Module 3.1 Innate Immunity

Question 1

Describe the vascular response to inflammation

Answer 1

1. Vasodilation: increased blood flow to the area resulting in redness and heat
2. Vascular permeability: increases resulting in outward leakage of plasma
3. Cellular infiltration: fluid, proteins, red blood cells and white blood cells adhere to the inner walls of vessels, and then emigrate through vessel walls to the site of injury.
4. Thrombosis: blood flow slows to allow chemical mediators and inflammatory cells to collect and respond to the stimulus. Platelets aggregate to form a clot at the site of injury.
5. Stimulation of nerve endings: Pain results from physical trauma, chemical mediators and/or pressure.

Question 2

Describe the cellular response to inflammation

Answer 2

1. Cells prevent infection & further damage by bringing in fluid to the area of inflammation to dilute toxins produced from the bacteria & from dying cells.
2. The influx of this fluid to the site activates plasma protein systems that help destroy and contain bacteria & it brings neutrophils & macrophages to destroy cellular debris & infectious agents
   
   • The plasma proteins systems limit and control the inflammatory process & prevent it from spreading to healthy tissues
3. Macrophages and lymphocytes interact with the adaptive immunity to elicit a more specific response to the pathogen
4. Macrophages then prepare the area of injury to heal by removing bacterial products, dead cells, and other products of inflammation.

Question 3

What is the role of histamine in the inflammatory response?

Answer 3

• Histamine is a potent vasoactive amine that causes temporary, rapid construction of the large vessel walls and dilation of the postcapillary venues, both of which result in ↑’d vascular permeability resulting from retraction of endothelial cells lining the capillaries
• Histamine is released by degranulation of the mast cell and binds to H1 and H2 cell receptors.

Question 4

What are the effects of histamine binding to the H1 receptor?

Answer 4

• Results in proinflammatory stimulation
• Stimulates neutrophils leading to ↑’d chemotaxis
• Stimulates mast cells leading to ↑’d prostaglandin synthesis
• H1 receptor is present on smooth muscle cells
  
  • H1 plays a significant role in allergic reactions because it causes bronchoconstriction when stimulated

Question 5

What are the effects of histamine binding to the H2 receptor?

Answer 5

• Histamine Is abundant on the parietal cells of the stomach mucosa and when it binds to these cells it induces the secretion of gastric acid.
• When histamine binds to the H2 receptors of leukocytes, it suppresses them resulting in an anti-inflammatory response
  
  • Lymphocytes → ↓’d activity
  • Eosinophil → ↓’d activity
  • Neutrophil → ↓’d chemotaxis
  • Mast Cells → ↓’d degranulation

Question 6

What is the role of leukotrienes in the inflammatory response?

Answer 6

• They are acidic, sulfur-containing lipids that produce effects similar to histamine (smooth muscle contraction, increased vascular permeability, and neutrophil & eosinophil chemotaxis)
• Are important in the later stages of the inflammatory response because they stimulate slower and more prolonged responses than do histamines

Question 7

What is the role of prostaglandins in the inflammatory response?

Answer 7

• Prostaglandin’s are synthesized by mast cells and cause:
  
  • increased vascular permeability
  • Neutrophil chemotaxis,
  • induce pain in response to a stimulus.
• They inhibit some aspects of inflammation by suppressing both the release of histamine from mast cells & the release of lysosomal enzymes (the ones that kill and digest microorganisms) from neutrophils.
• Enhancement or suppression of the inflammatory response may be related to the concentration of prostaglandins.

Question 8

How are mast cells activated?

Answer 8

• In response to physical injury (heat, x-ray, UV, trauma), chemical agents (toxins, antimicrobial peptides), immunologic reactions, or activation of TLR (toll-like receptors) by bacteria or viruses, mast cells are activated releasing biochemical mediators (including histamine, chemotactic factors, and cytokines) within seconds and exert their effects immediately.

Question 9

What role do chemotactic factors from mast cells play in inflammation?

Answer 9

• Neutrophil chemotactic factor - attracts neutrophils to the site
  
  • These are the predominant leukocytes at work during the early phases of acute inflammation
• ECF-A attracts eosinophils to the site of inflammation

Question 10

What are cytokines?

Answer 10

Soluble factors released by cells that contribute to the regulation of innate or adaptive resistance by affecting other neighboring cells. These molecules diffuse, bind to appropriate target cells and affect the function of the cell. These factors are either pro-inflammatory or anti-inflammatory.

• Cytokines: Interleukins, interferons, and tumor necrosis factor-alpha (TNF-alpha). Involved in the systemic effects of inflammation i.e., fever and leukocytosis, C - reactive protein.

Question 11

What is the role of bradykinin in the inflammatory response?

Answer 11

• Acts with prostaglandins to:
  
  1. stimulate nerve endings and induce pain,
  2. Causes smooth muscle cell contraction
  3. Increases vascular permeability
  4. May increase leukocyte chemotaxis
• Induces smooth muscle contraction more slowly than histamine, and is responsible for ↑’d vascular permeability in later phases of inflammation.

Question 12

What is the role of nitric oxide (NO) in the inflammatory response?

