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Cellular and Molecular Immunology > Inflammation and Cell Trafficking > Flashcards

Inflammation and Cell Trafficking Flashcards

1
Q

What is inflammation?

A
  • Response to injury or infection.
    Multiple cell types and classes of mediators are involved.
  • Acute Response - INNATE IMMUNE SYSTEM
  • Evolutionarily conserved
    Lower vertebrates and invertebrates have cells that respond to injury/infection.
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2
Q

Signs of inflammation

A
  1. Calor - Heat
  2. Rubor - redness (erythema)
  3. Tumor - swelling (edema)
  4. Dolor - Pain
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3
Q

Functions of Inflammation

A
  • Prevent/control infection
  • Promote tissue repair
  • Stimulate adaptive immunity
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4
Q

The major contributors in inflammation

A
  • Resident immune cells (mast cells, macrophages, dendritic cells, epithelial cells).
  • Inflammatory mediators (cell-derived and plasma-derived)
  • Vasculature (endothelial cells lining blood vessels)
  • Circulating immune cells (neutrophils and monocyte=leukocytes)
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5
Q

Resident inflammatory cells

Activation of tissue resident inflammatory cells stimulates recruitment of circulating cells.

A

Present in normal tissue; activated early; release mediators that recruit other cell types.
* Timeframe: Seconds/Minute to Hours.

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6
Q

Circulating cells

Activation of tissue resident inflammatory cells stimulates recruitment of circulating cells.

A

Recruited to sites of inflammation, only represent in inflamed tissues.
* Timeframe: Minutes/Hours to Days.

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7
Q

Infections or injury triggers the activation of resident inflammatory cells, these are:

Initiation of the inflammatory response

A
  • Mast cells
  • Macrophages
  • Dendritic Cells
  • Epithelial Cells
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8
Q

Release of cell-derived inflammatory mediators and activation of plasma proteins stimulates changes in vasculature that contribute to inflammation:

Initiation of the inflammatory response

A
  • Vasodilation increases blood flow (heat, redness).
  • Increase in vascular permeability results in leakage of pro-inflammatory plasma proteins and fluid into the tissue (swelling/edema)>
  • Expression of adhesion molecules by endothelial cells allows movement of inflammatory cells from the circulation into the tissue.
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9
Q

Types of inflammatory mediators (HOST) mediators

Cell-derived mediators

A
  • Peptide amines (histamine)
  • Cytokines
  • Chemokines
  • Lipids (prostaglandins, leukotriened, platelet activating factor)
  • Damage-assocaited molecular patterns (DAMPs or alarmins)
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10
Q

Types of inflammatory mediators (HOST) mediators

Plasma-derived mediators

A
  • Complement system
  • Kinin system
  • Clotting system
  • Fibrinolytic system
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11
Q

Cell-derived Inflammatory mediators

HISTAMINE

Peptide amines

A
  • One of the primary mediators of vascular permeability
  • Produced by platelets, basophils, and mast cells.
  • Primary source: mast cells adjacent to blood vessels.
  • Histamine is stored pre=formed in mast cell granules; degranulation of mast cells after stimulation results in rapid release of granule contents.
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12
Q

Cell-derived Inflammatory mediators

Cytokines and Chemokines

A

Multifunctional proteins that modulate immune responses
Pro-inflammatory cytokines
Chemokines are a subset of chemotactic cytokines
* Chemotaxis = the directed movement of cells
* Chemokine gradients recruit inflammatory cells to the site of injury or infection.
* IL-8 major driver of neutrophil recruitment
* MCP1/CCL2 major driver of monocyte recruitment.

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13
Q

Pro-inflammatory cytokines

A
  • Some of the first mediators released by resident cells to stimulate inflammatory responses.
  • Increase endothelial adehsion molecule expression
  • Activate inflammatory/immune cells.
  • Modulate systemic responses of organism (fever).
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14
Q

Cell-derived Inflammatory mediators

Lipids

Learn image

A

Pro-inflammatory lipids can increase vasodilation, vascular permeability, leukocyte adhesion, and chemotaxis; some also mediate pain and fever

