pathology exam 1

ID

• Lialyl lewis X modified proteins

• rolling

• Lialyl lewis X modified proteins

• Rolling and adhesion

ID

• L selectin

• Rolling (neutrophils, monocytes)

ID

• ICAM 1

• VCAM 1

ID

• CLUB DANCE 11/CD 18 integrins LFA 1

• VLA 4 integrin

ID

• CLUB DANCE 31 homotypic interaction

• transmission of leukocytes through endothelium

Extra 1

Homotypic interaction -- binds to itself (on both the endothelial and leukocyte molecule)

ID

1. Edema

2. neutrophils

3. monocyte/macrophage

ID

Bone marrow suppression

ID

Produuction of leukocytes

ID

Adhesion and chemotaxis

ID

Phagocytosis and microbial activity

ID

1. in b chain of CD 11/CD 18 integrins

2. Selectin receptor

ID

Chronic granulomatous disease

ID

Myeloperoxidase dificiency

Acute Inflammation

• Stimuli
  

  • Infectious agents

  • Physical agents (like trauma or foreign bodies)

  • Chemical agents

  • Immunologic reactions

  • [...] (surprising stimuli for me

Necrotic tissue

Acute Inflammation

• [...]: excess interstitial or serous cavity fluid 

Edema

Acute Inflammation

• [...]

  • inflammatory exudate rich in leukocytes and cellular debris

• [...]

  • inflammatory exudate with a high protein content (SG > 1.020)

• [...]

  • extravascular fluid with a low protein content (SG < 1.012)

• Purulent Exudate

• Exudate

• Transudate

Acute Inflammation

• Purulent Exudate

  • inflammatory exudate rich in leukocytes and cellular debris

• Exudate

  • inflammatory exudate with a [high or low] protein content (SG > 1.020)

• Transudate

  • extravascular fluid with a [high or low] protein content (SG < 1.012)

• high
  low

Acute Inflammation: immediate and early response to injury or infection

• Major components
  

  • Vascular

    • [...]

    • [...]

  • Cellular

    • Emigration of leukocytes (from circulating in blood)

    • Accumulation of leukocytes at site of injury 

• Vasodilation

• Increased vascular permeability (due to structural changes)

Acute Inflammation: immediate and early response to injury or infection

• Major components
  

  • Vascular

    • Vasodilation

    • Increased vascular permeability (due to structural changes)

  • Cellular

    • [...]

    • [...] 

• Emigration of leukocytes (from circulating in blood)

• Accumulation of leukocytes at site of injury 

Adhesion & Transmigration

• Determined by binding of [...] (complementary adhesion molecules on the leukocyte cell surface)

integrins

Integrins interact with their ligands on endothelial cells

Expression (intensity) is influenced by chemokines (chemical mediators) 

Adhesion Molecules – belong to four molecular families

1. [...]

2. [...]

3. [...]

4. [...] 

1. Selectins

2. Immunoglobulins

3. Integrins

4. Mucin-like glycoproteins

Changes in Vascular Flow and Caliber

• Changes
  

  • Transient [vasoconstriction or vasodilation] (lasting seconds)

  • [vasoconstriction or vasodilation]

  • Increased vascular permeability

  • Results in edema (can be a palpable mass aka tumor)

  • Slowing of circulation

  • Leukocyte margination 

• vasoconstriction

• Vasodilation

Changes in Vascular Flow and Caliber

• Changes
  

  • Transient vasoconstriction (lasting seconds)

  • Vasodilation

  • [increased or decreased] vascular permeability

  • Results in edema (can be a palpable mass aka tumor)

  • Slowing of circulation

  • Leukocyte margination 

Increased

Changes in Vascular Flow and Caliber

• Physiology
  

  • During acute inflammation, net flow is [in or out] in the arteriole, capillaries and venules due to [...]

• out

• increased hydrostatic pressure 

Chemical Mediators of Inflammation

• From [...] or [...]

