I. THE INNATE IMMUNE SYSTEM

D. EARLY INDUCED INNATE IMMUNITY

7. INFLAMMATION

Fundamental Statements for this Learning Object

1. Most of the body defense elements are located in the blood and inflammation is the means by which body defense cells and defense chemicals leave the blood and enter the tissue around the injured or infected site.
2. As part of the mechanism for inflammation, smooth muscles around larger blood vessels contract to slow the flow of blood through the capillary beds at the infected or injured site. This gives more opportunity for leukocytes to adhere to the walls of the capillary and squeeze out into the surrounding tissue.
3. As part of the mechanism for inflammation, the endothelial cells
that make up the wall of the smaller blood vessels contract. This increases the space between the endothelial cells resulting in increased capillary permeability.
4. As part of the mechanism for inflammation, adhesion molecules are activated on the surface of the endothelial cells on the inner wall of the capillaries and corresponding molecules on the surface of leukocytes called integrins attach to these adhesion molecules allowing the leukocytes to flatten and squeeze through the space between the endothelial cells. This process is called diapedesis or extravasation.
5. As part of the mechanism for inflammation, activation of the coagulation pathway causes fibrin clots to physically trap the infectious microbes and prevent their entry into the bloodstream.
6. Acute inflammation is essential to body defense.
7. As a result of this increased permeability, plasma flows out of the blood into the tissue delivering clotting factors, antibody molecules, complement pathway proteins, nutrients, antibacterial enzymes and peptides, and transferrin for innate body defense.
8. As a result of this increased permeability, leukocytes enter the tissue delivering phagocytic cells, inflammation-inducing cells, cytotoxic T-lymphocytes, effector T4-lymphocytes, and NK cells.
9. Inflammatory cytokines also, enable endothelial cells form a fine network of new capillaries into the injured area to supply blood, oxygen, and nutrients to the inflamed tissue, and enable fibroblasts to deposit the protein collagen in the injured area and form a bridge of connective scar tissue to close the open, exposed area.
10. Chronic inflammation can result in considerable tissue damage and scarring, primarily to extracellular killing by phagocytes and hypoperfusion.
11. Chronic inflammation is thought to also contribute to heart disease, Alzheimer's disease, diabetes, and cancer
.

 

LEARNING OBJECTIVES FOR THIS SECTION

 


D. Early Induced Innate Immunity

Early induced innate immunity begins 4 - 96 hours after exposure to an infectious agent and involves the recruitment of defense cells as a result of pathogen-associated molecular patterns or PAMPs (def) binding to pattern-recognition receptors or PRRs (def). These recruited defense cells include:

Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Instead, it is designed to recognize molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPs (def) and include LPS from the Gram-negative cell wall, peptidoglycan and lipotechoic acids from the Gram-positive cell wall, the sugar mannose (a terminal sugar common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial and viral unmethylated CpG DNA, bacterial flagellin, the amino acid N-formylmethionine found in bacterial proteins, double-stranded and single-stranded RNA from viruses, and glucans from fungal cell walls. In addition, unique molecules displayed on stressed, injured, infected, or transformed human cells also be recognized as a part of innate immunity. These are often referred to as danger-associated molecular patterns or DAMPs.

Most body defense cells have pattern-recognition receptors or PRRs (def) for these common PAMPs (see Fig. 1) enabling an immediate response against the invading microorganism. Pathogen-associated molecular patterns can also be recognized by a series of soluble pattern-recognition receptors in the blood that function as opsonins and initiate the complement pathways. In all, the innate immune system is thought to recognize approximately 103 of these microbial molecular patterns.

We will now take a closer look at inflammation.


7. Inflammation (def)

The inflammatory response is an attempt by the body to restore and maintain homeostasis (def) after injury and is an integral part of body defense. Most of the body defense elements are located in the blood and inflammation is the means by which body defense cells and defense chemicals leave the blood and enter the tissue around the injured or infected site. Inflammation is essentially beneficial, however, excess or prolonged inflammation can cause harm.

1. The Mechanism of Inflammation

Essentially, four processes make up the inflammatory mechanism:

a. Smooth muscles around larger blood vessels contract to slow the flow of blood through the capillary beds at the infected or injured site. This gives more opportunity for leukocytes to adhere to the walls of the capillary and squeeze out into the surrounding tissue.

b. The endothelial cells (def) that make up the wall of the smaller blood vessels contract. This increases the space between the endothelial cells resulting in increased capillary permeability. Since these blood vessels get larger in diameter as a result of this, the process is called vasodilation (see Fig. 1).

Scanning electron micrographs of a cross section of a capillary showing an endothelial cell and a capillary with a red blood cell; courtesy of Dennis Kunkel's Microscopy).

