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Flashcards in Pathology week 2 Deck (53):

What is the immune system composed of?

cells: white blood cells (leukocytes) derived from the hematopoietic stem cell pool

- Peripherpal: spleen (filters blood), lymph nodes (filters lymph), Peyer’s patches (intestine), tonsils, adenoids

- Central: (develops immune cells) thymus, bone marrow



Identify the consequences to the host when effective immune responses are not generated

Dire consequences occur when effective Immune Responses are not made: disease, allergy autoimmunity, death,



What are the cell derived mediators?

Cell derived: (2 categories)

  1. Preformed: intracellular granules, pre-formed, secreted
    • Histamin, serotonin
  2. Newly Synthesized: de novo
    • prostaglandins
    • Leukotrienes
    • Platelet activating factor
    • ROS
    • NO
    • Cytokines
    • Neuropeptides


Describe Histamine as an inflammation mediator:


- Source: Mast cells, basophils, platelets
- Action: Vasodilation, increased vascular permeability, endothelial activation
- Release: Preformed histamine from mast cell granules in response to:

  • physical injury such as trauma or heat
  • immune reactions involving binding of IgE antibodies to Fc receptors on mast cells
  • C3a and C5a fragments of complement, the so-called anaphylatoxins
  • Leukocyte-derived histamine-releasing proteins
  • Neuropeptides (e.g., substance P); and certain cytokines (e.g., IL-1, IL-8)


Describe Serotonin as an inflammation mediator: - source: - action:

Source: Platelets 
Action: Vasoconstriction
Release: platelet aggregation


Describe Platelet-activating factor as an inflammation mediator: - source: - action:

Platelet-activating factor
Source: Leukocytes, mast cells 
Action: Vasodilation, increased vascular permeability, leukocyte adhesion, chemotaxis, degranulation, oxidative burst (100-10,000x more potent than histamine) Stimulates leukocyte recruitment and activation, synthesis of AAs


Describe Reactive oxygen species (ROS) as an inflammation mediator: - source: - action:

Reactive oxygen species (ROS):

- Source: Leukocytes
- Action: Killing of microbes, tissue damage

  • Amplifying the cascade of inflammatory mediators
  • Tissue injury by several mechanisms, including
    1. endothelial damage, with thrombosis and increased permeability;
    2. protease activation and antiprotease inactivation, with a net increase in breakdown of the ECM; and
    3. direct injury to other cell types
  • countered by protective mechs (anti-oxidants): catalase, superoxide dimutase)


Describe chemokines as an inflammation mediator:

- source:
- action:

Source: Leukocytes, activated macrophages

Action: chemotaxis, leukocyte activation Recruit leukocytes to the site of inflammation and to control the normal anatomic organization of cells in lymphoid and other tissues


Describe nitric Oxide: as an inflammation mediator: - source: - action:

Source: Endothelium, macrophages

Action: Vascular smooth muscle relaxation; killing of microbes


Describe the mediator cytokines (Tumor Necrosis Factor (TNF), Interleukin: IL-1, IL-6):

Source: Macrophages, endothelial cells, mast cells


  • Local: endothelial activation (expression of adhesion molecules).
  • Systemic: fever, metabolic abnormalities, hypotension (shock)
  • Release: IC, endotoxin, T cells = Pyrogens (fever causing substance) cause macrophages to release IL-1 and TNF and increase COX activity in perivascular cells of hypothalamus, increased PGE2 raises temp set point


What are the plasma derived inflammation mediators?

Plasma derived:

  1. Complement,
  2. Factor XII (Hageman) activation
    • Kinin system
    • Coagulation/fibrinolysis


Describe the complement mediator pathway for inflammation:

Complement: proinflammatory serum proteins, circulate as inactive precursors, “complement inflammation”

  •  Definition: a set of 9 plasma proteins (C1-9) that act together to eliminate extracellular forms of pathogens
  • Major functions: Opsonization (a pathogen is marked for ingestion and destruction by a phagocyte) and Chemotaxis
  • Tip: Also involved in adaptive immune mechanisms (classic pathway)
  • All roads (3 pathways) lead to Rome or in this case the synthesis of C3 convertase