• Function as [...]

• Short lived

• May act on just one target cell or on a few

• Potential for harmful effects

• plasma or produced locally

• amplifiers

Chemotaxis

• Exogenous
  

  • [...]

• Endogenous
  

  • Components of the complement system

  • Products of the lipoxygenase pathway

  • Cytokines 

• Bacterial products

Chemotaxis

• Exogenous
  

  • Bacterial products

• Endogenous
  

  • [...]

  • [...]

  • [...] 

• Components of the complement system

• Products of the lipoxygenase pathway

• Cytokines 

Function of Adhesion Molecule

• Expression of E Selectin
  

  • Caused by

    • [...]

    • [...]

    • [...] 

• TNF

• IL-1

• Chemokines 

Function of Adhesion Molecule

• Redistribution of P selectin to the cell surface
  

  • [...] bodies are distributed to the site of injury

  • Caused by

    • Histamine

    • Thrombin

    • Platelet Activating Factor (PAF) 

Weibel-Palade

Function of Adhesion Molecule

• Redistribution of P selectin to the cell surface
  

  • Weibel-Palade bodies are distributed to the site of injury

  • Caused by

    • [...]

    • [...]

    • [...]

• Histamine

• Thrombin

• Platelet Activating Factor (PAF)

Function of Adhesion Molecule

• VCAM-1 and ICAM-1 Expression
  

  • Caused by:

    • [...]

    • [...] 

• TNF

• IL-1

Function of chemotactic agents

• Leukocyte activation

• Causes:
  

  • Production of [...] (causing amplification of the inflammatory reaction)

  • Degranulation, secretion of lysosomal enzyme & the oxygen burst

  • Modulation of leukocyte adhesion molecules 

arachidonic acid metabolites

Function of chemotactic agents

1. [...]

2. [...] activation 

1. Locomotion along a chemical gradient

2. Leukocyte

Historical Highlights

• Clinical Features
  

  • Rubor = [...]

  • Tumor = [...]

  • Calor = [...]

  • Dolor = [...]

  • Functio Laesa = [...] 

• Redness

• Mass

• Warmth

• Pain

• loss of function

Inflammation: Overview

• Attempts to eliminate [...] as well as cleaning up [...]

• Goal of inflammation
  

  • Host cells of defense normally circulate in blood. Inflammation tries to bring them to the site of damage

• the initial cause of cellular injury

• necrotic cells and tissue

Integrins

• Normally in a [high or low]-affinity form on the leukocyte surface

• Becomes activated when leukocytes are activated by chemokines
  

  • Integrins do not bind to their ligands until the leukocyte is activated

• Other cytokines activate endothelial cells, increasing their expression of ligands for integrins 

low

Integrins

• Normally in a low-affinity form on the leukocyte surface

• Becomes activated when [what happens?]
  

  • Integrins do not bind to their ligands until the leukocyte is activated

• Other cytokines activate endothelial cells, increasing their expression of ligands for integrins 

leukocytes are activated by chemokines

Leukocyte activation

• Stimuli for activation
  

  • [...]

  • [...]

  • [...] 

• Microbes

• Products of necrotic cells

• Mediators 

Location of adhesion molecules

• [Where are the following located?]
  

  • P-selectin

  • E-selectin

• Endothelial Cells

Location of adhesion molecules

• [Where are the following located?]
  

  • L-Selectin

  • VLA integrins

  • LFA 

• Leukocyte

Location of adhesion molecules

• [Where are the following located?]
  

  • P-Selectin 

• Platelets

Location of adhesion molecules

• [Where are the following located?]
  

  • ICAM-1

  • VCAM-1

  • GlyCam-1

  • PECAM (CD31) 

• Endothelial Cells

Margination and Rolling

• Leukocytes forced against the vascular walls [where] due to flow dynamics 

post-capillary venules

Margination and Rolling

• Rolling
  

  • Leukocytes roll along the vessel wall and transiently stick to the vessel (low adherence)

  • Mediated by [...] 

