due to histamine and chemoattractant molecules
  • Occurs most frequently in postcapillary venules
  1. Tethering (weak adhesion) to the endothelium
    • Mediated by L-selectins
      • Located on leukocytes
      • Receptors on endothelium
  2. Rolling along the endothelium as weak interactions break and form again
    • Mediated by
      • Integrins on leukocytes and their receptors on endothelium
      • P-selectins and E-selectins on inflamed endothelial cells and their receptors on leukocytes
  3. Arrest as stronger interactions form
  4. Diapedesis
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33
Q

Leukocyte Adhesion Deficiencies

A

LAD 1: lack of integrin expression of leukocytes.

LAD 2: lack of leukocyte receptors for P & E selectins.

Both result in:

decreased diapedesis

leukocytosis

recurrent infections

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34
Q

Chemotaxis

A
  • Migration along a concentration gradient of chemotactic factors
    • Positive = migration towards a greater concentration
      • Common
    • Negative = migration towards a lower concentration
      • Rare
  • After diapedesis leukocytes are guided to specific locations via chemotactic factors
    • WBCs can respond because they are motile
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35
Q

Chemotactic Factors

A

Different leukocytes respond to different factors.

  • Exogenous:
    • Bacterial peptides
      • Starts with N-formyl-methionine residues
  • Endogenous:
    • Some complement proteins
      • Ex C5a
    • Chemotactic cytokines (chemokines)
      • Ex. IL-8
36
Q

Leukocyte Activation

A
  • Induced by binding of activator molecules which are specific for each leukocyte type
  • Activator binding results in the synthesis and/or secretion of products specific for each leukocyte type ⇒ results in new or enhanced cell functions
  • Results in killing of microorganisms and contributes to inflammatory/immune reactions by altering behavior of other cell types.
  • Products carry out specific functions which fit into 3 broad categories:
    • Respiratory burst
      • increased oxygen intake
      • production of reactive oxygen and nitrogen species which are microbicidal
      • ex. O2-, H2O2, HOCl-
    • Degranulation
      • release of mediators from azurophillic or specific granules
      • Ex. myeloperoxidase and lysozymes
    • Synthesis and release of new mediators
      • Membrane lipid derivatives (usually arachidonic acid)
        • Ex. prostaglandins, leukotrienes
      • Cytokines
        • Proteins/peptides that affect the behavior of other cells
37
Q

Interleukins

A

Compound which is secreted by lymphocytes and affects other lymphocytes or itself.

38
Q

Cytokines

A

A secreted protein/peptide which influences the behavior of leukocytes.

39
Q

Distinguishing Granulocytes

A
  1. Extent of nuclear lobulation
    • neutrophils 3-5 lobes
    • eosinophils 2-3 lobes
    • basophils 2 poorly defined lobes
  2. Specific granules by LM
    • neutrophils have small & poorly staining specific granules
    • eosinophils have large eosinophilic specific granules
    • basophils have large basophilic specific granules
      • these often obscure the nuclear outline
40
Q

Basophil

Functions

A
  • Very similar function to mast cells
  • After activation, release preformed and newly synthesized mediators that:
    • Increase vascular permeability and aid diapedesis
    • Are chemotactic for other cells types (especially eosinophils)
  • Excessive activation can cause certain allergies (Type 1 hypersensitivity reactions)
41
Q

Basophil

Morphology

A
  • Least lobulated nucleus of all granulocytes
  • Heterochromatic
  • Specific granules:
    • Intensely basophilic with Romanovsky stains
    • Can be metachromatic with toluidine blue
    • Appear grainy or like whorls of membrane by EM ⇒ myelin figures (not really myelin)
42
Q

