I. THE INNATE IMMUNE SYSTEM

B. PATHOGEN-ASSOCIATED MOLECULAR PATTERNS (PAMPs), PATTERN-RECOGNITION RECEPTORS, AND CYTOKINES

The overall purpose of this Learning Object is:
1) to learn how the innate immune system uses pattern-recognition receptors to detect conserved microbial molecules in order to detect microbial invasion and initiate innate immune defenses; and
2) to learn introduce how cytokines function to regulate innate immune defenses.

LEARNING OBJECTIVES FOR THIS SECTION

 

Innate immunity is an antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to almost any microbe. This is the immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection.

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 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 act as PAMPS.

Most body defense cells have pattern-recognition receptors for these common PAMPS and so there is 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.

The innate immune responses do not improve with repeated exposure to a given infection and involve the following:

Examples of innate immunity include anatomical barriers, mechanical removal, bacterial antagonism, pattern-recognition receptors, antigen-nonspecific defense chemicals, the complement pathways, phagocytosis, inflammation, and fever.

We will now take a closer look at pattern-recognition receptors and cytokines.

B. Pathogen-Associated Molecular Patterns (PAMPs), Pattern-Recognition Receptors, and Cytokines

1. Pathogen-Associated Molecular Patterns (PAMPs)

In order to protect against infection, one of the first things the body must do is detect the presence of microorganisms. The body initially does this by recognizing molecules unique to groups of related microorganisms and are not associated with human cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPs. In addition, unique molecules displayed on stressed, injured, infected, or transformed human cells also act as PAMPs. In all, the innate immune system is thought to recognize approximately 103 molecular patterns.

Examples of microbial-associated PAMPs include:

a. lipopolysaccharide (LPS) from the outer membrane of the gram-negative cell wall (see Fig. 2);

b. bacterial lipoproteins and lipopeptides (see Fig. 2);

c. porins in the outer membrane of the gram-negative cell wall (see Fig. 2);

d. peptidoglycan found abundantly in the gram-positive cell wall and to a lesser degree in the gram-negative cell wall (see Fig. 3);

e. lipoteichoic acids found in the gram-positive cell wall (see Fig. 3);

f. lipoarabinomannan found in acid-fast cell walls (see Fig. 4)

g. mannose-rich glycans (short carbohydrate chains with the sugar mannose or fructose as the terminal sugar). These are common in microbial glycoproteins and glycolipids but rare in those of humans.

h. flagellin found in bacterial flagella;

i. bacterial and viral nucleic acid. Bacterial and viral genomes contain a high frequency of unmethylated cytosine-guanine dinucleotide or CpG sequences (a cytosine lacking a methyl or CH3 group and located adjacent to a guanine). Mammalian DNA has a low frequency of CpG sequences and most are methylated;

j. N-formylmethionine, an amino acid common to bacterial proteins;

k. double-stranded viral RNA unique to many viruses in some stage of their replication;

l. single-stranded viral RNA from many` viruses having an RNA genome;

m. lipoteichoic acids, glycolipids, and zymosan from yeast cell walls; and

n. phosphorylcholine and other lipids common to microbial membranes.

Examples of PAMPs associated with stressed, injured, infected, or transformed host cells and not found on normal cells include:

a. heat-shock proteins

b. altered membrane phospholipids

 

2. Pattern-Recognition Receptors (PRRs)

To recognize PAMPs such as those listed above, various body cells have a variety of corresponding receptors called pattern-recognition receptors or PRRs (see Fig. 5) capable of binding specifically to conserved portions of these molecules. Cells that typically have pattern recognition receptors include macrophages (def), dendritic cells (def), endothelial cells (def), mucosal epithelial cells, and lymphocytes (def).

Many pattern-recognition receptors are located on the surface of these cells where they can interact with PAMPs on the surface of microbes. Others PRRs are found within the phagolysosomes of phagocytes where they can interact with PAMPs located within microbes that have been phagocytosed. Some PRRs are found in the cytosol of the cell.