  • Classical pathway: C1 binds to IgG or IgM that is bound to antigen pneumonic:“GM makes classic cars”
  • Alternative pathway: microbial products directly activate complement Mannose binding lectin pathway - MBL binds mannose on microorganisms and activates complement
    • Result: C3 convertase => C5 convertase => formation of MAC (creates hole in organism) C3a and C5a - trigger mast cell degranulation C5a
      • chemotactic for neutrophils; helps activates neutrophils C3b
      • opsonin for phagocytosis MAC - lyses microbes by creating holes in cell membrane


Describe Kinins: as an inflammation mediator:

- source:

- action:

Source: Plasma (produced in liver)

Action: Increased vascular permeability, smooth muscle contraction, vasodilation, pain


Describe Proteases activated during coagulation as an inflammation mediator: - source: - action:

Source: Plasma (produced in liver)

Action: Endothelial activation, leukocyte recruitment


What is inflammation?

Inflammatory cells, plasma proteins, and fluid are allowed to exit blood vessels and enter the interstitial space.


What characterizes acute inflammation and what is it in response to?

Characterized by presence of edema and neutrophils (key inflammatory cell) in tissue Arises in response to infection or tissue necrosis

  • *acute inflammation and necrosis therefore 24 hrs after infarction increased WBC count and presence of neutrophils & edema*
  • Goal: eliminate pathogen or clear necrotic debris
  • Immediate response with limited specificity, part of the innate immunity


What are the steps in the inflammatory response?

The steps of the inflammatory response can be remembered as the five Rs:

  1. Recognition of the injurious agent
  2. Recruitment of leukocytes,
  3. Removal of the agent,
  4. Regulation (control) of the response
  5. Resolution (repair)


What are the mediators of acute inflammation?

TLR, arachidonic acid, mast cell, complement, Hageman Factor (Factor XII)


Describe how TLR mediates acute inflammation:

TLR: (toll like receptor) present on cells of the innate immune system. (macrophages and dendritic cells).

  • Activated by pathogen associated molecular patterns (PAMPs) that are commonly shared by microbes.
    • example: CD14 on macrophages recognizes LPS on the outer membrane of GN bateria (LPS is the PAMP)
  • TLR activation results in upreguation of NF-kB (a nuclear transcription factor that activates immune response genes leading to the production of multiple immune mediators.)
  • TLR also mediates in chronic inflammation


Compare and contrast the cell types that are active in innate vs adaptive immune responses

Innate: (always immediately available but not specific, first line of defense)

Phagocytes (neutrophils, dendritic cells and  macrophages) and Natural Killer cells

Adaptive: specific (can take up to a week) needs sufficient signal to be activated

B and T lymphocytes (CD4 T cells help both B cells and CTL precursors to become effector cells)

Adaptive immune response have two arms: humoral (antibody-mediated) and cell-mediated


Extracellular pathogens are eliminated by Ab & phagocytosis; Intracellular pathogens are eliminated by immune-mediated killing of infected cells



What is the purpose of vascular changes as an inflammatory response?

Designed to bring blood cells and proteins to the sites of infection or injury


Describe the types of vascular changes that occur in an inflammatory response.

  • Vasodilation:
    • Arteriolar vasodilation
    • Causes erythema (redness and warmth)
  • Increased Vascular permeability
    • Endothelial contraction leads to intercellular gaps (mediators histamine, bradykinin, leukotrienes); rapid
    • Direct injury (infections, burns)
    • Leukocyte mediated injury
  • Endothelial cells are activated
    • increased adhesion of leukocytes
    • migration of leukocytes through the vessel wall


Descibe cellular events that take place during inflammatory responses.

  • Recruitment of leukocytes from circulation and accumulation in the focus of the injury
  • Followed by activation of leukocytes to  eliminate offending agent
  • Phagocytosis
  • Destroy phagocytosed microbes or intercellular killing
  • Produce mediators which amplify inflammatory response


List the classic signs of inflammation

Dolor - pain

Calor - heat

Rubor - redness

Tumor - swelling

Functio laesa - loss of function


What is dolor?

Pain. It is one of the cardinal signs of inflammation.

Dolor - pain

Calor - heat

Rubor - redness

Tumor - swelling

Functio laesa - loss of function


What is calor?

