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11.3D: Harmful Effects Associated with Abnormal Pattern-Recognition Receptor Responses, Variations in Innate Immune Signaling Pathways, and/or Levels of Cytokine Production

 Skills to Develop

  1. Describe how an overactive TLR-4 receptor can increase the risk of SIRS in a person if Gram-negative bacteria enter the bloodstream.
  2. Briefly describe two specific examples of how an improper functioning PRR can lead to an increased risk of a specific infection or disease.

The Ability of Pathogen-Associated Molecular Patterns or PAMPs to Trigger the Synthesis and Secretion of Excessive Levels of Inflammatory Cytokines and Chemokines

As learned in Unit 3 under sepsis and systemic inflammatory response syndrome (SIRS), during severe systemic infections with large numbers of bacteria present, high levels of cell wall PAMPs are released resulting in excessive cytokine production by the defense cells and this can harm the body (see Fig. 10). In addition, neutrophils start releasing their proteases and toxic oxygen radicals that kill not only the bacteria, but the surrounding tissue as well. Harmful effects include high fever, hypotension, tissue destruction, wasting, acute respiratory distress syndrome (ARDS), disseminated intravascular coagulation (DIC), and damage to the vascular endothelium. This can result in shock, multiple system organ failure (MOSF), and death.

Harmful Effects Associated with either an Overactive or an Underactive Innate Immune Response

There are a number of harmful effects that are known to occur as a result of either an overactive or an underactive innate immune response. This occurs as a result of people possessing different polymorphisms in the various genes participating in PRR signaling.

  • People born with underactive PRRs or deficient PRR immune signaling pathways are at increased risk of infection by specific pathogens due to a decrease innate immune response.
  • People born with overactive PRRs or deficient PRR immune signaling pathways are at increased risk of inflammatory damage by lower numbers of specific pathogens.

Examples include:

1. People with an underactive form of TLR-4, the toll-like receptor for bacterial LPS, have been found to be five times as likely to contract a severe bacterial infection over a five year period than those with normal TLR-4. People with overactive TLR-4 receptors may be more prone to developing SIRS from gram-negative bacteria.

2. Most people that die as a result of Legionnaire's disease have been found to have a mutation in the gene coding for TLR-5 that enables the body to recognize the flagella of Legionella pneumophila.

3. B-lymphocytes, the cells responsible for recognizing foreign antigens and producing antibodies against those antigens, normally don't make antibodies against the body's own DNA and RNA. The reason is that any B-lymphocytes that bind the body's own antigens normally undergo apoptosis, a programmed cell suicide. People with the autoimmune disease systemic lupus erythematosus have a mutation in a gene that signals the cell to undergo apoptosis. As a result, these B-cells are able to bind and engulf the body's own DNA and RNA and place them in an endosome or phagolysosome where the the DNA can be recognized by TLR-9 and the RNA by TLR-7. This, in turn, triggers those B-lymphocytes to make antibody molecules against the body's own DNA and RNA. Another gene error enables these B- cells to increase the expression of TLR-7.

4. TLR-4, MyD88, TLR-1 and TLR-2 have been implicated in the production of atherosclerosis in mice and some humans.

5. Mutations resulting in loss-of-function in the gene coding for NOD-2 that prevents the NOD-2 from recognizing muramyl dipeptide make a person more susceptible to Crohn's disease, an inflammatory disease of the large intestines. Mutations resulting in over-activation in the gene coding for NOD-2 can lead to an inflammatory disorder called Blau syndrome.

6. People with chronic sinusitis that does not respond well to treatment have decreased activity of TLR-9 and produce reduced levels of human beta-defensin 2, as well as mannan-binding lectin needed to initiate the lectin complement pathway.

7. Pathogenic strains of Staphylococcus aureus producing leukocidin and protein A, including MRSA, cause an increased inflammatory response. Protein A, a protein that blocks opsonization and functions as an adhesin, binds to cytokine receptors for TNF-alpha. It mimics the cytokine and induces a strong inflammatory response. As the inflammatory response attracts neutrophils to the infected area, the leukocidin causes lysis of the neutrophils. As a result, tissue is damaged and the bacteria are not phagocytosed.