There are two functionally different major classes of pattern-recognition receptors: endocytic pattern-recognition receptors and signaling pattern-recognition receptors.

a. Endocytic Pattern-Recognition Receptors

Endocytic pattern-recognition receptors are found on the surface of phagocytes and promote the attachment of microorganisms to phagocytes leading to their subsequent engulfment and destruction. They include:

1. mannose receptors

Mannose receptors on the surface of phagocytes bind mannose-rich glycans, the short carbohydrate chains with the sugar mannose or fructose as the terminal sugar that are commonly found in microbial glycoproteins and glycolipids but are rare in those of humans. Human glycoproteins and glycolipids typically have terminal N-acetylglucosamine and sialic acid groups. C-type lectins found on the surface of phagocytes are mannose receptors (see Fig. 6).

2. scavenger receptors

Scavenger receptors found on the surface of phagocytic cells bind to bacterial cell wall components such as LPS, peptidoglycan and teichoic acids (see Fig. 7). There are also scavenger receptors for certain components of other types of microorganisms, as well as for stressed, infected, or injured cells . Scavenger receptors include CD-36, CD-68, and SRB-1.

3. opsonin receptors

Opsonins are soluble molecules produced as a part of the body's immune defenses that bind microbes to phagocytes. One portion of the opsonin binds to a PAMP on the microbial surface and another portion binds to a specific receptor on the phagocytic cell.

  • Acute phase proteins in the plasma, such as:
    • mannose-binding lectin (also called mannose-binding protein) that recognize short carbohydrate chains with the sugar mannose or fructose as the terminal sugar; and
    • C-reactive protein (CRP) that binds to phosphorylcholine in bacterial membranes and phosphatidylethenolamine in fungal membranes.
  • Complement pathway proteins, such as C3b (see Fig. 8) and C4b recognize a variety of PAMPS.
  • Surfactant proteins in the alveoli of the lungs, such as SP-A and SP-D are opsonins.
  • During adaptive immunity, the antibody molecule IgG can function as an opsonin.

 

 

4. N-formyl Met receptors

N-formyl methionine is the first amino acid produced in bacterial proteins since the f-met-tRNA in bacteria has an anticodon complementary to the AUG start codon. This form of the amino acid is not typically seen in mammalian proteins. FPR and FPRL1 are N-formyl receptors on neutrophils and macrophages. Binding of N-formyl Met to its receptor promotes the motility and the chemotaxis of these phagocytes. It also promotes phagocytosis.

 

b. Signaling Pattern-Recognition Receptors

Signaling pattern-recognition receptors bind a number of microbial molecules: LPS, peptidoglycan, teichoic acids, flagellin, pilin, unmethylated cytosine-guanine dinucleotide or CpG sequences from bacterial and viral genomes; lipoteichoic acid, glycolipids, and zymosan from fungi; double-stranded viral RNA, and certain single-stranded viral RNAs. Binding of microbial PAMPs to their PRRs promotes the synthesis and secretion of intracellular regulatory molecules such as cytokines that are crucial to initiating innate immunity and adaptive immunity.

1. signaling PRRs found on cell surfaces (see Fig. 5):

A series of signaling pattern-recognition receptors known as toll-like receptors (TLRs) are found on the surface of a variety of defense cells and other cells. These TLRs play a major role in the induction of innate immunity and contribute to the induction of adaptive immunity.

The binding of a microbial PAMP to its TLR (or other PRR) transmits a signal to the host cell's nucleus inducing the expression of genes coding for the synthesis of intracellular regulatory molecules called cytokines. The cytokines, in turn, bind to cytokine receptors on other defense cells.

Different combinations of TLRs appear in different cell types and may occur in pairs. Different TLRs directly or indirectly bind different microbial molecules. For example::

a. TLR-2 - recognizes peptidoglycan, bacterial lipoproteins, lipoteichoic acid, and porins;
b. TLR-4 - recognizes lipopolysaccharide (LPS) from gram-negative cell wall, fungal mannans, viral envelope proteins, parasitic phospholipids, heat-shock proteins;
c. TLR-5 - recognizes bacterial flagellin;
d. TLR-1/TLR-2 pairs - bind uniquely bacterial lipopeptides and glycosylphosphatidylinositol (GPI)-anchored proteins in parasites;
e. TLR-2/TL6 pairs - bind lipoteichoic acid from gram-positive cell walls, bacterial lipopeptides, and peptidoglycan.

Many of the TLRs, especially those that bind to bacterial and fungal cell wall components, stimulate the transcription and translation of cytokines such as interleukin-1 (IL-1), tumor necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8), and interleukin-12 (IL-12). These cytokines trigger innate immune defenses such as inflammation, fever, and phagocytosis in order to provide an immediate response against the invading microorganism . Because cytokines such as IL-I, TNF-alpha, IL-8, and IL-12 trigger an inflammatory response, they are often referred to as inflammatory cytokines.

