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You
can be allergic to things that touch your skin – like poison ivy,
things
injected, like bee venom, things eaten – like foods, or things
inhaled
– like perfumes. But now we need to add something else
to
this list – cold? On the right you see a common way to test for
allergy.
Anything that produces a wheal and flare reaction
(blanched
and raised surrounded by red) is considered positive.
But
what if they’re just allergic to the metal needle?
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Histamine release can lead to itching, watery eyes, runny
nose, and even hives (urticaria,
from Latin for nettle, see the post on nettle toxins). The IgE is good for
helping you learn to avoid poisons and such, but what if your body makes and
IgE to something that isn’t dangerous, like peanuts or latex?
Sometimes it isn’t even a case of building an antibody to
something that is normally not deemed foreign. Sometimes a peanut molecule just
looks enough like some other antigen
that an IgE is tricked into binding to the peanut molecule or the banana
molecule.
The fruit-latex
syndrome is a good example of this. In many cases of people being allergic
to latex (Hevea brasiliensis), they
also have an allergy to avocados, kiwi fruit, bananas, or chestnuts. The IgE that
recognizes the latex hevein protein
cross reacts with a beta-glucanase enzyme protein from the fruits.
In the cases of cross-reacting antibodies, there are antibodies to
innocuous antigens, your body reacts to them just like they were something
dangerous. Histamine release results from IgEs grouping around an allergen and
then attaching to a mast cell. If you have encountered this allergen before and
have ramped up the number of IgEs that recognize this antigen, the mechanisms
can lead to anaphylaxis. This life
threatening condition is marked by inflammation that can cut off airways and a
lowering of blood pressure that could kill the brain.
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Spina
bifida patients often develop latex and tropical fruit allergies.
Spina
bifida is an incomplete closing of the spinal cord in the fetus
and
can lead to severe difficulties in leg movement. It can range from
undetectable
to very evident, like in the right image above. Lots of
treatment
means lots of chances to develop latex hypersensitivity,
and
almost 2/3 of spina bifida patients develop a latex allergy. A 2011
study
says that they first develop allergy to latex, and then this cross-
reacts
with the fruit. So patients without latex allergy don’t have
to
avoid the fruits.
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Like we said, this is how allergies can and sometimes do
work. But there are exceptions. Did you know that you can be allergic to cold
weather? Yes, I hear you out there, chuckling that you’ve been allergic to
shoveling snow for years. But what I’m talking about is a physical allergy –
hives, breathing problems, itching, and cough – just because your skin and airways
are exposed to cold air.
No – you can’t make an antibody to an environmental
condition like cold – at least not as far as I know. But remember that TRPM8 is
a cool sensor, stimulated by cold temperatures. What if your body skipped the
antibody part and the cold temperature itself stimulated mast cell degranulation (release of histamine
granules)? Maybe it does, but whether the cold acts via TRPM8 is another
question.
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Mast
cells (in red) degranulate in response to allergens.
The
allergen (1) is recognized and bound by the
appropriate
IgE antibodies (2). The end of the antibody
opposite
the allergen binding site has a receptor on the
mast
cell surface (3). Crosslinking of more than one
surface
recpeotr with Ab causes degranulation and
release
of inflammatory mediators, like histamine (4)
from
the granules usually stored in the cytoplasm (5).
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But the very next year, another study said it was unlikely
that TRPM8 was responsible for cold-induced urticaria. This study used human
mast cells and mice. Although they did find TRPM8 channels on the mouse mast
cells, they didn’t release histamine in the presence of cold in their
experimental model. And the researchers didn’t even find TRPM8 expressed on the
human cells. This is a bit unusual, since mice are usually a great model for
human physiology.
In mast cells from mice with no TRPM8 channels (TRPM8
knockout mice), the mast cell response to cold was normal, so this study
concluded that TRPM8 is not involved in cold urticaria. Confusing, but a good
opportunity to cheer the relentlessness of science. Study will continue until something
is repeatable and can’t be proved wrong. Maybe it will be you – curing cold
allergy might not make you rich, but cold-triggered
asthma follows a similar stimulation – and solving that little problem will
get you a Nobel Prize and a big fat check.
How about another exception? One important difference
between TRPV1 warm/hot sensor and TRPM8 cool/cold sensor is that TRPV1 is often
located on pain neurons, while TRPM8 is located on other types of neurons and
other cell types. TRPM8 activation is not associated with pain sensation
directly, since they don’t help depolarize pain neurons. But there is an
exception – your teeth.