8. People with chronic mucocutaneous candidiasis disease have a mutation either in the gene coding for IL-17F or the gene encoding IL-17F receptor. TH17 cells secrete cytokines such as IL-17 that are important for innate immunity against organisms that infect mucous membranes.

9. A polymorphism in the gene for TLR-2 makes individuals less responsive to Treponema pallidum and Borrelia burgdorferi and possibly more susceptible to tuberculosis and staphylococcal infections.

10. Polymorphisms in a gene locus called A20, a gene that helps to control inflammation, are considered as risk alleles for rheumatoid arthritis, systemic lupus erythematosus, psoriasis, type I diabetes, and Chron’s disease.

11. The innate immune response to Mycobacterium tuberculosis and the severity of tuberculosis depends on the response of TLRs 1/2, TLR 6, and TLR 9 to the bacterium. Polymorphisms in Toll-interacting protein (TOLLIP), a negative regulator of TLR signaling, influence the response of the patient to M. tuberculosis.

Exercise: Think-Pair-Share Questions

  1. What is the significance of underactive and overactive PRRs in innate immunity?

Therapeutic Possibilities

Researchers are now looking at various ways to either artificially activate TLRs in order to enhance immune responses or inactivate TLRs to lessen inflammatory disorders. Examples of agents being evaluated in clinical studies or animal studies include:

1. TLR activators to activate immune responses

a. Both TLR-4 and TLR-9 activators are being tried in early clinical trials as vaccine adjuvants to improve the immune response to vaccines. TLR-9 activators are being tried as an adjuvant for the hepatitis B and anthrax vaccines and a TLR-4 activator is being tried as an adjuvant for the vaccine against the human papillomaviruses that cause most cervical cancer.
b. Both TLR-7 and TLR-9 activators are being tried in early clinical trials as an antiviral against hepatitis C. Activation of these TLRs triggers the synthesis and secretion of type I interferons that block viral replication within infected host cells.
c. TLR-9 activators are being tried in early clinical trials as an adjuvant for chemotherapy in the treatment of lung cancer.
d. TLR-9 activators are being tried in early clinical trials to help in the treatment and prevention of allergies and asthma. Activation of TLR-9 in macrophages and other cells stimulates these cells to kill TH2 cells, the subclass of T-helper lymphocytes responsible for most allergies and asthma.

2. TLR inhibitors to suppress immune responses

a. General TLR inhibitors might one day be used to treat autoimmune disorders.
b. A TLR-4 inhibitor, a mimic of the endotoxin from the gram-negative cell wall, is being tried in early clinical trials to block or reduce the death rate from Gram-negative sepsis and SIRS.
c. TLR-4, TLR-2, and MyD88 inhibitors might possibly one day lessen atherosclerotic plaques and the risk of heart disease.

Of course using TLR activators or TLR inhibitors to turn up or turn down immune responses also carries risks. Trying to suppress harmful inflammatory responses may also result in increased susceptibility to infections; trying to activate immune responses could lead to SIRS or autoimmune disease.

 

Summary

  1. In severe bacterial infections, pathogen-associated molecular patterns or PAMPs can trigger the synthesis and secretion of excessive levels of inflammatory cytokines and chemokines leading to systemic inflammatory response syndrome or SIRS.
  2. People born with underactive PRRs or deficient PRR immune signaling pathways are at increased risk of infection by specific pathogens due to a decrease innate immune response.
  3. People born with overactive PRRs or deficient PRR immune signaling pathways are at increased risk of inflammatory damage by lower numbers of specific pathogens.
  4. Researchers are now looking at various ways to either artificially activate underactive PRRs in order to enhance immune responses, or inactivate overactive PRRs to lessen inflammatory disorders.

Contributors

  • Dr. Gary Kaiser (COMMUNITY COLLEGE OF BALTIMORE COUNTY, CATONSVILLE CAMPUS)