• selectins (an adhesion molecule) 

Mechanisms of Vascular Leakage in acute inflammation

• Direct Endothelial Injury
  

  • Where: 

    • [...]

  • Why:

    • [...]

• arterioles, capillaries, and venules (basically everywhere)

• Toxins, burns, chemicals 

Mechanisms of Vascular Leakage in acute inflammation

• Forms [...] due to:
  

  • [...]

    • Where: in venules

    • Why: vasoactive mediators (primarily histamine and leukotrienes)

  • [...]

    • Where: mostly in venules but also capillaries

    • Why:

      • Cytokines (IL-1 & TNF)

      • Hypoxia 

• gaps

• Endothelial cell contraction

• Cytoskeletal reorganization

Mechanisms of Vascular Leakage in acute inflammation

• Forms gaps due to:
  

  • Endothelial cell contraction

    • Where: [...]

    • Why: [...]

  • Cytoskeletal reorganization

    • Where: mostly in venules but also capillaries

    • Why:

      • Cytokines (IL-1 & TNF)

      • Hypoxia 

• in venules

• vasoactive mediators (primarily histamine and leukotrienes)

Mechanisms of Vascular Leakage in acute inflammation

• Forms gaps due to:
  

  • Endothelial cell contraction

    • Where: in venules

    • Why: vasoactive mediators (primarily histamine and leukotrienes)

  • Cytoskeletal reorganization

    • Where: [...]

    • Why:

      • [...]

      • [...] 

• mostly in venules but also capillaries

• Cytokines (IL-1 & TNF)

• Hypoxia 

Mechanisms of Vascular Leakage in acute inflammation

• Increased transcytosis -- cell takes up fluid on one side and releases it on the other side
  

  • Where: [...]

  • Why: [...]

• venules

• VEGF (Vascular Endothelial Growth Factor) 

Mechanisms of Vascular Leakage in acute inflammation

• Leukocytes dependent injury aka friendly fire
  

  • Where: mostly in [...] but also in [...]

  • When: [...] 

• venules

• pulmonary capillaries

• late response (takes days) 

NOD-like Receptors

• Capase-1
  

  • Function 

    • [...]

• cleaves precursor form of inflammatory IL-1b into its active form of IL-1

IL-1 is an important mediator of leukocyte recruitment

NOD-like Receptors 

• Receptors signal via the [...] 

inflammasome 

NOD-like Receptors

• The inflammasome is a multi-protein cytoplasmic complex

• Triggering of the inflammasome results in activation of [...]

capase-1

Pattern Recognition Sensors

• Phagocytes, dendritic cells, and epithelial cells express receptors

• Four major classes of receptors
  

  • [...]

  • [...]

  • [...]

  • [...] for viral nucleic acids 

• TLRs

• NOD-like Receptors (NLRs)

• C-type Lectic Receptors

• RIG-like receptors (RLRs)

Phagocytosis

• Engulfment
  

  • One step if

    • [...]

  • More steps required if:

    • [...]

• Triggered by binding of the opsonized particle to the Fc portion of IgG

• Binding to C3 receptors alone 

Phagocytosis

• Killing or degradation
  

  • Two mechanisms

    • Oxygen dependent

      • [...]

    • Oxygen independent

      • BPIP (bactericidal permeability increasing protein)

      • Lactoferrin

      • Lysozyme

      • Major basic protein

      • Defensins 

• Oxidase

Phagocytosis

• Killing or degradation
  

  • Two mechanisms

    • Oxygen dependent

      • Oxidase

    • Oxygen independent

      • [...]

      • [...]

      • [...]

      • [...]

      • [...] 

• BPIP (bactericidal permeability increasing protein)

• Lactoferrin

• Lysozyme

• Major basic protein

• Defensins 

Phagocytosis

• Recognition and attachment
  

  • Via [...]

