Biology Concepts – innate immunity, acquired immunity,
memory response, influenza
Your body is exposed to tens of thousands of foreign
molecules every day. Some can do you harm, some can’t. Your immune system sorts
them by matching receptors on immune cells to molecules on the foreign objects.
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Legos
and biology are a good fit. They can be used to analogize
the
rearrangement T cell receptor genes or hypervariable
regions
of antibody genes, or they can be
used to model the entire
body. One scientist uses them
to model building
complex systems from repetitive
units. And they’re fun.
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The receptors exist on many types of cells, and antibodies sometimes function as receptors when attached to the surface of specialized immune cells. Even circulating antibodies (Ab) in the blood take the form of key and lock systems, whether as single Ab, dimers (2) or pentamer (5) complexes.
The immune system of higher animals can be described as several sets of pairs. Each member of a pair attacks a problem in a certain way, and has independent pathways, but each pair also has overlap and must work together in an overall response. We could spend weeks just on this system, but lets look at the major parts by describing each pair, from largest to smallest.
Innate immunity vs. adaptive immunity – the innate immune responses are fast but short. They don’t depend on your immune system recognizing the specific foreign molecule (antigen) with a specific receptor, but respond with the same types of reactions no matter what it is. Almost all plants and animals have some form of innate immune system.
Vertebrates take the immune system further. They have
developed an adaptive immune system that does depend on your immune system
recognizing the specific foreign invader. It then generates a tailored response
to that one foreign organism or molecule. The faster, but more general, innate
response helps the slower, but longer lasting and more specific, adaptive
response to kick in.
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These
are cartoons of an antibody. The model on the left is a
much
more realistic image. The Fc portion is the same through
most
antibodies (c= constant), while the gene rearrangement
takes place
in the light chain and heavy chain variable
regions. The
different variable regions are the Lego blocks
that can be put
together differently to make the millions
of different antigen
binding sites.
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The immune cells can generate an antibody response (humoral
immunity) and/or trigger specific killing and directing cells to be produced
(cellular immunity). The antibody (produced by B lymphocytes) is a protein that
recognizes the specific antigen. The cellular immune response is mediated
primarily by T lymphocytes.
However, B cell-produced antibodies are important for T
cells to do their work, and antibodies also help the innate immune response to
keep working after specific recognition has been made. In addition, the
cellular immune response can control and ramp-up the humoral response. You see
what I mean about each pair being separate but connected.
Effector T cells
vs. regulatory T cells – There
are pairs of T cells as well. I use the term “effector T” cells to lump CD8+
and CD4+ lymphocytes together (CD = cluster of differentiation markers
on the cell surfaces). Effector T lymphocytes are either directly cytotoxic
(CD8+, cyto = cell and toxic = damaging) or command (CD4+)
the many adaptive responses. Effector cells are contrasted with regulatory
cells, which include regulatory and suppressor T lymphocytes. The purpose of
these cells is to stem the effector response so it doesn’t get out of hand; parts
of the immune response are inflammation and non-specific cell killing – too
much of that and you die too.
Memory Immune
System – This last part of the immune response is not a member of a
pair. When your innate immune system is activated, it ramps up, does its job,
and hopefully is turned back off. The adaptive immune system responds to the
antigen by producing more cells, antibodies and chemical signals (cytokines), and after the invader is
vanquished you want this response to diminish as well. The innate system
always starts over from zero, but the adaptive system remembers the infection
you had.
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The
dendritc cell on the left is an innate immune cell that works
to present the antigen to the adaptive immune cells (Th1,
Th2, and B cells). The adaptive cells reproduce and
make
cytokines to stimulate other immune cells. They also
generate
some memory cells that recognize the same antigen,
but stay
around for a long time and can react strongly
and quickly.