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15
Q

Cell-derived Inflammatory mediators

Damage Associated Molecular Patterns
DAMPs/ALARMINs

Inflammation is stimulated by infection or injury

A
  • Endogenous host molecules that trigger “sterile” inflammation.
  • Analogous to exogenous PAMP (Pathogen Associated Molecular Patterns, LPS, flagellin)
  • Can derive from nucleus or cytoplasm of cell - released from cells upon damage or stimulation.
  • Cytokine-like activity when released extracellularly - stimulated receptors on neighboring cells (toll-like receptors, TLRs, others) - initiate pro-inflammatory signaling cascades (NF-kB activation).
  • DAMP and PAMP bind to - Pattern Recogntion Receptros (PRR).
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16
Q

Plasma-derived inflammatory mediators

Most plasma-derived mediators are parts of complex, cross-regulated protease cascades

A
  • Complement cascade
  • Kinin cascade
  • Clotting system
  • Fibrinolytic System
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17
Q

Plasma-derived inflammatory mediators

Complement cascade

A
  • Opsonins - Coat microbes and enhance phagocytosis
  • Formation of membrane attacj complex on microbes (direct lysis of microbes)
  • Recruits and activates leukocytes (C3a, C5a)
18
Q

Plasma-derived inflammatory mediators

Kinin cascade

A

Bradykinin - increases vascular permeability, vasodilation and pain.

19
Q

Plasma-derived inflammatory mediators

Clotting System

A
  • Activation of thrombin (pro-inflammatory) leads to fribrin clot formation.
  • Assists in recruitment and trafficking of immune cells.
20
Q

Plasma-derived inflammatory mediators

Fibrinolytic System

A
  • Counterbalances the clotting system.
  • Plasmin leaves C3 to produce C3 fragments that enhance inflammation and cleaves fibrin to form pro-inflammatory fibrin products.
21
Q

Inflammatory Cell Traficking

A

Leukocyte accumulation in tissues is the hallmark of inflammation.

22
Q

How do circulating inflammatory cells get from the blood into the tissue

Steps of Inflammatory Cell Trafficking

A
  1. Rolling (selectins)
  2. Integrin activation (chemokines)
  3. Stable adhesion (integrins)
  4. Transmigration (intercellular adhesion molecules)
23
Q

Steps of Inflammatory Cell Trafficking

Rolling
(Initial Step)

  • White cells (leukocytes) migrate from the bloodstream to sites of inflamation or injury.
  • Leukocyte extravasation, involves multiple steps that allow leukocytes to exit the bloodstream and enter tissues to fight infections, repair damage, or maitain immune surveillance.
A
  • Rolling is mediated by molecules called selectins, expressed on edothelial cells or leukocytes.
  • It is the initial, weak interaction between leukocytes and the endothelial cells lining blood vessels.
  • Selectins bind glycoproteins and lycolipids bearing sialyl Lewis (sLeX) residueson the surface of leukocytes (PSGL-1 on leuckocytes). These interactions are relatively weak and transient, allowing the leukocytes to roll along the vessel wall rather than stick firmly.
  • Low affinity binding with fast off-rates allows repetitive attachment/deattchment of cells.

Structure

24
Q

Rolling
(Selectin Expression)

A
  • Surface expression rapidly increases on edothelial cells from stimulation with pro-inflammatory mediators produced by activated resident cells (TNF, histamine, C5a, LTB4).
  • P-selectin is stored in Weibel-Palade bodies in endothelial cells for rapid redistribution to cell membrane after stimulation (timeframe: minutes).
  • E-selectin is synthesized de novo (timeframe: hours).
25
Q

Steps of Inflammatory Cell Trafficking

Integrin Activation
(Step 2)

A
  • Inside-out siganling mediated by chemokines alters the affinity of integrins to increase binding.
  • Chemokines signaling induces conformational change in integrins from low affinity (folded) conformation to high affinity (extended) conformation.
26
Q

Steps of Inflammatory Cell Trafficking

Stable adhesion
(Step 3)

A
  • Chemokines signaling in leukocyte results in the activation of integrins (LFA-1 and VLA-4) that bind strongly to ICAM-1 or ICMA-2 (Intracellular Adhesion Molecule-1 or -2) or VCAM-1 (Vascular Cell Adhesion Molecule-1) on the endothelial cells, which mediate stable adhesion of leukocytes to endothelial cells.
  • Integrin family of proteins mediate cell-cell or cell ECM (extracellular matrix) binding.
  • Structure: Non-covalently linke aB heterodimers. Each subunit has a large extracelullar domain, single transmembrane domain and a short cytoplasmic domain.
  • This firm adhesion alows the leuckocytes to stop rolling and attach firmly to the endothelium at the site of inflammation.
27
Q

