Download Lecture Guide-InnateImmune (CH14)_7e

Lecture Guide
Innate Defense (CH14)
The immune system is composed of two “branches”, the innate immune response
and the adaptive immune response. This chapter focuses on the natural mechanisms at
work to protect us from infections on a daily basis, the mechanisms that we care born
with (innate) that make up the innate immune response. This innate immune response
consists of protective layers (such as the skin and mucus membranes), sensor systems in
the body to detect the presence of invaders (such as toll-like receptors and complement
proteins), and white blood cells (such as phagocytes and dendritic cells). Let’s take a
closer look at some of the key concepts and ideas in this chapter.
When you think about the components of the innate immune response, think of
what a bacterial organism would need to do to enter into the body and cause disease. The
first lines of defense (…think of the first structures that an organism must pass through to
enter the body) are the skin and mucous membranes, and the antimicrobial secretions
found in these areas. The skin is an amazing organ, made up of two layers, the epidermis
and the dermis. The epidermis is where most of the “protective” mechanisms come into
play with 20-30 layers of dead keratinized cells. The mucous membranes found in the
interior regions of the body which open to the outside, such as the respiratory tract and
digestive tract, are coated with secretions to continually wash the microbes from the
surface. There are additional structures to help remove bacteria, the cilia in the
respiratory tract, and peristalsis in the digestive tract. Many of the secretions found in
these areas also have antimicrobial substances such as lysozyme, lactoferrin, and
defensins.
As you know, the normal microbiota also play a role at protecting the body from
other bacterial organisms. These normal microbiota protect by competitive exclusion,
making it hard for a new organism to grow and establish themselves in a particular
environment. For example, E. coli produces toxins known as bacteriocins which kill
closely related bacteria such as Salmonella and Shigella.
Once an “invader” has made it past the first lines of defense, the next protective
layer consists of cells, specifically the phagocytes. The two key types of phagocytes
important in the innate response are the neutrophils and the macrophages. The
neutrophils are considered the professional phagocytes, first to arrive at the scene of an
infection and better at killing pathogens than macrophages. Not only do neutrophils have
powerful granules but they can release the contents of their DNA along with the granules
(remember these are a type of granulocyte) and trap bacteria in what is known as
neutrophil extracellular traps (NETs). Macrophages are the second phagocyte to arrive at
the scene of an infection. Good at cleaning up any cellular debris and eliminating any
remaining bacteria. They are long lived and continually regenerate their lysosomes (the
cellular structures that contain the digestive enzymes).
These phagocytic cells are capable of phagocytosis, a process in which the cell
ingests the foreign cell/organism and destroys it. The key steps in the process of
phagocytosis are outlined nicely on p 347, please review the steps and what happens at
each step. One of the steps of phagocytosis is attachment, in order for a phagocytic cell to
ingest something it has to BIND to it. I wanted to point out this step as it is critical to the
entire process of phagocytosis. There are ways in which cells can bind directly (via
receptors) and indirectly (via opsonization….a process that happens when complement
proteins are activated or when specific antibodies bind to the pathogen). Some really
virulent pathogens have evolved mechanisms to evade the process of phagocytosis…can
you think of some ways in which an organism could evade phagocytosis? We’ll talk
more about this when we discuss pathogenesis.
Cells of the immune system need to be connected and communicating with each
other to coordinate complex responses. Communication between cells occurs through
surface receptors, cytokines, and adhesion molecules. The surface receptors function
to bind chemicals, such as cytokines, and the binding elicits a response by the cell. There
are many different kinds of cytokines that are important in the innate immune response.
Chemokines, for example, are important in chemotaxis and promote cell migration
towards areas of inflammation. Review the function of the following kinds of cytokines:
chemokines, colony-stimulating factors, interferons, interleukins, and tumor necrosis
factor.
There are sensor systems that help detect the presence of foreign invaders and set
in motion either other cells or a specific response that rely on binding parts of microbes
or viruses. These sensor systems are also known as pattern recognition receptors
(PRRs). There are three types of pattern recognition receptors mentioned in this chapter,
Toll-like receptors, NOD-like receptors, and RIG-like receptors.