Another cell surface PRR is CD14. CD14 is found on monocytes, macrophages, and neutrophils and promotes the ability of TLR-4 to respond to LPS. Interaction of LPS with CD14 and TLR-4 leads to an elevated synthesis and secretion of proinflammatory cytokines such as IL-1, IL-6, IL-8, TNF-alpha, and platelet-activating factor (PAF). These cytokines then bind to cytokine receptors on target cells and initiate inflammation and activate both the complement pathways and the coagulation pathway (see Fig. 9).

.

The signaling process for the CD14 and TLR-4 response to LPS is shown in Fig. 15.

TLRs also participate in adaptive immunity by triggering various secondary signals needed for humoral immunity (the production of antibodies) and cell-mediated immunity (the production of cytotoxic T-lymphocytes and additional cytokines). Without innate immune responses there could be no adaptive immunity.

a. T-independent (TI) antigens allow B-lymphocytes to mount an antibody without the requirement of interaction with T4-lymphocytes. The resulting antibody molecules are generally of the IgM isotype and do not give rise to a memory response. There are two basic types of T-independent antigens: TI-1 and TI-2. TI-1 antigens are pathogen-associated molecular patterns such as lipopolysaccharide (LPS) from the outer membrane of the gram-negative cell wall and bacterial nucleic acid. These antigens activate B-lymphocytes by binding to their specific toll-like receptors rather than to B-cell receptors (see Fig. 11). Antibody molecules generated against TI-1 antigens are often called "natural antibodies" because they are always being made against bacteria present in the body.

b. The activation of naive T-lymphocytes requires co-stimulatory signals involving the interaction of accessory molecules on antigen-presenting cells (APCs) with their corresponding ligands on T-lymphocytes. These co-stimulatory molecules are only synthesized when toll-like receptors on APCs bind to pathogen-associated molecular patterns of microbes (see Fig. 12).

2. Signaling PRRs found in the membranes of the endosomes (phagolysosomes) used to degrade pathogens (see Fig. 5):

a. TLR-3 - binds double-stranded viral RNA;
b. TLR-7 - binds uracil-rich single-stranded viral RNA such as in HIV;
c. TLR-8 - binds single-stranded viral RNA;
d. TLR-9 - binds unmethylated cytosine-guanine dinucleotide sequences (CpG DNA) found in bacterial and viral genomes.

Most of the TLRs that bind to viral components trigger the synthesis of cytokines called interferons that block viral replication within infected host cells.

 

3. Signaling PRRs found in the cytoplasm:

a. NODs (nucleotide-binding oligomerization domain)

NOD proteins, including NOD-1 and NOD-2, are cytostolic proteins that allow intracellular recognition of peptidoglycan components.

1. NOD-1 recognizes peptidoglycan containing the muramyl dipeptide NAG-NAM-gamma-D-glutamyl-meso diaminopimelic acid, part of the peptidoglycan monomer in common gram-negative bacteria and just a few gram-positive bacteria.

2. NOD-2 recognizes peptidoglycan containing the muramyl dipeptide NAG-NAM-L-alanyl-isoglutamine found in practically all bacteria (see Fig. 5).

As macrophages phagocytose either whole bacteria or peptidoglycan fragments released during bacterial growth, the peptidoglycan is broken down into muramyl dipeptides. Binding of the muramyl dipetides to NOD-1 or NOD-2 leads to the activation of genes coding for inflammatory cytokines such as IL-1, TNF-alpha, IL-8, and IL-12 in a manner similar to the cell surface TLRs.

b. CARD-containing proteins

CARD (caspase activating and recruitment domain)-containing proteins, such as RIG-1 (retinoic acid-inducible gene-1) and MDA-5 (melanoma differentiation-associated gene-5), are cytoplasmic sensors that bind viral RNA molecules produced in viral-infected cells and trigger the synthesis of cytokines called interferons that block viral replication within infected host cells in a manner similar to the endosomal TLRs.