Basophil

Activation

A
  • Activation by immunoglobulin E (IgE)
    1. IgE made by plasma cells during first exposure to antigen (primary immune response)
    2. IgE binds to receptors on basophils that are specific for its Fc portion
    3. Basophils now primed (armed)
    4. If antigen is subsequently encountered it binds to the IgE on basophils
    5. Crosslinking of IgE molecules causes basophil activation
  • Other mechanisms independent of IgE
    • Binding of certain complement fragments to their receptors on basophil membrane
      • C3a
      • C5a
43
Q

Activated Basophils

Effector Functions

A
  1. Degranulation
    • Histamine
      • increases vascular permeability
    • ECF (eosinophil chemotactic factor)
    • NCF (neutrophil chemotactic factor)
    • Proteases
      • helps break down ECM & facilitate WBC movement
  2. Synthesis and secretion of cytokines
    • IL-4
    • IL-13
  3. Activation of phospholipases that cleave basophil membrane lipids and convert them into:
    • Platelet Activating Factor (PAF)
      • Not from arachidonic acid
      • Histamine like
    • Leukotriene C4 (LTC4)
      • Arachidonic acid derivative
      • Histamine like
      • Takes longer to appear but lasts longer than histamine
44
Q

Basophil Mediators

Major Effects

A
  1. Vasodilation & increased vascular permeability
    • Endothelial cells retract from one another forming gaps
    • Mediated by histamine, PAF, and LTC4
    • Increased permeability leads to edema
    • Facilitates movement of WBCs, Ab, complement proteins etc to areas of need
  2. Contraction of airway smooth muscles
    • Bronchioles most effected = bronchoconstriction
    • Mediated by LTC4 and histamine
    • Narrowing airway increases air flow velocity making coughs more effective
    • Excessive effects results in restrictions in airflow
  3. Increased mucus secretion
    • By goblet cells and mucous glands
    • Mediated by histamine
    • Helps trap antigens
    • Excessive effects clogs bronchiolar lumens & causes nasal congestion
  4. B-lymphocyte class switching
    • Causes activated B-lymphocytes to stop producing other classes of Ab and switch to IgE
  5. Chemotaxis of eosinophils/neutrophils
    • Mediated by ECF and NCF
  6. Itch (Pruritis)
    • Mediated by histamine
45
Q

Type I Hypersensitivity

A

Immediate Hypersensitivities

Caused by excessive basophil and/or mast cell activation.

  • Hay Fever
  • Asthma
  • Urticaria
  • Anaphylaxis
46
Q

Anaphylaxis

A
  • Systemic activation of basophils and/or mast cells
  • Results in massive degranulation
  • Can result in fatal hypovolemic shock (anaphylactic shock)
  • Most often occurs in response to particular antigens
    • Drugs
    • Foods
    • Insect stings
  • There may be some genetic predisposition
47
Q

Eosinophil

Morphology

A
  • Nucleus usually bi-lobed (maybe 3) and heterochromatic
  • Contains azurophilic granules
  • Many large specific granules
    • Eosinophilic & sometimes refractile by LM
    • Irregular crystalloid embedded in an amorphous matrix by EM
    • Crystalloid made up by major basic protein (MBP)
48
Q

Eosinophil

Lifecycle

A
  • IL-5 stimulates eosinophil maturation in bone marrow and secretion into blood
  • Normally circulate in the blood for several hours
  • Responds to many chemotactic factors
    • IL-5
    • Eotaxin
      • Made by epithelial cells especially in the respiratory and GI tract
    • Histamine
    • ECF
  • Can survive an additional 8-12+ days in CT
  • 100-1000 times more common in extravascular tissues than blood
    • Esp. lamina propria and respiratory tract
  • Die by apoptosis
49
Q

Eosinophil

Activation

A
  • Can be activated by many stimuli
  • Ex. cross-linking of IgA bound to their plasmalemma
50
Q

Activated Eosinophils

A
  • Cleave membrane lipids and synthesize mediators
    • LTC4 and PAF
  • Undergo a respiratory burst and produce reactive oxygen and nitrogen species
  • Degranulate
  • Synthesize and secrete many cytokines
51
Q