    • Fc portion of IgG

    • C3b (and C3bi – its inactive form)

    • Collectins   

opsonins

Phagocytosis

• Recognition and attachment
  

  • Via opsonins

    • [...]

    • [...]

    • [...]   

• Fc portion of IgG

• C3b (and C3bi – its inactive form)

• Collectins   

Phagocytosis

• Three distinct steps
  

  • [...]

    • Microbes bind to phagocyte receptors

  • [...]

    • Phagocyte membrane zips up around microbe

    • Microbe is ingested in phagosome

    • Fusion of phagosome with lysosome

  • [...]

    • by lysosomal enzymes in phagolysosomes

    • by ROIs and NO

• Recognition and attachment

• Engulfment

• Killing or degradation

Recruitment of Inflammatory Cells

• Leukocytes must be stopped and brought to the site of injury from normal circulation

• Cellular Events (in order)
  

  • [...]

  • [...]

  • [...]

  • [...]

  • [...] 

• Margination

• Adherence

• Transmigration

• Chemotaxis and Leukocyte activation

• Phagocytosis

Response of Lymphatic Vessels (to deal with edema)

• Lymph flow is [increased or decreased] during inflammation

• Leukocytes, cell debris, and microbes are drained to lymph nodes (where we start making antibodies and recognizing them)

increased

Response of Lymphatic Vessels (to deal with edema)

• [...] – lymphatic vessels getting secondarily inflamed

• [...] – draining lymph nodes become inflamed 

• Lymphangitis

• Lymphadenitis

Terminating the Acute Inflammatory Response

• Tight controls are needed

• Short half-lives of chemical mediators

• Inflammation simultaneously triggers a variety of stop signals
  

  • Switch from pro-inflammatory leukotrienes to [...]

  • [...] (anti-inflammatory)

  • [...]

• anti-inflammatory lipoxins

• Liberation of TGF-b from macrophages

• Neural impulses (cholinergic) inhibit production of TNF in macrophages

[...]

• Locomotion along a chemical gradient

• Induce a response in all granulocytes, monocytes and, to a degree, lymphocytes

• Can be endogenous (produced by us) or exogenous (produced by debris or bacteria) 

Chemotaxis

Chemotaxis

• Locomotion along a chemical gradient

• Induce a response in all granulocytes, monocytes and, to a degree, [...]

• Can be endogenous (produced by us) or exogenous (produced by debris or bacteria) 

lymphocytes

[...]

• Present on leukocyte surface

• Are transmembrane heterodimeric glycoproteins that also function as cell receptors for extracellular matrix 

Integrins

[...]

• Due to phagolysosome leaking its products into the extracellular space

• Includes:
  

  • Lysosomal enzymes

  • Oxygen-derived active metabolites

  • Products of arachidonic acid metabolism 

Leukocyte-Induced Tissue Injury

Leukocyte-Induced Tissue Injury

• Due to phagolysosome leaking its products into the extracellular space

• Includes:
  

  • [...]

  • [...]

  • [...]

• Lysosomal enzymes

• Oxygen-derived active metabolites

• Products of arachidonic acid metabolism

[...]

• High concentration of antimicrobial substances at sites of infection to prevent the spread of microbes 

Neutrophil Extracellular Traps (NETs)

[...]

• It’s an extracellular fibrillar network produced by neutrophils in response to infectious pathogens and inflammatory cytokines
  

  • Infectious pathogens – bacteria or fungi

  • Inflammatory mediators – chemokines, cytokines, complement, and ROS

• Contain a framework of nuclear chromatin with embedded granule protein 

Neutrophil Extracellular Traps (NETs)

[...] Receptors & the Inflammasome

• Cytosolic receptors

• Function – recognizes a wide variety of substances
  

  • Products of necrotic cells (uric acid and released ATP)

  • Ion disturbances

  • Some microbial products 

NOD-like

NOD-like Receptors & the Inflammasome

• Cytosolic receptors

• Function – recognizes a wide variety of substances
  

  • Products of [...]