Answer 12

• Nitric oxide is a gas released by endothelial cells that under normal conditions maintains vascular tone
• Inflammation induces additional endothelial nitric oxide synthase, increasing the amount of NO production
• Nitric oxide:
  
  • Causes vasodilation by inducing relaxation of vascular smooth muscle, a response that is local and short-lived
  • Suppresses mast cell function, platelet adhesion & aggregation

Question 13

What are interleukins and what is their role in inflammation?

Answer 13

• They are biochemical messengers produced predominately by macrophages and lymphocytes in response to their recognition of a microorganism or stimulation by other products of inflammation
• They enhance the adaptive immune response against pathogenic microorganisms and other foreign substances
• IL-1
  
  • Causes fever → enhanced activity by phagocytes and leukocytes
  • Neutrophils → Induces their proliferation, causes chemotaxis, ↑ cellular respiration, and ↑’d lysosomal enzyme activity
• IL-6
  
  • Induces hepatocytes to produce proteins needed in inflammation
  • Stimulates the growth & differentiation of blood cells in the bone marrow.

Question 14

What are interferons and what is their role in inflammation?

Answer 14

• Low molecular weight proteins that primarily protect against viral infections and modulate the inflammatory response.
• They are produced and released by virally infected cells in response to viral RNA, are also produced by macrophages, & t-lymphocytes
• Interferons enhance the efficiency of developing an adaptive immune response
• Interferons can also increase the microbicidal activity of macrophages

Question 15

What is TNF-α and what is its role in inflammation?

Answer 15

• It is secreted by macrophages and mast cells and:
  
  1. It induces fever by acting as an endogenous pyrogen
  2. Causes ↑’d synthesis of proinflammatory proteins by the liver
  3. Causes muscle wasting (cachexia) and intravascular thrombosis as a consequence of prolonged production in cases of severe infection or cancer

Question 16

What is the role of neutrophils in the inflammatory process?

Answer 16

• They are the predominant phagocytes in the early inflammatory site; arriving 6-12 hours after the initial injury, where they ingest (phagocytose) bacteria, dead cells, and cellular debris.
• They have short lives at the site of inflammation and when they die they become a component of the purulent exudate (pus).
  
  • Bands are immature neutrophils and increase during acute infections
• Their primary role is the removal of debris in sterile lesions such as burns, and phagocytosis of bacteria in nonsterile lesions.

Question 17

What is the role of eosinophils in the inflammatory process?

Answer 17

• They serve as the body’s primary defense against parasites and they help regulate vascular mediators released from mast cells.

Question 18

What is the role of monocytes & macrophages in the inflammatory process?

Answer 18

• Monocytes are produced in the bone marrow, enter the circulation, and migrate to sites of inflammation where they develop into macrophages.
• Macrophages are larger than monocytes and are more active as phagocytes than their monocytic precursors.

Question 19

Describe the process of phagocytosis

Answer 19

• Monocytes move toward the highest concentration of chemotactic factors.
• Once at the site of inflammation, the process of phagocytosis involves 4 steps:
  
  1. Opsonization - Regocnition of the target and adherence to it
  2. Engulfment - of the microorganism by ingestion or endocytosis
  3. Fusion - w/ lysosomal granules within the phagocyte (w/ its phagolysosome)
  4. Destruction - of the target

Question 20

What is the role of natural killer cells in the inflammatory process?

Answer 20

• These cells recognize and eliminate cells infected w/ viruses, although they are also somewhat effective at elimination of other abnormal host cells (ex: cancer)
• They are more efficient when they encounter an infected cell within the circulatory system as opposed to within tissues.

Question 21

What are the local manifestations of inflammation?

Answer 21

• All local manifestations of acute inflammation result from vascular changes and the subsequent leakage of circulating components into the tissue
  
  • Heat & redness - caused by vasodilation & ↑’d blood flow through the injured site
  • Swelling - occurs as exudate (fluid and cells) accumulates
  • Pain - Is usually caused by the pressure exerted by exudate accumulation, as well as by prostaglandins and bradykinin.

Question 22

What are the systemic manifestations of acute inflammation?

Answer 22

• The 3 primary systemic changes associated w/ acute inflammation are fever, leukocytosis (a transient ↑ in the levels of circulating leukocytes), and plasma protein synthesis (↑’d lvls of circulating plasma proteins)
  
  1. Fever is induced by cytokines released from neutrophils & macrophages; they act directly on the hypothalamus increasing the body’s temperature.
  2. Leukocytosis leads to a “left shit” with an increased ratio of immature (bands) to mature (neutrophils, macrophages) cells
  3. The erythrocyte sedimentation rate increases because of an increase in fibrinogen and other acute phase reactants. This is clinically useful as a nonspecific sign of inflammation

Question 23

Describe chronic inflammation

Answer 23

• Chronic inflammation lasts 2 weeks or longer, regardless of cause
• Is sometimes proceeded by an unsuccessful acute inflammatory response
• Chronic inflammation is characterized by pus formation, suppuration (purulent discharge), incomplete wound healing, and dense infiltration of lymphocytes and macrophages
• The body may wall off and isolate the site of infection to form a granuloma