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The
left cartoon shows the dentinal pores and how they have
odontoblast
processes in them. If the dentin is expose by
receding
gums or by decay, the pores are then exposed. On
the
right, different stimuli can cause the fluid in the pores to
move,
which then puts strain or stretch on the processes, this
causes
shifts in ions and that can cause the neurons to fire. These
neurons
only carry one message – pain.
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The dentin has minute pores that travel out from the middle
to the base of the enamel layer. If decay or some other stimulus reaches the pore,
processes (like fingers) of the odontoblasts in the pores can react to the stimuli. These then signal the
neurons in the pulp. However, the pulp has only
pain sensing neurons. So every stimulus that reaches the pulp will be
interpreted as pain.
The odontoblasts have TRPV1 channels, TRPM8 channels and
TRPA1 channels (we will talk more about these next week). The hydrodynamic theory of tooth pain says that the changes in
temperature that reach the odontoblast processes result in pressure changes and
this puts mechanical stress (stretch or shear) on the membranes. These then
trigger the channels and the signal is passed to the pain neuron.
A 2013 PLoS study says this is partially true. Their results
seem to indicate that very cold and very hot stimuli do produce mechanical
pressure on the membrane, so TRPV1 and TRPA1 are responsible for
mechano-sensitive pain. But they suggest that in the case of TRPM8, cool/cold
temperatures trigger the odontoblasts and neuron. The neuron only has one thing
to say - pain – so when triggered by TRPM8 signals in the neighboring
odontoblast, it responds the only way it knows how. Too bad, but it has spawned
a million dollar industry in toothpastes for people with sensitive teeth.
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This
is a cartoon of the head of a sea urchin sperm, but many
of
the concepts apply in humans as well. See all the red
arrows?
Those represent the places where calcium flux is
important
in maturation and function. And what do TRPV1
and
TRPM8 move the best – calcium. The acrosome reaction
actually
dissolved the membrane around the acrosome so that
it
can more easily enter the ova. This has to be done at a proper
time;
TRPM8 activation prevents it from happening too early.
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TRPM8 signaling prevents the acrosome reaction, but when the
egg is near, a chemical called CRISP4 is released from the egg or parts near
there. CRISP4 is a TRPM8 inhibitor. When TRPM8 is inhibited, now TRPV1 can be
stimulated to trigger the acrosome reaction.
The interesting part here is that up to the point of CRISP4
release, something is constantly stimulating
TRPM8 activity in the sperm cell. I really doubt that there's a cold stimulus way
up inside the uterus, so just what is activating TRPM8? We know about lots of
endogenous activators of TRPV1, but there has only been one study saying that
TRPM8 might have a body-produced agonist, a type of lipid called
lysophopholipids. But I think we are missing a bunch of other agonists – maybe
you could look for those someday.
OK, here’s the last weird function for TRPM8 today. Would
you believe it works in morphine action and withdrawal (when addicted)?
Opiates like morphine are analgesic and
cold antinociceptive. You take morphine and you don’t sense cold – of course,
you won’t sense much of anything else either. For cold, we know how it acts.
Opiates cause the internalization of TRPM8 channels on neurons. If there are no
exposed channels, they can’t be triggered to allow ions into the neuron.
It goes even further; this isn’t some byproduct or side
effect. Menthol is known to create analgesia (one of the reasons they use it in
cigarettes). But according to a 2013 paper, if you give naloxone (an opiate
blocker) at the same time as menthol – no analgesia. TRPM8 internalization is
required for morphine to work.
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The
term, “cold turkey” is fairly old, first appearing in print
around
1910. It means “without preparation,” but just where
it
came from is a matter of question. It might refer to the fact
that
cold turkey after Thanksgiving doesn’t need preparation.
It
might also be related to “talk turkey, which means to get
down
to business. But the way that drug addicts feel cold,
sweat,
are pale and have goose bumps – the visual aspect is
not
wasted. By the way – who would smoke a cold turkey?
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The naloxone that is used to treat morphine addiction binds
to the opioid receptor, but doesn’t produce the analgesia. It also allows the
TRPM8 to remain externalized, so they don’t have the rebound feeling of cold
and pain. Pretty impressive – and now you know how it works.
Next week – TRPM8 is for cold, then there’s the cold that
hurts. That is a different receptor, called TRPA1. It makes cold hurt, abut it
also saves you from the cold.
Cho Y, Jang Y, Yang YD, Lee CH, Lee Y, & Oh U (2010). TRPM8 mediates cold and menthol allergies associated with mast cell activation. Cell calcium, 48 (4), 202-8 PMID: 20934218
For
more information or classroom activities, see:
Cold
allergy –
Hydrodynamic
theory of tooth pain –
Sperm
maturation –
Drug
withdrawal –