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During
the adaptive response, some of the produced immune cells become “memory cells,” they still recognize the
antigen from the initial infection, but hang around in larger numbers; in many
cases they circulate in your body for the rest of your life. If your body sees
that specific antigen again, the memory response can be re-initaited very quickly and very
aggressively. You might be infected again, but your memory response is so fast
and effective that you never know it.
In a world without vaccines, you are infected, get the
disease, recover (hopefully), and then have a memory immune system for that
antigen. Vaccines take the initial infection and disease out of the equation;
you get to develop a memory without having had the experience!
As we discussed last week with smallpox, vaccines present your immune system
with the antigen in the form of a dead or weakened pathogen, or just the
antigen molecule itself. Your body doesn’t know the difference, it develops an
adaptive and memory response just as if it were the real infection.
In the majority of cases, you develop memory B and T
lymphocytes when infected or vaccinated. However, there are exceptions. Most
antigens cannot fully activate B cells to make antibody, they have to be helped
along by antigen-activated T cells. But there are T cell-independent antigens
that can fully activate B cells on their own. In these infections, you can
develop a B cell memory without a T cell memory.
On the other hand, there are other infections that develop a
full memory response, but it is not useful. Influenza is an example of this.
Influenza has been around for thousands of years; some years we have severe
epidemics or even world-wide pandemics. The 1918-1919 Spanish flu pandemic
killed over 50 million people, many more than the contemporaneous WWI (16
million deaths).
Flu is difficult to vaccinate against because it keeps
changing. Influenza virus has two antigens, called H (hemagglutinin) and N
(neuraminidase). These are the molecules on the virus particle that your body
mounts an immune response against.
The H molecule on the viral coat binds to sialic acid
receptors on respiratory cells and allows the virus to enter. When the newly
produced viruses bud off of the cell, they place H on the cell surface, but
there are still host sialic acid receptors there as well. These receptors would bind
up the H and prevent the new viral particles from attaching to and infecting
other cells, so the N molecule cleaves the sialic acid receptors from the new
viral particles.
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Influenza
virus can mutate by antigenic drift or antigenic
shift.
The top line shows that by passing from person to
person,
the antigens (and virulence) shift slightly. The lower
line
shows that by passing through other animals and
recombining,
the antigens can have small or big changes. When
shifted virus moves into humans, it’s a recipe for a pandemic.
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Different strains of influenza virus can infect the same
animal (often pigs and ducks – thus avian flus and swine flus) and can mix their
H’s and N’s. What emerges and might be transmitted to humans can be a virus
with H’s and N’s similar to years past, or with new H’s or N’s. That is why a
new vaccine must be produced each year, after scientists see which H’s and N’s
the new virus has and how much they have drifted. Avian flu is H5N1, while
swine flu is H1N1. However, antigenic drift means that each H1N1 will not be
exactly like the previous H1N1 to emerge. The 1918 pandemic was caused by an
antigenically shifted H1N1 sub-strain.
Like flu, other infections may not provide life-long memory.
If the memory response is weak or the initial response was not strong, then
memory may fade over time. This is why some vaccinations require boosters in
later years. A fading of the memory response to influenza is also implicated in
the need for yearly vaccinations.
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Here's a great
book that discusses both the biology
and sociology
of influenza. There are great personal
stories
as well as medical detective work. This
pandemic
was a jolt that brought infectious
disease
research into a new century. I highly
recommend it.
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The 2009 seasonal flu vaccine did not have any
cross-reactivity with pandemic H1N1, so the scientists suggest that previous
years seasonal influenzas did generate some memory response that was partially
effective against 2009’s H1N1 swine flu. Cross-reactivity means that the H and
N antigens were not identical to previous version; the Legos don’t fit together
exactly, but they were similar enough to fit together and initiate a partial
response. Once again, we see that getting sick may save your life down the line.
Next week will look at examples wherein having one disease
can protect you from catching another.
For more information or classroom activities, see:
innate
immunity:
adaptive
immunity:
memory
immune response:
influenza
virus:
http://www.xvivo.net/zirus-antivirotics-condensed/
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