Heat. One of the classic signs of inflammation.

Dolor - pain

Calor - heat

Rubor - redness

Tumor - swelling

Functio laesa - loss of function


What is rubor?

Redness. One of the cardinal signs of inflammation.

Dolor - pain

Calor - heat

Rubor - redness

Tumor - swelling

Functio laesa - loss of function


What is tumor (wrt inflammation)?

Swelling. One of the cardinal signs of inflammation.

Dolor - pain

Calor - heat

Rubor - redness

Tumor - swelling

Functio laesa - loss of function


What is functio laesa?

Loss of function. One of the cardinal signs of inflammation.

Dolor - pain

Calor - heat

Rubor - redness

Tumor - swelling

Functio laesa - loss of function


What are the principal events in the inflammatory process?

  1. Recognition of the injurious agent.
  2. Recruitment of leukocytes
  3. Removal of the agent
  4. Regulation of the response
  5. Resolution (repair)


Describe what happens when leukocytes are recruited to the injured area.

  1. Margination, adhesion and rolling

    1. Marginations: laminar flow slows to allow leukocytes to move from center of vessels to the periphery

    2. Adhesion: slowing leukocytes transiently stick along the vessel walls (rolling)

    3. Weak and transient adhesions are due to selectin molecules--receptors on leukocytes which bind sugars

      1. E-selectin: expressed on endothelial cells; induced by IL-1 and TNF

      2. P-selectin: expressed on endothelial ells and platelets; upregulated after stimulation by mediators (histamine)

  2. Firm adhesion to endothelium

    1. Integrins: transmembrane glycoproteins found on leukocytes

      1. Low affinity state conformationally changes to high affinity state by chemokines

      2. Binds endothelial ligands

      3. Binds leukocytes ICAM-I and VCAM-I

  3. Transmigration between endothelial cells

    1. Migrate through vessel at intercellular junctions

    2. Diapedesis: capillaries and venules

    3. Driven by chemokines and PECAM-I (platelet endothelial cell adhesion molecule I)

  4. Migration to stimulus through interstitial tissue


Describe what happens when the host recognizes an injurious agent. 

Phagocytes, dendritic cells, and other cells express PRRs that recognize structures that are common to many microbes, products of necrotic cells, mediators

  • Common PRRs
    • Toll-like receptors (TLR)- microbial sensors that recognize products of bacteria, viruses, and other pathogens
    • Located in plasma membranes and endosomes so they can detect extracellular and ingested microbes
  • Bound receptors activate transcription factors that stimulate the production secreted and membrane proteins (mediators of inflammations, antiviral cytokines (interferons), and proteins that promote lymphocyte activation and even more potent immune responses
  • Inflammasomes - protein complex that recognizes products of dead cells (uric acid and extracellular ATP) which triggers leukocyte recruitment


What cells are involved in the chronic inflammatory response?

  1. Macrophages

    1. Derived from monocytes

    2. Normally part of connective tissue

    3. Lives for one day circulating before entering tissue

    4. Large, flat, eosinophilic

    5. Activated by:

      1. Bacterial endotoxins

      2. Cytokines

      3. Mediators

      4. Fibroconectin (ECM proteins)

      5. Secretion of products that signal killing of bacteria, activate other inflammatory cells, initiate healing

  2. Lymphocytes

    1. Mobilized from circulation to inflammatory site

    2. B and T cells

    3. Interact with macrophages bidirectional

  3. Plasma cells

  4. Eosinophils

    1. Characteristic for allergic reactions and parasitic infections

    2. Mediated by IgE

    3. Contains specific granules, major basic protein, toxic to parasites but also causes epithelial cell necrosis

  5. Mast cells

    1. Seen with both acute and chronic reactions

    2. Common in allergic patients, armed with IgE

    3. Release histamines and mediators when activated by environmental factors

    4. Central in allergic reactions


What cells are involved in the acute inflammatory response?

Neutrophils: clearing the area

Other cells: produce inflammatory mediators


What type of inflammatory response are macrophages associated with?

Chronic inflammatory response


What type of inflammatory response are neutrophils associated with?

Acute inflammatory response


What are the types of acute inflammation?