Eosinophil Mediators

Major Effects

A
  1. Kill larvae of certain parasitic worms (helminths) by binding to their surface and secreting substances that damage them
    • From specific granules
      • Major basic protein (MBP) in the crystalloid
      • Eosinophil cationic protein (ECP)
      • Eosinophil peroxidase (EPO)
      • Eosinophil-derived neurotoxin (EDN)
    • From respiratory burst
      • Nitric oxide (NO)
      • Hydrogen peroxide (H2O2)
  2. Phagocytize and destroy antigen-antibody complexes
    • Prevents excessive activation of complement
    • Poorly phagocytic cells otherwise
  3. Modulate basophil and mast cell activity
    • Release enzymes from specific granules that can destroy mediators released from activated basophils/mast cells
      • Ex. Histaminase
    • Major basic protein activates basophils and mast cell
    • Can have either stimulatory or inhibitory effects on mast cells and basophils
      • May be explained by eosinophil’s ability to release different mediators in response to different stimuli ⇒ piecemeal degranulation
52
Q

Eosinophils & Asthma

A

Eosinophils contribute to chronic lung damage in asthma.

  • Attracted to lungs by chemotactic factors including eotaxin from bronchiolar epithelium
  • Activated and release mediators that kill bronchiolar epithelial cells
    • MBP
    • ECP
  • Decrease in # of ciliated cells interferes with clearance of mucus from the airway
  • LTC4 and PAF cause bronchoconstriction and vasodilation that leads to airway edema
  • MBP also affects airway smooth muscle making it hyper-reactive to mediators that cause contriction
53
Q

Neutrophil

Function

A
  1. Highly phagocytic cells
    • Specialized for bacteria
  2. Promote inflammation by secreting mediators
    • IL-1: pyrogen which causes a fever by acting on temperature-regulating area of hypothalamus
  3. Abundant in anemias associated with Vit B12 or folate deficiency
54
Q

Neutrophil

Morphology

A
  • Heterochromatic nucleus
  • 2-5 lobes (usually 3) connected by thin strands
    • More than 5 lobes = hypersegmented neutrophils
  • In females, inactivated X-chromosome (Barr body) forms a drumstick-like appendage visible in some nuclei
  • Small and inconspicous azurophillic and specific granules
55
Q

Neutrophil

Lifecycle

A
  1. Large reserve of mature neutrophils exists in bone marrow
    • Azurophilic granules (primary granules) formed first in the bone marrow during differentiation only
      • Contains myeloperoxidase (MPO) which can be used in histochemistry
    • Specific granules (secondary granules) are made second in the bone marrow
  2. Rapidly mobilized when stimulated by IL-1 & IL-6
  3. Half-life in blood ~ 12 hours
  4. Leaves vessels via diapedesis
  5. Shows positive chemotaxis towards:
    • Complement fragments such as C5a
    • N-formyl methionyl peptides
  6. Activation induced by many stimuli
    • Including act of phagocytosis
  7. Activated neutrophils:
    • Undergo respiratory burst
    • Release mediators from granules
    • Synthesize and secrete new cytokines
  8. Activated neutrophils die by apoptosis
    • Dead neutrophils and damaged tissue are major components of pus
    • Pus is removed by macrophages
56
Q

Neutrophil

Phagocytosis

A

Rate of phagocytosis greatly increased by binding the particle to the neutrophil plasma membrane.