 

 

c. Molecules called selectins are produced on the membrane of the leukocyte and are able to reversibly bind to corresponding selectin glycoprotein receptors on the inner wall of the venule. This reversible binding enables the leukocyte to roll along the inner wall of the venule. This reversible binding enables the leukocyte to roll along the inner wall of the venule. Adhesion molecules are activated on the surface of the endothelial cells on the inner wall of the capillaries. Corresponding molecules on the surface of leukocytes called integrins (def) attach to these adhesion molecules (def) allowing the leukocytes to flatten and squeeze through the space between the endothelial cells. This process is called diapedesis (def) or extravasation.

d. Activation of the coagulation pathway causes fibrin clots to physically trap the infectious microbes and prevent their entry into the bloodstream. This also triggers blood clotting within the surrounding small blood vessels to both stop bleeding and further prevent the microorganisms from entering the bloodstream.

 

a. Early Inflammation and Diapedesis (def)

Most leukocyte diapedesis (extravasation) occurs in post-capillary venules because hemodynamic shear forces are lower in these venules. This makes it easier for leukocytes to attach to the inner wall of the vessel and squeeze out between the endothelial cells. We will look at this process in more detail below.

1) During the very early stages of inflammation, stimuli such as injury or infection trigger the release of a variety of mediators of inflammation such as leukotrienes, prostaglandins, and histamine. The binding of these mediators to their receptors on endothelial cells leads to vasodilation, contraction of endothelial cells, and increased blood vessel permeability. In addition, the basement membrane surrounding the capillaries becoming rearranged so as to promote the migration of leukocytes and the movement of plasma macromolecules from the capillaries into the surrounding tissue.

Mast cells in the connective tissue as well as basophils, neutrophils and platelets leaving the blood from injured capillaries, release or stimulate the synthesis of vasodilators (def) such as histamine (def), leukotrienes (def), kinins (def), and prostaglandins (def). Certain products of the complement pathways (def) (C5a and C3a) can bind to mast cells and trigger their release their vasoactive agents. In addition, tissue damage activates the coagulation cascade and production of inflammatory mediators like bradykinins (def).

2) The binding of histamine to histamine receptors on endothelial cells triggers an upregulation of P-selectin molecules (def) and platelet-activating factor (def) or PAF on the endothelial cells that line the venules.

3). The P-selectins then are able to reversibly bind to corresponding P-selectin glycoprotein ligands (PSGL-1) on leukocytes. This reversible binding enables the leukocyte to now roll along the inner wall of the venule.

4) The binding of PAF to its corresponding receptor PAF-R on the leukocyte upregulates the surface expression of an integrin (def) called leukocyte function-associated molecule-1 (LFA-1) on the surface of the leukocyte.

5) The LFA-1 molecules on the rolling leukocytes can now bind firmly to an an adhesion molecule (def) called intercellular adhesion molecule-1 (ICAM-1) found on the surface of the endothelial cells forming the inner wall of the blood vessel (see Fig. 4).

6) The leukocytes flatten out, squeeze between the constricted endothelial cells, and use enzymes to breakdown the matrix that forms the basement membrane surrounding the blood vessel.  The leukocytes then migrate towards chemotactic agents such as the complement protein C5a and leukotriene B4 generated by cells at the site of infection or injury (see Fig. 5).

 

b. Late Inflammation and Diapedesis

1. Usually within two to four hours of the early stages of inflammation, activated macrophages and vascular endothelial cells release inflammatory cytokines (def) such as TNF and IL-1 when their toll-like receptors bind pathogen-associated molecular patterns (def) - molecular components associated with microorganisms but not found as a part of eukaryotic cells. This enables vascular endothelial cells of nearby venules to increase their expression of adhesion molecules such as P-selectins (def), E-selectins, intercellular adhesion molecules (ICAMs), and chemokines (def).

2) The binding of TNF and IL-1 to receptors on endothelial cells triggers an maintains the inflammatory response by upregulation the production of the adhesion molecule (def) E-selectin and maintaining P-selectin expression on the endothelial cells that line the venules.

3). The E-selectins on the inner surface of the endothelial cells can now bind firmly to its corresponding integrin (def) E-selectin ligand-1 (ESL-1) on leukocytes (see Fig. 4).

4) The leukocytes flatten out, squeeze between the constricted endothelial cells, and move across the basement membrane as they are are attracted towards chemokines such as interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) generated by cells at the site of infection or injury (see Fig. 5). Leakage of fibrinogen (def) and plasma fibronectin (def) then forms a molecular scaffold that enhances the migration and retention of leukocytes at the infected site.

 

 

2. Benefits of Inflammation

As a result of this increased permeability:

a. Plasma (def) flows out of the blood into the tissue.