  1. Serous Inflammation:

    1. Watery protein poor fluid

    2. Effusion = fluid in a cavity

  2. Fibrinous Inflammation:

    1. Results from injury and increased vascular permeability allowing larger molecules to pass

    2. Fibrinogen - eosinophilic threads

    3. Line body cavities

    4. Exudate

    5. May resolve (normal) or scar (organize)

  3. Suppurative Inflammation (Purulent)

    1. Purulent exudate (pus)

    2. Neutrophils, necrotic cells, edema

    3. Bacterial organisms may be present

  4. Abscess

    1. Focal collection of pus

    2. Central necrotic area rimmed by neutrophils

    3. Surrounded by dilated vessels, fibroblasts

    4. Liquefactive necrosis

  5. Ulcer

    1. Defect in an organ of tissue surface produced by necrosis and sheds necrotic inflammatory tissue

      1. Mouth, GI, mucosa

      2. Ischemia of lower extremities

      3. Pressure


What type of inflammation is characterized by watery, protein-poor fluid?

Serous Inflammation


What is the definition of acute inflammation?

rapid in onset and short duration (few minutes-few days); characterized by fluid and plasma protein exudation and predominantly neutrophilic leukocyte accumulation


What stimulates acute inflammation?

  • Infections: bacterial, viral, fungal, parasitic
  • Trauma: blunt and penetrating
  • Tissue necrosis: ischemia, physical/chemical injury
  • Foreign bodies: splinters, dirt, etc.
  • Immune Reactions: hypersensitivity reactions against environmental substances or self-tissues (tends to persist)


Define chronic inflmmation.

Insidious onset; Long (day to years); lymphocytes, macrophages, vascular proliferation, scarring


What are the stimuli of chronic inflammation?

  • Persistent infections: difficult to eradicate
  • Immune mediated inflammatory diseases
  • Prolonged exposure to toxic agents


Describe how Arachidonic Acid mediates acute inflammation: Arachidonic Acid:

  • Released from the phospholipid cell membrane by phospholipase A2
  • Acted on by cyclooxygenase or 5-lipooxygenase
  • Cyclooxygenase produces prostaglandins (PG)
    • PGI2, PGD, PGE2 mediate vasodilation (arteriole) and increased vascular permeability (post-capillary venule)
    • PGE2 also mediates fever and pain
  • 5-lipoxygenase produces leukotrienes (LT)
    • LTB4 attracts and activates neutrophils (other key mediators that attract neutrophils: C5A, IL8, bacteria)
    • LTC4, LTD4, LTE4 cause smooth muscle to contract therefore mediates vasoconstriction, bronchospasm, and increased vascular permeability
      • LT contracts the smooth muscle under the cells lining a vessel which allows fluid out of the vessel


Describe prostaglandins as an inflammation mediator:

Source: Mast cells, leukocytes

  • Products of the cyclooxygenase pathway include prostaglandin E 2 (PGE 2), PGD 2, PGF 2α, PGI 2 (prostacyclin), and thromboxane A 2 (TXA 2)

Action: Vasodilation, pain, fever

  • PGE 2 augments pain sensitivity to a variety of other stimuli and interacts with cytokines to cause fever.


Describe how Mast Cell mediates acute inflammation:


Mast Cell: widely distributed through connective tissue

  • Activated by: trauma, complement protein C3a and C5a, cross linking of cell surface IgE by antigen
  • Immediate response: release histamine granules => mediates vasodilation of arterioles and increased vascular permeability (postcapillary venule)
  • Delayed response: production of arachnidonic acid metabolites, particularly leukotrines


Describe defects in leukocyte adhesion.

In leukocyte adhesion deficiency type 1 (LAD-1), defective synthesis of the CD18 β subunit of the leukocyte integrins LFA-1 and Mac-1 leads to impaired leukocyte adhesion to and migration through endothelium, and defective phagocytosis and generation of an oxidative burst.Leukocyte adhesion deficiency type 2 (LAD-2) is caused by a defect in fucose metabolism resulting in the absence of sialyl–Lewis X, the oligosaccharide on leukocytes that binds to selectins on activated endothelium. Its clinical manifestations are similar to but milder than those of LAD-1.