Two methods for binding:

  1. Pathogen-associated molecular patterns (PAMPs)
    • Highly conserved molecular configurations on the surface of pathogenic particles
      • Found on bacteria
    • Pattern recognition receptors (PRRs) on the neutrophils (& macrophages) bind to the PAMPs
  2. Opsonization
    • Opsonins are extrinsic molecules that bind to pathogenic particles
    • Specific receptors on neutrophils & macrophages recognize each oposin
    • Opsonins act as bridges that physically bind the particle and the phagocyte together
    • Common opsonins:
      • IgG antibodies specific for antigens on the particle
        • Recognized by neutrophil Fc receptors for IgG
      • C3b fragment of the C3 complement protein
        • Produced during complement activation
        • C3b recognized by C3b receptors on the neutrophil
57
Q

Neutrophil

Respiratory Burst

A

The Respiratory Burst

  • A measurable increase in oxygen consumption that is triggered by phagocytosis
  • Multi-step enzymatic process (cascade)
    • Phagocytosis causes polymerization and activation of the cytoplasmic & membrane bound NADPH oxidase which catalyzes the first step in ROS production
  • Results in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS)
  • ROS/RNS kill microbes by reacting with microbial macromolecules, especially lipids & DNA
  • Includes:
    • Superoxide anion radical (O2-) produced from O2 by NADPH oxidase
    • Hydrogen peroxide (H2O2) produced from O2- by superoxide dismutase
    • Hypochlorous acid (HOCl) produced from (H2O2) by the myeloperoxidase of azurophilic granules
      • HOCl dissociates to form hypochlorite (OCl-)
58
Q

Chronic Granulomatous Disease

(CGD)

A
  • Caused by genetic defects in any 4 of the NADPH oxidase subunits
  • Characterized by a decreased or absent respiratory burst
  • Leads to recurrent bacterial and fungal infections
  • Shortened life expectancy
59
Q

Neutrophils

Azurophilic Granules

A

Contributes antimicrobial mediators:

  1. Myeloperoxidase
    • Catalyzes production of HOCl from H2O2 during the later stages of respiratory burst
  2. Bactericidal permeability-increasing protein (BPI)
    • Damages membranes of gram-negative bacteria
  3. Lysozyme
    • Enzyme that attacks cell walls of bacteria, especially gram-positive
  4. Defensins
    • Small cationic proteins that permeabilize bacterial membranes, probably by forming pores
60
Q

Neutrophils

Specific Granules

A

Contributes:

  1. Lysozyme
    • Present in azurophilic & specific granules
    • Attacks cell walls of bacteria, especially gram-positive
  2. Lactoferrin
    • Bacteriostatic protein that competes with bacteria for iron and copper which are required for bacterial replication
61
Q

Chediak-Higashi

Syndrome

A
  • Genetic defect in the targeting of proteins to azurophilic granules
  • Leaves granules without the contents necessary to kill bacteria
  • Neutrophils contain abnormally large vacuoles resulting from fusion of azuorphilic granules with one another
    • Easily seen by LM
  • Often fatal in childhood
62
Q

Neutrophil

Adverse Effects

A
  • Neutrophils can damage healthy tissues.
  • During phagocytosis neutrophils partially release granule contents into the extracellular space
  • Can cause significant damage to healthy tissues nearby
  • Examples:
    • Elastase from azurophilic granules
    • Type IV collagenase from specific granules
63
Q

Clinical Signs

of

Acute Inflammation

A
  1. Leukocytosis
    • An increase in the number of circulating neutrophils
    • Due to neutrophils leaving bone marrow in greater numbers than usally seen
    • Used as a clinical marker of infection
  2. “Shift to the left” phenomenon
    • Distribution of neutrophils by age in the plasma is shifted towards more immature forms
64
Q

Acute Inflammation

Time Course

A
  1. Edema
    • Due to vessels made leaky by histamine and other mediators
  2. Neutrophils arrive within 1 day
    1. Typical of the acute phase
  3. Monocytes arrive in a second wave of leukocytes around day 2
    • Neutrophils secrete chemotactic factors that attract monocytes
  4. Monocytes differentiate into macrophages
    • Typical of late phase of inflammation
    • Macrophages phagocytize dead neutrophils
65
Q

Monocytes

Lifecycle

A
  • Considered monocytes in the blood
    • Can circulate for several hours to days (~12-100 hours)
  • Migrate out of vessels by diapedesis
  • Differentiation into macrophages can be during diapedesis and finishes in extravascular tissues
66
Q