  • [...]

  • Some [...] 

• necrotic cells (uric acid and released ATP)

• Ion disturbances

• microbial products 

[...]

• Receptor that is expressed on leukocytes and endothelium

• Mediates rolling

• Contains an extracellular domain that binds to sugars

• Normally in low levels on endothelial cells
  

  • Up-regulated by specific mediators

  • Makes sure binding of leukocytes are restricted to site of injury 

Selectins

Selectins

• Receptor that is expressed on leukocytes and endothelium

• Mediates rolling

• Contains an extracellular domain that binds to sugars

• Normally in [high or low] levels on endothelial cells
  

  • Up-regulated by specific mediators

  • Makes sure binding of leukocytes are restricted to site of injury 

low

[...]

• Function – Microbial sensors
  

  • Recognizes products of bacteria (endotoxin, bacterial DNA, and other pathogens)

• Located in the plasma membrane and endosomes

• Complemented by:
  

  • Cytoplasmic and membrane molecules

  • Other families that recognize microbial products 

Toll-like Receptors (TLRs)

Toll-like Receptors (TLRs)

• Function – [...]
  

  • Recognizes products of [...]

• Located in the plasma membrane and endosomes

• Complemented by:
  

  • Cytoplasmic and membrane molecules

  • Other families that recognize microbial products 

• Microbial sensors

• bacteria (endotoxin, bacterial DNA, and other pathogens)

Toll-like Receptors (TLRs)

• Function – Microbial sensors
  

  • Recognizes products of bacteria (endotoxin, bacterial DNA, and other pathogens)

• Located in the [...] and [...]

• Complemented by:
  

  • Cytoplasmic and membrane molecules

  • Other families that recognize microbial products 

• plasma membrane

• endosomes

[...]

• Migration of leukocytes through vessel wall via space in between cells at intercellular junctions

• Mediated by PECAM-1 (aka CD31) 

Transmigration

Transmigration

• Migration of leukocytes through vessel wall via space in between cells at intercellular junctions

• Mediated by [...] 

• PECAM-1 (aka CD31) 

Complement System 

• All pathways converge on C3 and cause a splitting of C3
  

  • [...] – attaches to microbe

    • [...] goes on to work on [...] which splits again

      • [...] – attaches and goes to C6-C9→MAC

      • [...] – goes into blood stream→ trigger mast cell degranulation

  • [...] – goes off into bloodstream → trigger mast cell degranulation 

• C3b

• C3b

• C5

• C5b

• C5a

• C3a

Complement System 

• All pathways converge on C3 and cause a splitting of C3
  

  • C3b – attaches to microbe

    • C3b goes on to work on C5 which splits again

      • C5b – attaches and goes to C6-C9→[...]

      • C5a – goes into blood stream→ trigger mast cell degranulation

  • C3a – goes off into bloodstream → trigger mast cell degranulation 

MAC

Complement System

• 20 plasma proteases

• Source of vasoactive mediators

• Important role in immunity

• Present in the plasma in an inactive form but sequentially activated by three independent pathways
  

  • Classical Pathway 

    • activated by [...]

  • Alternate Pathway 

    • activated by [...]

  • Lectin Pathway 

    • activated by [...] 

• IgG / IgM (memory cells, 2nd line of defense)

• surface molecules - microbes (1st line of defense)

• MBL binding to mannose on microorganisms

Anti-Inflammatory Mechanisms

• Mediators are short-lived and destroyed by degrative enzymes

• Counteractive measures
  

  • [...]

  • [...]

  • [...]

    • Down-regulate the responses of activated macrophages

  • [...]

• Lipoxins

• Complement regulatory proteins

• IL-10

• TGF-b

Arachidonic Acid Metabolites

• [Which] pathway is active even when you take NSAIDs 

5-Lipoxygenase

Cells of Chronic Inflammation

• Two major pathways of macrophage activation
  

  • Classically activated (M1)

    • Produced by:

      • [...]

