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Acute Phase Protein
Acute Phase Protein
After completing this section you should be able to perform the following
objectives.
a. C-reactive protein
b. mannose-binding lectin
ANTIGEN:A substance that reacts with antibody molecules and antigen receptors on
lymphocytes. An immunogen is an antigen that is recognized by the body as nonself and
stimulates an adaptive immune response.
Unlike adaptive immunity, innate immunity does not recognize every possible
antigen. Instead, it is designed to recognize a few highly conserved
structures present in many different microorganisms. The structures
recognized are called pathogen-associated molecular patterns and include
LPS from the gram-negative cell wall, peptidoglycan, lipotechoic acids from the
gram-positive cell wall, the sugar mannose (common in microbial glycolipids and
glycoproteins but rare in those of humans), bacterial DNA, N-formylmethionine
found in bacterial proteins, double-stranded RNA from viruses, and glucans from
fungal cell walls. Most body defense cells have pattern-recognition receptors
for these common pathogen-associated molecular patterns (see Fig. 1) 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 molecular patterns. All of this will be discussed in
greater detail in upcoming sections.
The acute phase response is an innate body defense seen during acute illnesses
and involves the increased production of certain blood proteins termed acute
phase proteins (def).
These cytokines travel through the blood and stimulate hepatocytes in the
liver to synthesize and secrete acute phase proteins. This response provides
an early defense and enables the body to recognize foreign substances early on
in the infection process prior to the full activation and implementation of the
immune responses. Two important acute phase proteins are C-reactive protein
and mannose-binding protein. They function as soluble pattern-recognition
receptors.
CYTOKINES
Review from Unit-2 and Unit-3
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.
Examples include:
2. Interleukin-1 (IL-1)
3. Chemokines (def)
4. Interleukin-12 (IL-12)
5. 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 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.
6. Interleukin-6 (IL-6)
7. Interleukin-10 (IL-10)
8. Interleukin 15 (IL-15)
Examples include:
1. Interleukin-2 (IL-2)
2. Interleukin-4 (IL-4)
4. Interferon-gamma (IFN-gamma)
6. Lymphotoxin (LT)
7. Interleukin-13 (IL-13)
Examples include:
Stem cell factor makes stem cells in the bone marrow mor responsive to
the various CSFs. It is made mainly by bone marrow stromal cells.
3. Interleukin-3 (IL-3)
IL-3 supports the growth of multilineage bone marrow stem cells. IL-3 is
made primarily by T-lymphocytes.
4. Interleukin-7 (IL-7)
PATTERN-RECOGNITION RECEPTORS
Review from Unit-2
Pattern-Recognition Receptors (Including Toll-Like Receptors) and
Cytokines
1. Pattern-Recognition Receptors
In order to protect against infection, one of the things the body must initially do is
detect the presence of microorganisms. The body does this by recognizing
molecules unique to microorganisms that are not associated with human
cells. These unique molecules are called pathogen-associated molecular
patterns (see Fig. 1). In all, the innate immune system is thought to recognize
approximately 103 molecular patterns.These include:
a. lipopolysaccharide (LPS) from the gram-negative cell wall (see Fig. 2);
The Gram-negative cell wall is composed of a thin, inner layer of peptidoglycan
and an outer membrane consisting of molecules of phospholipids,
lipopolysaccharides (LPS), lipoproteins and sutface proteins. The
lipopolysaccharide consists of lipid A and O polysaccharide.
c. lipoteichoic acids found in the gram-positive cell wall (see Fig. 3);
The Gram-positive cell wall appears as dense layer typically composed of
numerous rows of peptidoglycan, and molecules of lipoteichoic acid, wall teichoic
acid and surface proteins.
g. bacterial and viral nucleic acid. Bacterial and viral genomes contain a high
frequency of unmethylated cytosine-guanine dinucleotide sequences (a cytosine
lacking a methyl or CH3 group and located adjacent to a guanine). Mammalian
DNA has a low frequency of cytosine-guanine dinucleotides and most are
methylated;
j. lipoteichoic acids, glycolipids, and zymosan from yeast cell walls; and
To recognize these microbial molecules, various body defense cells have on their
surface a variety of receptors called pattern-recognition receptors (see Fig. 4)
capable of binding specifically to conserved portions of these molecules.
Key: Different combinations of TLRs appear in different cell types and seem to
appear as TLR pairs. For example:
1. TLRs found on cell surfaces:
a. TLR-1/TLR-2 pairs bind uniquely bacterial lipopeptides and GPI-anchored
proteins in parasites;
b. TLR-2/TL6 pairs bind lipoteichoic acid from gram-positive cell walls and
zymosan from fungi;
c. TLR-4/TLR-4 pairs bind lipopolysaccharide from gram-negative cell walls;
d. TLR-5* binds bacterial flagellin;
2. TLRs found in the membranes of the endosomes used to degrade pathogens:
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.
*other member of pair is unknown
a. mannose receptors
b. scavenger receptors
Different combinations of TLRs appear in different cell types and may appear in
pairs. Different TLRs directly or indirectly bind different microbial
molecules. For example:
The binding of a microbial molecule to its TLR transmits a signal to the 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.
Many of the TLRs, especially thost that bind to bacterial and fungal cell wall
components, stimulate the transcription and translation of cytokines such as
interleukin-2 (IL-2), tumor necrosis factor-alpha (TNF-alpha), and interleukin-8
(IL-8) that trigger innate immune defenses such as inflammation, fever, and
phagocytosis in order to provide an immediate response against the invading
microorganism. Most of the TLRs that bind to viral components trigger the
synthesis of cytokines called interferons that block viral replication within
infected host cells. Cytokines such as interleukin-6 (IL-6) that promotes B-
lymphocyte activity and interleukin-12 that promotes T-lymphocyte activity
are also produced. The signaling process for TLR-4 and its response to LPS is
shown in Fig. 10.
b. CD14
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.
Examples include:
b. Interleukin-1 (IL-1)
c. Chemokines (def)
d. Interleukin-12 (IL-12)
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 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)
g. Interleukin-10 (IL-10)
h. Interleukin 15 (IL-15)
i. Interleukin-18 (IL-18)
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 an
Overactive Innate Immune Response
The products of the coagulation pathway (def) lead to the clotting of blood to
stop bleeding, more inflammation, and localization of infection.
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. 5). 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. 6).
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 noemal 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.
e. 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.
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
include:
ANTIGEN:A substance the body recognizes as nonself and toward which it mounts an
immune response.