Describe defects in microbicidal activity:


An example is chronic granulomatous disease, a genetic deficiency in one of the several components of the phagocyte oxidase enzyme that is responsible for generating ROS. In these patients, engulfment of bacteria does not result in activation of oxygen-dependent killing mechanisms. In an attempt to control these infections, the microbes are surrounded by activated macrophages, forming the “granulomas” (see later) that give the disease its distinctive pathologic features and its somewhat misleading name.


Describe defects in phagolysosome formation

One such disorder, Chédiak-Higashi syndrome, is an autosomal recessive disease that results from disordered intracellular trafficking of organelles, ultimately impairing the fusion of lysosomes with phagosomes. The secretion of lytic secretory granules by cytotoxic T lymphocytes is also affected, explaining the severe immunodeficiency typical of the disorder.


Describe gain-of-function mutations in genes encoding some components of the inflammasome,

One of which is called cryopyrin, are responsible for rare but serious diseases called cryopyrin-associated periodic fever syndromes (CAPSs), which manifest with unrelenting fevers and other signs of inflammation and respond well to treatment with IL-1 antagonists.


Describe the systemic effects of inflammation, and how these are regulated.

  • Fever: 
  • Elevated plasma levels of acute-phase proteins:
  • Leukocytosis
  • Increased heart rate and blood pressure
  • Decreased sweating, mainly as a result of redirection of blood flow from cutaneous to deep vascular beds, to minimize heat loss through the skin
  • Rigors (shivering), chills (perception of being cold as the hypothalamus resets the body temperature), anorexia, somnolence, and malaise, probably secondary to the actions of cytokines on brain cells.


Describe elevated plasma levels of acute phase protein in systemic response to inflammation:

Sythesized in liver: 3 of the best known of these proteins are C-reactive protein (CRP), fibrinogen, and serum amyloid A (SAA) protein.

Hepatocytes is stimulated by cytokines, especially IL-6. Many acute-phase proteins, such as CRP and SAA, bind to microbial cell walls, and they may act as opsonins and fix complement, thus promoting the elimination of the microbes.

Fibrinogen binds to erythrocytes and causes them to form stacks (rouleaux) that sediment more rapidly at unit gravity than individual erythrocytes.

This is the basis for measuring the erythrocyte sedimentation rate (ESR) as a simple test for the systemic inflammatory response, caused by any number of stimuli, including LPS.

Serial measurements of ESR and CRP are used to assess therapeutic responses in patients with inflammatory disorders such as rheumatoid arthritis.

Elevated serum levels of CRP are now used as a marker for increased risk of myocardial infarction or stroke in patients with atherosclerotic vascular disease. It is believed that inflammation is involved in the development of atherosclerosis and increased CRP is a measure of inflammation.


Describe the fever response in inflammation:

***Fever: Pyrogens cause macrophages to release IL-1 and TNF and increase COX activity in perivascular cells of hypothalamus, increased PGE2 raises temp set point


Describe the systemic leukocytosis response in inflammation:

  • Think infection: leukocyte count usually climbs to 15,000 to 20,000 cells/mL, but in some extraordinary cases it may reach 40,000 to 100,000 cells/mL.
  • extreme elevations: leukemoid reactions similar to those seen in leukemia.
  • occurs initially because of accelerated release of cells (under the influence of cytokines, including TNF and IL-1) from the bone marrow postmitotic reserve pool.
  • Both mature and immature neutrophils may be seen in the blood; the presence of circulating immature cells is referred to as a “shift to the left.”
  • Prolonged infection also stimulates production of colony-stimulating factors (CSFs), which increase the bone marrow output of leukocytes, thus compensating for the consumption of these cells in the inflammatory reaction.
  • Most bacterial infections induce an increase in the blood neutrophil count, called neutrophilia. Viral infections, such as infectious mononucleosis, mumps, and German measles, are associated with increased numbers of lymphocytes (lymphocytosis). Bronchial asthma, hay fever, and parasite infestations all involve an increase in the absolute number of eosinophils, creating an eosinophilia.
  • Certain infections (typhoid fever and infections caused by some viruses, rickettsiae, and certain protozoa) are paradoxically associated with a decreased number of circulating white cells (leukopenia), likely because of cytokine-induced sequestration of lymphocytes in lymph nodes.

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