 

4. Secreted signaling PRRs found in plasma and tissue fluid

In addition to the PRRs found on or within cells, there are also secreted pattern-recognition receptors. These PRRs bind to microbial cell walls and enable them to activate the complement pathways, as well as by phagocytes. For example, mannan-binding lectin (also known as mannan-binding protein) is synthesized by the liver and released into the bloodstream as part of the acute phase response discussed later in this unit. Here it can bind to the carbohydrates on bacteria, yeast, some viruses, and some parasites. This, in turn, activates the lectin complement pathway (discussed later in Unit 4) and results in the production of a variety of activated complement proteins that are able to trigger inflammation, chemotactically attract phagocytes to the infection site, promote the attachment of antigens to phagocytes via enhanced attachment or opsonization, and cause lysis of gram-negative bacteria and infected or transformed human cells.

 

2. Cytokines

Cytokines (def) are low molecular weight, soluble proteins that are produced in response to an antigen and function as chemical messengers for regulating the innate and adaptive immune systems. They are produced by virtually all cells involved in innate and adaptive immunity, but especially by T helper (Th) lymphocytes. The activation of cytokine-producing cells triggers them to synthesize and secrete their cytokines. The cytokines, in turn, are then able to bind to specific cytokine receptors on other cells of the immune system and influence their activity in some manner.

Cytokines are pleiotropic, redundant, and multifunctional.

Some cytokines are antagonistic in that one cytokine stimulates a particular defense function while another cytokine inhibits that function. Other cytokines are synergistic wherein two different cytokines have a greater effect in combination than either of the two would by themselves.

There are three functional categories of cytokines:

1. cytokines that regulate innate immune responses,
2. cytokines that regulate adaptive Immune responses, and
3. cytokines that stimulate hematopoiesis.

Cytokines that regulate innate immunity are produced primarily by mononuclear phagocytes such as macrophages and dendritic cells although they can also be produced by T-lymphocytes, NK cells, and other cells. They are produced primarily in response to pathogen-associated molecular patterns such as LPS, peptidoglycan monomers, teichoic acids, and double-stranded DNA. Most act on leukocytes and the endothelial cells that form blood vessels in order to promote and control early inflammatory responses.

Examples include:

a. Tumor necrosis factor-alpha (TNF-alpha)

TNF-alpha is the principle cytokine that mediates acute inflammation. In excessive amounts it also is the principal cause of systemic complications such as the shock cascade. Functions include acting on endothelial cells to stimulate inflammation and the coagulation pathway; stimulating endothelial cells to produce selectins and ligands for leukocyte integrins during diapedesis; stimulating endothelial cells and macrophages to produce chemokines that contribute to diapedesis, chemotaxis and the recruitment of leukocytes; stimulating macrophages to secrete interleukin-1 (IL-1) for redundancy; activating neutrophils and promoting extracellular killing by neutrophils; stimulating the liver to produce acute phase proteins, and acting on muscles and fat to stimulate catabolism for energy conversion. In addition, TNF is cytotoxic for some tumor cells; interacts with the hypothalamus to induce fever and sleep; stimulates the synthesis of collagen and collagenase for scar tissue formation; and activates macrophages. TNF is produced by monocytes,macrophages, dendritic cells, Th1 cells, and other cells.

b. Interleukin-1 (IL-1)

IL-1 function similarly to TNF in that it mediates acute inflammatory responses. It also works synergistically with TNF to enhance inflammation. Functions of IL-1 include promoting inflammation; activating the coagulation pathway, stimulating the liver to produce acute phase proteins, catabolism of fat for energy conversion, inducing feverand sleep; stimulates the synthesis of collagen and collagenase for scar tissue formation; stimulates the synthesis of adhesion factors on endothelial cells and leukocytes for diapedesis; and activates macrophages. IL-1 is produced by monocytes, macrophages, dendritic cells, and a variety of other cells in the body.

c. Chemokines (def)

Chemokines are a group of cytokines that enable the migration of leukocytes from the blood to the tissues at the site of inflammation. They increase the affinity of integrins on leukocytes for ligands on the vascular wall during diapedesis, regulate the polymerization and depolymerization of actin in leukocytes for movement and migration, and function as chemoattractants for leukocytes. In addition, they trigger some WBCs to release their killing agents for extracellular killing and induce some WBCs to ingest the remains of damaged tissue. Chemokines also regulate the movement of B-lymphocytes, T-lymphocytes, and dendritic cells through the lymph nodes and the spleen. Certain chemokines have also been shown to suppress HIV, probably by binding to the chemokine receptors serving as the second binding factor for HIV on CD4+ cells. When produced in excess amounts, chemokines can lead to damage of healthy tissue as seen in such disorders as rheumatoid arthritis, pneumonia, asthma, adult respiratory distress syndrome (ARDS), and septic shock. Examples of chemokines include IL-8, MIP-1a, MIP-1b, MCP-1, MCP-2, MCP-3, GRO-a, GRO-b, GRO-g, RANTES, and eotaxin. Chemokines are produced by many cells including leukocytes, endothelial cells, epithelial cells, and fibroblasts.