      • [what kind of cytokines?]

    • Microbicidal

  • Alternative macrophage activation (M2)

    • Activated by 

      • [what kind of cytokines?]

        • [specifically?]

        • [specifically?]

    • NOT microbicidal – principle role is in tissue repair 

• Microbial products

• Cytokines (IFN-g)

• cytokines other than IFN-g

  • IL-13

  • IL-4

Cells of Chronic Inflammation

• Two major pathways of macrophage activation
  

  • Classically activated (M1)

    • Produced by:

      • Microbial products

      • Cytokines (IFN-g)

    • [Is it microbicidal?]

  • Alternative macrophage activation (M2)

    • Activated by 

      • cytokines other than IFN-g

        • IL-13

        • IL-4

    • [Is it microbicidal?] 

• Microbicidal

• NOT microbicidal – principle role is in tissue repair 

Chemokines

• Classified into four group, but the two major groups:
  

  • [...]

    • Act primarily on neutrophils

  • [...]

    • Monocyte chemoattractant protein-1

    • Macrophage inflammatory protein – 1a

• CXC chemokines

• CC chemokines

Chemokines

• Classified into four group, but the two major groups:
  

  • CXC chemokines

    • Act primarily on [...]

  • CC chemokines

    • Monocyte chemoattractant protein-1

    • Macrophage inflammatory protein – 1a

neutrophils

Chemokines

• Classified into four group, but the two major groups:
  

  • CXC chemokines

    • Act primarily on neutrophils

  • CC chemokines

    • [...]

    • [...]

• Monocyte chemoattractant protein-1

• Macrophage inflammatory protein – 1a

Chemokines

• Family of small (8 to 10 kDa) structurally related proteins

• Act primarily as a [...] for different subset of leukocytes 

chemoattractant

Chemokines

• Mediate their activities by binding to specific G protein coupled receptors on target cells
  

  • [...] & [...]

    • Important in binding and entry of HIV into cells 

• CXCR4 & CCR5

Chronic Inflammation

• Characteristics
  

  • Prolonged duration

  • Tissue destruction

  • Repair – involving [...] and [...]

  • Active inflammation involving [what type of] cells 

• angiogenesis and fibrosis

• mononuclear

Scar formation; tissue will not return to normal

mononuclear cells -- macrophages, lymphocytes, plasma cells 

Chronic Inflammation

• Histologic Features
  

  • Infiltration with mononuclear cells

    • [...]

    • [...]

    • [...] cells

  • Tissue destruction

  • Attempts at healing by connective tissue replacement of damaged tissue via:

    • Angiogenesis

    • Fibrosis 

• Macrophages

• Lymphocytes

• Plasma

Chronic Inflammation

• Histologic Features
  

  • Infiltration with mononuclear cells

    • Macrophages

    • Lymphocytes

    • Plasma cells

  • Tissue destruction

  • Attempts at healing by connective tissue replacement of damaged tissue via:

    • [...]

    • [...] 

• Angiogenesis

• Fibrosis

Clotting System

• [...]
  

  • Increases vascular permeability

  • Increases leukocyte emigration 

• Factor Xa

Clotting System

• [...]
  

  • Activates kinin cascade 

• Factor XIIa

Clotting System

• [...]
  

  • Increased leukocyte adhesion and fibroblast proliferation

  • During the formation of the fibrin clot, fibrinopeptides  are formed which increase vascular permeability and chemotaxis 

• Thrombin

Clotting System

• Thrombin
  

  • Increased leukocyte adhesion and fibroblast proliferation

  • During the formation of the fibrin clot, [...]  are formed which increase vascular permeability and chemotaxis 

fibrinopeptides

Complement System

• Anaphylatoxins
  

  • C5a

    • Activates the [...] pathway of arachidonic acid metabolism

    • [major function?]

• lipoxygenase

• Chemotactic factor