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Innate immunity refers to
antigen-nonspecific defense mechanisms that a host uses immediately or
within several hours after exposure to an antigen
. 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 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 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 innate immune
responses involve:
-
phagocytic cells (neutrophils,
monocytes, and macrophages);
-
cells that release
inflammatory mediators (basophils, mast cells, and eosinophils);
-
natural killer cells (NK
cells); and
-
molecules such as
complement proteins, acute phase proteins, and cytokines.
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. In the next several sections we will look at each of these in
greater detail.
We will now take a closer
look at the 3 pathways of the complement system.
The complement system
refers to a series of proteins circulating in the blood and bathing
the fluids surrounding tissues. The proteins circulate in an inactive
form, but in response to the recognition of molecular components of
microorganism, they become sequentially actived, working in a cascade
where in the binding of one protein promotes the binding of the next
protein in the cascade.
There are 3 complement
pathways that make up the complement system: the classical
complement pathway, the lectin pathway, and the alternative complement
pathway. The pathways differ in the manner in which they are
activated and ultimately produce a key enzyme called C3
convertase:
We will now take a closer
look at the classical complement pathway.
The
Classical Complement Pathway
Although at least 21
different serum proteins have thus far been identified as part of
the classical complement pathway, one can look at it as a pathway
that is primarily activated by either IgG or IgM binding to an
antigen
and involves 11 major serum protein components.
IgG and IgM are classes
of antibody molecules that will be discussed in greater detail in
Unit 3, but as mentioned previously, one of the major defenses
against microbes is the immune defenses' production of antibody
molecules
against that microbe.
The "tips" of the antibody (the Fab portion have shapes that are complementary to epitopes
- portions of microbial proteins and
glycoproteins found on the surface of the microbe. The Fc portion
of IgG and IgM can activate the classical complement pathway by
enabling the first enzyme in the pathway, C1, to assemble.
The reactions are as
follows:
a. Typically to
activate the classical complement pathway, IgG or IgM
is made in response to an antigen. The Fab
portion of IgG (2 molecules) or IgM (1 molecule)
reacts with epitopes of that antigen. A protein called
C1q first binds to the Fc
portion of antigen-bound IgG or IgM after which
C1r and C1s attach to form C1, the first enzyme of
the pathway
b. The activated C1
now enzymatically cleaves C4 into C4a and C4b . The C4b then binds to adjacent proteins and
carbohydrates on the surface of the antigen and then binds C2. The
activated C1 cleaves C2 into C2a and C2b forming C4b2a, the C3
convertase . Now the classical complement pathway is
activated. C3 convertase can now cleave hundreds of molecules
of C3 into C3a and C3b.
c. Some molecules of
C3b bind to C4b2a, the C3 convertase, to form C4b2a3b, a C5 convertase that cleaves C5 into C5a
and C5b .
d. C5b binds to the
surface of the target cell and subsequently binds C6, C7, C8, and
a number of monomers of C9 to form C5b6789n,
the Membrane Attack Complex (MAC).
As mentioned above,
components of the complement pathways carry out 6
beneficial innate defense functions. These include:
a. triggering
inflammation
-
C5a is the
most potent complement protein triggering inflammation. It
causes mast cells to release vasodilators such as
histamine
so that blood vessels become more permeable;
it increases the expression of adhesion molecules on
leukocytes and the vascular endothelium so that leukocytes
can squeeze out of the blood vessels and enter the tissue (diapedesis);
it causes neutrophils to release toxic oxygen radicals
for extracellular killing; and it induces fever. To a
lesser extent C3a and C4a also promote
inflammation.
As we will see later in this unit, inflammation is a process
in which blood vessels dilate and become more permeable, thus
enabling body defense cells and defense chemicals to leave the
blood and enter the tissues.
b.
chemotactically attracting phagocytes to the infection site
c. promoting the
attachment of antigens
to phagocytes (enhanced attachment or
opsonization
)
-
C3b and
to a lesser extent, C4b can function as opsonins, that
is, they can attach antigens to phagocytes. One portion
of the C3b binds to proteins and polysaccharides on microbial
surfaces; another portion attaches to CR1 receptors on
phagocytes, B-lymphocytes, and dendritic cells for enhanced
phagocytosis. . Actually, C3b molecule can bind to pretty
much any protein or polysaccharide. Human cells,
however, produce Factor H that binds to C3b and
allows Factor I to inactivate the C3b. On the other hand,
substances such as LPS on bacterial cells facilitate the
binding of Factor B to C3b and this protects the C3b
from inactivation by Factor I. In this way, C3b does not
interact with our own cells but is able to interact with
microbial cells. C3a and C5a increase the expression of C3b
receptors on phagocytes and increase their metabolic activity.
d. causing lysis
of gram-negative bacteria and human cells displaying foreign
epitopes
; and
-
C5b6789n,
functions as a Membrane Attack Complex (MAC)
. This helps to destroy gram-negative
bacteria as well as human cells displaying foreign antigens
(virus-infected cells, tumor cells, etc.) by causing their
lysis; and . It can also damage the envelope of enveloped
viruses.
-
e. serving
as a second signal for activating naive B-lymphocytes
;
f. removing
harmful immune complexes from the body
-
C3b and
to a lesser extent, C4b
help to remove
harmful immune complexes from the body.
The C3b and C4b
attach the immune complexes to CR1 receptors on erythrocytes.
The erythrocytes then deliver the complexes to fixed
macrophages within the spleen and liver for destruction.
Immune complexes can lead to a harmful Type III
hypersensitivity, as will be discussed later in Unit 3 under
Hypersensitivities.
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