d. Interleukin-12 (IL-12)

IL-12 is a primary mediator of early innate immune responses to intracellular microbes. It is also an inducer of cell-mediated immunity. It functions to stimulate the synthesis of interferon-gamma by T-lymphocytes and NK cells; increases the killing activity of CTLs and NK cells; and stimulates the differentiation of naive T4-lymphocytes into interferon-gamma producing Th1 cells. It is produced mainly by macrophages and dendritic cells.

e. Type I Interferons

Interferons modulate the activity of virtually every component of the immune system. Type I interferons include more than 20 types of interferon-alpha, interferon-beta, interferon omega, and interferon tau. There is only one type II interferon, interferon-gamma.

Type I interferons, produced by virtually any virus-infected cell, provides an early innate immune response against viruses. Interferons induce uninfected cells to produce enzymes capable of degrading mRNA. These enzymes remain inactive until the uninfected cell becomes infected with a virus. At this point, the enzymes are activated and begin to degrade both viral and cellular mRNA. This not only blocks viral protein synthesis, it also eventually kills the infected cell (see Fig. 13A and Fig. 13B). They also promote body defenses by enhancing the activities of CTLs, macrophages, dendritic cells, NK cells, and antibody-producing cells.

Type I interferons also induce MHC-I antigen expression needed for recognition of antigens by CTLs; augment macrophage, NK cell, CTL, and B-lymphocyte activity; and induce fever. Interferon-alpha is produced by T-lymphocytes, B-lymphocytes, NK cells, monocytes/macrophages; interferon-beta by virus-infected cells, fibroblasts, macrophages, epithelial cells, and endothelial cells.

f. Interleukin-6 (IL-6)

IL-6 functions to stimulate the liver to produce acute phase proteins; stimulates the proliferation of B-lymphocytes; and increases neutrophil production. IL-6 is produced by many cells including T-lymphocytes, macrophages, monocytes, endothelial cells, and fibroblasts.

g. Interleukin-10 (IL-10)

IL-10 is an inhibitor of activated macrophages and dendritic cells and as such, regulates innate immunity and cell-mediated immunity. IL-10 inhibits their production of IL-12, co-stimulator molecules, and MHC-II molecules, all of which are needed for cell-mediated immunity. IL-10 is produced mainly by macrophages, and Th2 cells.

h. Interleukin 15 (IL-15)

IL-15 stimulates NK cell proliferation and proliferation of T-lymphocytes. IL-15 is produced by various cells including macrophages.

i. Interleukin-18 (IL-18)

IL-18 stimulates the production of interferon-gamma by NK cells and T-lymphocytes and thus induces cell-mediated immunity. It is produced mainly by macrophages.

 

3. Harmful Effects Associated with Pattern-Recognition Receptors and Cytokine Production

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. These include:

a. Sepsis (Systemic Inflammatory Response Syndrome or SIRS) from a severe systemic infection or an overactive innate immune response

Cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-8 (IL-8) are known as proinflammatory cytokines because they promote inflammation. Some cytokines, such as IL-8, are also known as chemokines (def). They promote an inflammatory response by enabling white blood cells to leave the blood vessels and enter the surrounding tissue, by chemotactically attracting these white blood cells to the infection site, and by triggering neutrophils to release killing agents for extracellular killing. In addition to promoting an inflammatory response, these same cytokines activate the complement pathways (def) as well as the coagulation pathway (def).