Steps of Inflammatory Cell Trafficking

Transmigration
(Step 4)

A

Once firmly adhered, leukocytes migrate through the endothelial cell layer and into the underlying tissue.
* Paracellular route:
Through intercellular junctions
Involves PECAM-1 (expressed by leukocytes and endothelial cells), JAM molecules, and CD99.
* Transcellular route:
Through the endothelial cell body.
Involves ICAM-1, F-actin, and caveolin-1.

28
Q

In vitro assays of Transmigration (transendothelial)

A
  1. Attach to apical surface of the endothelium
  2. Migrate to the intercellular junction.
  3. Diapedese between the endothelial cells.
  4. Detach from th endothelial cells and penetrate their basal lamina.
  5. Crawl through the filter
  6. Detach from the filter and fall into the chamber below.
29
Q

Summary of leukocyte trafficking

A
  1. Rolling - Selectins on endothelium bind weakly to s-Lex on PGSL-1
  2. Activation of integrins (high affinity) by inside-out chemokine signaling.
  3. Stable adhesion - Strong binding of integrins to ICAMs on endothelium.
  4. Transmigration (paracellular or transcellular) of leukocyte through endothelium, basement membrane, pericyte layer, and tissue toward chemokine/chemoattractant gradient.
30
Q

Chemotaxis

A

After passing transmigrating through endothelium, leukocytes migrate through the tissue following a chemoattractant gradient, eventually reaching the site of inflammation.
* Degrade and migrate through the basement memebrane (proteases, MMPs).
* Migrate through pericyte layer.
* Migrate through tissue to site of inflammation.

31
Q

Chemotaxis

Chemoattractans include:

A

Chemokines
IL-8 (neutrophils)
MCP-1/CCL2 (monocyte)
Bacterial products
N-formylmethionine peptides
Complement cascade components
C5a
Lipids
LTV4

32
Q

Outcome of acute inflammation

A

Resolution (The most desired outcome)
Removal of inital stimulus
Termination of inflammation to limit tissue damage
Restoration of tissue to normal state.
Worsening/exacerbation of inflammation - death or acute damge (acute respiratory distress syndrome, multi-organ failure, sepsis).
Chronic Inflammation
Presistence of inflammation
Tissue remodeling, fibrosis.

33
Q

Resolution of Acute Inflammation

The mechanisms by which inflammation resolves are not completely understood, but the production of anti-inflammatory and pro-resolving mediators suggest that resolution is an active process.

A

Elimination of intial inflammatory stimulus.
Degradation/neutralization of pro-inflammatory mediators.
Return to normal vascular permeability.
Drainage of edema fluid and proteins into lymphatics or pinocytosis by macrophages.
Neutrophils undergo programmed cell death (apoptosis).
Phagocytosis of apoptotic neutrophils and cellular debris by macrophages.
Removal of recruited macrophages by apoptosis or migration.
Production of anti-inflammatory cytokines and pro-resolving lipids.

34
Q

Pro-resolving lipids

A

Newly discovered class of lipid mediators

35
Q

Types of anti-inflammatory/pro-resolving lipids

A
  • Lipoxins
  • Resolvins (resolution phase interaction products)
  • Protectins
  • Maresins (macrophage mediator in resolving inflammation).
36
Q

Functions of anti-inflammatory/pro-resolving lipids

A
  • Inhibit vascular permeability
  • Inhibit neutrophil recruitment
  • Stimulate neutrophil clearance by macrophage
37
Q

Lipid mediators of inflammation

A

Most arachidonic acid metabolites (eicosanoids) are pro-inflammatory

38
Q

Lipid mediators of inflammation

A

Anti-inflammatory/pro-resolving lipids are also derived from fatty acids.

39
Q

Differential kinectis of neutrophil and monocyte directed migration towards a focal tissue damage site

A

**Leukotriene B4 (LTB4) **
* Directs neutrophil migration/swarming to site of inflammation

40
Q

Summary

A

Cellular and Molecular Immunology (15 decks)

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