Monocytes

Morphology

A
  • Largest leukocyte
  • Irregularly shaped nucleus but not lobulated
    • Can be horseshoe shaped or folded on itself
  • Lacy chromatin with sharp boundaries between euchromatin and heterochromatin
  • Abundant paler staining cytoplasm
  • Few azurophilic granules
  • No specific granules
  • Large pale vacuoles
  • Well-developed Golgi
    • Can produce Azurophilic granules throughout the monocyte lifespan unlike neutrophils
67
Q

Mononuclear Phagocytic Systems

A

Macrophages and related cells which derive from monocytes.

  • Histiocytes: ordinary macrophages in CT
  • Kupffer cells: in the liver
  • Alveolar macrophages (dust cells): in alveoli of the lung
  • Microglia: in the brain
  • Mesangial cells: in the kidneys
68
Q

Macrophage

Morphology

A
  • Larger and more phagocytic than monocytes
  • Best recognized by presence of phagocytized material in cytoplasm
  • By EM have more:
    • Phagosomes
    • Secondary lysosomes
    • Plasma membrane pseudopods
  • Irregular nucleus
  • Can live for several months in extravascular tissues
69
Q

Macrophage

Activation

A

Classical Pathway

  • Leads to productions of mediators that stimulate inflammation
  • Induced by many stimuli including:
    • Interferon-γ (IFN-γ) from the TH1 subset of T-helper cells
  • Classically activated macrophages increase in size and become more efficient in their activities (eg phagocytosis, secretion, etc)

Alternative Activation

  • Leads to production of anti-inflammatory mediators
  • Induced by stimuli including:
    • IL-4 and IL-13 from TH2 subset of T-helper cells
    • Phagocytosis of apoptotic cells
70
Q

Macrophages

Chronic Inflammation

A
  • Can enlarge and congregate into groups to become epithelioid cells
  • Can fuse to form multinucleated giant cells
    • Stimulated by IFN-γ
    • Can occur when macrophages encounter an object too large to phagocytize alone
71
Q

Monocyte/Macrophage

Phagocytosis

A
  1. Functions in killing microorganisms
  2. Adapted for specilaized functions:
    • Removal of apoptotic cells
      • Recognized by the presence of phosphatidylserine (PS) on the outer leaflet of apoptotic cell plasma membrane
      • Examples:
        • Apoptotic neutrophils in inflammation
        • Apoptotic lymphocytes in the lymphoid tissue
72
Q

Macrophage

Rate of Phagocytosis

A

Phagocytosis can be enhanced by:

  • Opsonins
  • Pattern recognition receptors (PRRs) on the macrophage
    • Macrophage class A scavenger receptor: recognizes modified forms of LDLs
73
Q

Foam Cells

A

When excessive accumulation of LDLs occurs in macrophages causing them to become “foam cells” in atherosclerotic lesions of arterial walls.

74
Q

Monocyte/Macrophage

Antigen Presentation

A

Monocytes & macrophages can act as antigen presenting cells (APCs) to help activate T-helper (TH) cells.

  1. Take up antigen by endocytosis.
  2. Partially degrade antigen in phagolysosomes leaving some peptide fragments intact.
  3. Peptides bind to major histocompatibility II (MCHII) proteins that are part of the vacuolar membrane.
  4. Vacuoles fuse with the plasma membrane, delivering the peptide/MHC-II complex to the cell surface where it can activate TH cells
75
Q

Monocyte/Macrophage

Mediators

A

Monocytes & Macrophages secrete productions that regulation processes other than inflammation:

  • Colony-stimulating factors (GM-CSF, G-CSF, M-CSF) that promote hematopoiesis
  • Proteases important in normal turnover of ECM
    • Collagenases
    • Elastase
  • Growth factors important in wound healing
    • Tumor necrosis factor (TNF) stimulates fibroblasts
    • Transforming growth factor (TGF) stimulates keratinocytes
76
Q