  • Inflammation is the first response to infection and injury and is critical to body defense. Basically, the inflammatory response is an attempt by the body to restore and maintain homeostasis after injury. 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 an injured or infected site. The release of proinflammatory cytokines eventually leads to vasodilation of blood vessels. Vasodilation (def) is a reversible opening of the junctional zones between endothelial cells (def) of the blood vessels and results in increased blood vessel permeability. This enables plasmathe liquid portion of the blood, called plasma, to enter the surrounding tissue. The plasma contains defense chemicals such as antibody molecules, complement proteins, lysozyme, and defensins. Increased capillary permeability also enables white blood cells to squeeze out of the blood vessels and enter the tissue. As can be seen, inflammation is necessary part of body defense. Excessive or prolonged inflammation can, however, cause harm as will be discussed below.
  • As mentioned in a previous section, products of the complement pathways (def) lead to more inflammation, opsonization of bacteria, chemotaxis of phagocytes to the infected site, and MAC lysis of gram-negative bacteria.

The products of the coagulation pathway (def) lead to the clotting of blood to stop bleeding, more inflammation, and localization of infection.

At moderate levels, inflammation, products of the complement pathways, and products of the coagulation pathway are essential to body defense. However, these same processes and products when excessive, can cause considerable harm to the body.

When there is a minor infection with few bacteria present, low levels of cell wall components are present. This leads to moderate cytokine production with the results being primarily beneficial (see Fig. 9). However, in the case of a severe infection with very large numbers of bacteria present, high levels of cell wall components are present. This leads to excessive cytokine production with the results causing damage to the body (see Fig. 10). People with overactive TLR-4 receptors may be prone to developing SIRS from gram-negative bacteria.

This excessive inflammatory response is referred to as Systemic Inflammatory Response Syndrome or SIRS. Death is a result of what is called the shock cascade. The sequence of events is as follows:

This is seen during septicemia (def), a condition where bacteria enter the blood and cause harm. There are approximately 750,000 cases of septicemia per year in the U.S. and the mortality rate is between 20% and 50%. Over 210,000 people a year in the U.S. die from septic shock. Approximately 45% of the cases of septicemia are due to gram-positive bacteria, 45% are a result of gram-negative bacteria, and 10% are due to fungi (mainly the yeast Candida).

b. 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.

c. 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.

d. People with the autoimmune disease systemic lupus erythematosus have an altered form of TLR-9 that reacts with the body's own DNA.

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

f. Mutations in the gene coding for NOD2 that prevent the NOD2 from recognizing muramyl dipeptide make a person more susceptible to Crohn's disease, an inflammatory disease of the large intestines.

g. 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 and mannan-binding protein needed to initiate the lectin complement pathway.

4. 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. TLR-4 and TLR-9 activators: as vaccine adjuvants to activate the immune system.
b. TLR-7 and TLR-9 activators: as an antiviral against hepatitis C.
c. TLR-9 activators: as an adjuvant for chemotherapy of lung cancer.
d. TLR-9 activators: stimulating macrophages and other cells to to kill the TH2 responsible for most allergies and asthma.

2. TLR inhibitors to suppress immune responses

a. General TLR inhibitors: to treat autoimmune disorders.
b. TLR-4 inhibitor: to block gram-negative sepsis and SIRS.
c. TLR-4, TLR-2, and MyD88 inhibitors to lessen atherosclerotic plaques.

A number of human cytokines produced by recombinant DNA technologies are now being used to treat various infections or immune disorders. These include:

1. recombinant interferon alfa-2a (Roferon-A): a cytokine used to treat Kaposi's sarcoma, chronic myelogenous leukemia, and hairy cell leukemia.
2. peginterferon alfa-2a (Pegasys) : used to treat hepatitis C (HCV).
3. recombinant interferon-alpha 2b (Intron A): a cytokine produced by recombinant DNA technology and used to treat Hepatitis B; malignant melanoma, Kaposi's sarcoma, follicular lymphoma, hairy cell leukemia, warts, and Hepatitis C.
4. peginterferon alfa-2b (PEG-Intron; PEG-Intron Redipen): used to treat hepatitis C (HCV).
5. recombinant Interferon alfa-2b plus the antiviral drug ribavirin (Rebetron): used to treat hepatitis C (HCV).
6. recombinant interferon-alpha n3 (Alferon N): used to treat warts.
7. recombinant iInterferon alfacon-1 (Infergen) : used to treat hepatitis C (HCV).
8. G-CSF (granulocyte colony stimulating factor): for reduction of infection in people after myelotoxic anticancer therapy for solid tumors.
9. GM-CSF (granulocyte-macrophage colony stimulating factor): for hematopoietic reconstruction after bone marrow transplant in people with lymphoid cancers.

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