Beneficial molecules in the plasma (see Fig. 2) include:

1. Clotting factors. Tissue damage activates the coagulation cascade causing fibrin clots to form to localize the infection, stop the bleeding, and chemotactically attract phagocytes.

2. Antibodies (def). These help remove or block the action of microbes through a variety of methods that will be explained in Unit 6.

3. Proteins of the complement pathways (def). These, in turn: 1) stimulate more inflammation (C5a, C3a, and C4a), 2) stick microorganisms to phagocytes (C3b and C4b), 3) chemotactically attract phagocytes ( C5a), and 4) lyse membrane-bound cells displaying foreign antigens (membrane attack complex or MAC).

4. Nutrients. These feed the cells of the inflamed tissue.

5. Lysozyme (def), cathelicidins (def), phospholipase A2 (def), and human defensins (def). Lysozyme degrades peptidoglycan. Cathelicidins are  cleaved into two peptides that are directly toxic to microbes and can neutralize LPS from the gram-negative bacterial cell wall. Phospholipase A2 hydrolyzes the phospholipids in the bacterial cytoplasmic membrane. Human defensins put pores in the cytoplasmic membranes of many bacteria. Defensins also activate cells involved in the inflammatory response.

6. Transferrin (def). Transferrin deprives microbes of needed iron.

 

b. Leukocytes enter the tissue through a process called diapedesis (def) or extravasation, discussed above under early inflammation and late inflammation.

Benefits of diapedesis (def) include (see Fig. 2):

1. Increased phagocytosis. Neutrophils, monocytes that differentiate into macrophages when they enter the tissue, and eosinophils are phagocytic leukocytes.

2. More vasodilation. Basophils, eosinophils, neutrophils, and platelets enter the tissue and release or stimulate the production of vasoactive agents that promote inflammation.

3. Cytotoxic T-lymphocytes (CTLs) (def), effector T4-cells (def), and NK cells (def) enter the tissue to kill cells such as infected cells and cancer cells that are displaying foreign antigens (def) on their surface (discussed in Unit 6).

     

 

Cytokines called chemokines (def) are especially important in this part of the inflammatory response. They play key roles in diapedesis -enabling white blood cells to adhere to the inner surface of blood vessels, migrate out of the blood vessels into the tissue, and be chemotactically attracted to the injured or infected site. They also trigger extracellular killing by neutrophils.

Finally, within 1 to 3 days, macrophages release the cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-α). These cytokines stimulate NK cells and T-lymphocytes to produce the cytokine interferon-gamma. (IF-γ). The IF-γ then binds to receptors on macrophages causing them to produce fibroblast growth factor and angiogenic factors for tissue remodeling. With the proliferation of endothelial cells and fibroblasts, endothelial cells (def) form a fine network of new capillaries into the injured area to supply blood, oxygen, and nutrients to the inflamed tissue. The fibroblasts (def) deposit the protein collagen in the injured area and form a bridge of connective scar tissue to close the open, exposed area. This is called fibrosis or scarring, and represents the final healing stage.

Inflammation is normally carefully regulated by cytokines (def). Inflammatory cytokines such as interferon-gamma and interleukin-12 enhance the inflammatory response whereas the cytokine interleukin-10 inhibits inflammation by decreasing the expression of inflammatory cytokines.

So as can be seen, acute inflammation is essential to body defense. Chronic inflammation, however, can result in considerable tissue damage and scarring. With prolonged increased capillary permeability, neutrophils (def) continually leave the blood and accumulate in the tissue at the infected or injured site. As they discharge their lysosomal contents and reactive oxygen species or ROS (def), surrounding tissue is destroyed and eventually replaced with scar tissue. Anti-inflammatory agents such as antihistamines or corticosteroids may have to be given to relieve symptoms or reduce tissue damage.

For example, as learned in Unit 3, during severe systemic infections with large numbers of microorganisms present, high levels of pathogen-associated molecular patterns (PAMPs) (def) are released resulting in excessive cytokine production by macrophages and this can harm the body. In addition, neutrophils (def) start releasing their proteases (def) and reactive oxygen species (def) that kill not only the bacteria, but the surrounding tissue as well. Harmful effects include high fever, hypotension (def), tissue destruction, wasting, acute respiratory distress syndrome or ARDS (def), disseminated intravascular coagulation or DIC (def), damage to the vascular endothelium, hypovolemia (def), and reduced perfusion (def) of blood through tissues and organs resulting to shock (def), multiple system organ failure (MOSF), and often death. This excessive inflammatory response is referred to as Systemic Inflammatory Response Syndrome or SIRS or the Shock Cascade.

 

TPS Question

 

Chronic inflammation also contributes to heart disease, Alzheimer's disease, diabetes, and cancer.

     

 


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