Lymphocytes

Lifecycle

A
  • Lymphocytes represent 25-30% of blood WBC’s but 99% of lymph WBC’s.
  • Major cell type of immune system
  • Undergo diapedesis mainly from high endothelium venules (HEVS)
  • Many lymphocytes recirculate into the blood after leaving HEVs and entering lymphatic capillaries
  • Constantly travel throughout the body “patrolling” for antigens and presenting to cells in lymphoid tissues ⇒ immune surveillance
77
Q

High Endothelium Venules

(HEV)

A
  • Post-capillary venules with cuboidal to collumar endothelial cells
  • Typical of lymph nodes and certain other lymphoid tissues/organs
  • Only lymphocytes can cross the walls of HEVs
78
Q

Lymphocyte

Morphology

A

Can exist as small, medium, or large lymphocytes depending on activation state.

Undergo blast transformation after activation.

  • Small lymphocytes
    • Account for > 90% in the blood
    • Currently inactive
    • Round or kidney bean heterochromatic nucleus
    • Very thin rim of “sky blue” cytoplasm
  • Large lymphocytes
    • More euchromatic nucleus with “smudged” pattern by LM
    • Cytoplasm increases
79
Q

Blast Transformation

A
  • When activated by the immune response small lymphocytes increase in size and divide to form medium and large lymphocytes (lymphoblasts).
  • Immunoblasts then divide to form a clone of cells.
  • From clones, various effector cells develop and carry out the immune response.
    • Example: Plasma cells are effector cells derived from activated B lymphocytes.
80
Q

Cell-Mediated Immunity

A

Immune reactions that require live lymphocytes.

Immunity cannot be transferred passively from one individual to another by plasma alone.

81
Q

T-Cells

A

Required for cell-mediated immunity

Can be divided into several subclasses:

T helper cells

T cytotoxic cells

82
Q

T-Helper Cells

(TH)

A
  • Carry CD4+ surface markers
  • Effector cells derived from activated TH cells
  • Function by secreting cytokines
  • Two subsets which secrete different cytokines:
    • TH1 cells
    • TH2 cells
83
Q

T cytotoxic cells

(TC cells)

A

Carry CD8+ surface marker

Effector cells derived from activated Tc cells are called cytotoxic T lymphocytes (CTL).

  • CTL can lyse some altered-self cells
    • Virus-infected cells
    • Tumor cells
    • Genetically different cells in a tissue graft
  • CTL recognizes antigens on target cells
  • Killing requires binding of CTL to target cell
  • One method by which CTL kill target cells involves secretion of:
    • Perforin: protein that aggregates to form pores in the targe cell membrane
    • Proteases called granzymes (fragmentins) that enter target cells through the pores and induces apoptosis
84
Q

Humoral Immunity

A

Immune reactions that require antibodies.

Immunity can be transferred passively from one individual to another by the antibodies alone.

Does not require transfer of live plasma cells.

85
Q

B Cells

A
  • Major cell type in humoral (antibody-mediated) immunity
  • Plasma cells are effector cells derived from activated B-cells
86
Q

Plasma Cells

A
  • Effector cells derived from activated B-cells
  • Secrete antibodies
  • Are relatively short-lived (10-30 days)
  • Old plasma cells become Russell body cells
    • Contain large distended RER cisternae called Russell bodies
    • Full of antibody and stain very eosinophillic
87
Q

Natural Killer Cells

(NK cells)

A
  • Do not carry CD4 or CD8 on their plasma membranes
  • Make up 5-10% of lymphocytes in peripheral blood
  • Functions to kill target cells
    • Virus-infected cells
    • Tumor cells
  • Uses some of the same mediators as CTL (perforins and granzymes)
  • Recognize target cells via different mechanisms than CTL
  • Previously called large granular lymphocytes (LGLs) due to large diameter and high content of azurophillic granules obvious by LM

IMS: Microanatomy (16 decks)

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