Toll-like receptors (TLRs) are really cool membrane receptor proteins that allow
cells to “see” molecules that signify the presence of microbes. These receptors are found
on many different kinds of cells and when bound by such parts of microbes as
peptidoglycan, flagella, or LPS, they activate gene expression. LPS bound to a specific
TLR on macrophages activates the cell to produce chemokines that attract additional
macrophages to the area. How cool to have a mechanism to alert the cell that an invader
is present and produce a chemical to attract other phagocyte cells!
NOD-like receptors (NLRs) are cytoplasmic proteins that detect intracellular
(inside of the cell) bacterial components and activate a series of events to protect the host
cell.
RIG-like receptors (RLRs) are cytoplasmic proteins that detect intracellular
viral dsRNA. Once the viral dsRNA is detected the cell responds by producing interferon.
Interferon is a protein cytokine that signals neighboring uninfected cells to produce
inactive antiviral proteins. When the virus tries to infect this neighboring host cell with
the inactive antiviral proteins, the antiviral proteins are activated and the host cell dies.
This prevents the virus from replicating to other host cells!
The complement system consists of a collection of interacting proteins that are
found in the blood and tissue fluids. They circulate in these body spaces in an
“inactivated” form and are activated in a cascade-type fashion. The most important
aspects of the complement system (for our discussion) is to recognize how the proteins
are activated and the three different outcomes that occur when these proteins are
activated.
There are three main pathways to activate the complement system, the alternative
pathway, the lectin pathway, and the classical pathway. The alternative pathway of
activation occurs when protein C3b binds to cell surfaces and promotes the formation of
an activation complex. The lectin pathway requires the binding of mannose-binding
lectins to mannose to activate the complement proteins. The classical pathway of
activation requires the presence of antibodies bound to antigen, this binding activates the
complement proteins.
Once the complement proteins are activated there are three things that happen, the
targeted cell may lyse (this is a good thing if the targeted cell is a pathogen),
inflammation occurs (again a good response, think of what happens in the process of
inflammation (see below)), and opsonization occurs. Opsonization is necessary when a
phagocyte tries to ingest an organism with a capsule. The capsule layer makes it hard for
the phagocyte to “grab on” or bind to the pathogen…remember I said that one of the key
steps in phagocytosis is binding..! Once the complement proteins are activated, one of
them (C3b) can bind to the surface of the target cell. This binding of C3b promotes
phagocytosis of the cell by phagocytes such as macrophages.
The last mechanisms to discuss in this chapter important in the innate response
are inflammation and fever. Inflammation is an important process set in motion by
cellular damage and the release of cytokines. There are four characteristic symptoms of
inflammation and they are; redness, heat, pain, and swelling. The process of
inflammation begins when pro-inflammatory cytokines promote the blood vessels to
dilate, shunting the blood flow to the damaged area. The blood vessels also become leaky
or more permeable, promoting the loss of fluid from the vessels into the tissue space. The
loss of fluid also allows the flow of blood to slow down so that the neutrophils can attach
to receptors on the inside of the blood vessel wall and migrate into the tissue space. This
is called diapedesis. Once at the site of the infection the neutrophils ingest bacterial and
other cellular debris. Macrophages arrive later to ingest any remaining pathogens and
clean up cellular debris so that the healing process can begin.
The fever response is also a key mechanism indicating a bacterial infection. How
many times have you been sick and the physician will ask if you have a fever? There are
pro-inflammatory cytokines that can cause a fever response and are also called pyrogens.
Remember the LPS layer of gram negative cell walls can also promote a fever response
in the body. A fever response helps with the immune response because it increases the
rate of cellular reactions and hopefully promotes more “activated” cells, and the increase
in temperature makes it harder for organisms to grow.
We will use some of the key ideas in this chapter to build on the ideas in the next
chapter on the adaptive immune response. Begin to think about the innate immune
response mechanisms that can protect you against a bacterial infection….or even a viral
infection.