Loose tooth

In the fall of my 16th year, a girl walked up behind me as I was getting off the red line at JFK/UMass. She grabbed my shoulder from behind and punched me in the mouth. I hit her back and she got back on the train as the doors closed. It happened in a matter of seconds.

A few minutes later, I realized my mouth was bleeding. I ran a finger along my bottom teeth and one in the front wiggled. I was so mad. It bloomed white hot inside of me, this rage. I balled my hands into fists, my fingernails digging into my palms. I called my mother from a payphone and went to the dentist.

It doesn’t bleed anymore, but it has been loose ever since. Not very loose, but loose. I pushed it back and forth with my tongue as I rode the train home today, on a different red line train, thinking about anger.

I was always very independent. It wasn’t a lifestyle or a decision; I just am that way. I started making my own money in my early teen years and was working fulltime by 16. I moved out at 17 and that was that. It had nothing to do with my family – we are close, and I wasn’t leaving to get away from them – but I like to be myself, making my own decisions. I like being responsible for myself.

And also, if I’m being honest – I like it that way because I am weird and kind of unpredictable. I like things a certain way. I either care a lot about something or I don’t care at all. I am a very extreme person. I like to interact with people on my own terms. And yes, because I’m sure someone is thinking it – I have some mad scientist behaviors, where I like jump out of bed in the middle of the night and realize what we should be measuring to really figure out if some cellular process is happening, and that is weird and disruptive to people who aren’t me. I have flow charts and index cards taped up next to my bed and I recently drew out the Krebs Cycle at 2am, tracking carbons to see if I could still do it. My wackness is useful, but it’s big and hard to miss.

Since we’re talking broadly about the ways in which I am weird, I recently found out that it’s not unusual for people to feel like they are underqualified for their positions even when they are.  This is called Imposter Syndrome.  I feel like this pretty much all the time.  I logically understand that I know a lot about mast cell disease, but I still feel like the universe has made some cosmic mistake in handing me this huge audience of cool people.  When I say that I really thought five people would read this blog, I am not being self depricating.  I really can’t believe how big this has become and it makes me feel like I walked out onto a stage with no pants on.  So there’s that.

Independence gives me freedom to deal with my emotions, which can be very volatile, and sometimes for reasons I don’t understand. Being able to retreat to a safe environment alone is how I cope with things that stress me out. When I don’t have that option, it is much harder for me to function effectively.

At the beginning of 2014, I was physically such a mess that I was incapable of doing basic things on my own. I was living alone. I couldn’t make my bed. I couldn’t stand up long enough to do the dishes. My blood pressure was really unstable and I was trying not to pass out all the time. And the pain was bad, too.

I am extremely fortunate to live close to friends and family that I have good relationships with. And because I am a phenomenally lucky individual, these people help me even though I am sick in a way that is sometimes visceral and gross and cranky in a way that is unbecoming of an adult. I have made some big gains in the last year, and these have been won in large part because of the things these people do for me.

I almost never drive anymore and I don’t always feel well enough to take public transportation, so people have to drive me to work/the hospital/to get groceries/insert necessary life activity here. My father comes over every morning to feed Astoria and bring her down to his yard so she can run around. My parents have to wake me up every day because alarms don’t usually work. Every single time someone wakes me up, I am enraged. It’s not logical and I wish so badly that I didn’t react that way, but I do. It scares me and so I wake up every day in a state of panic. And that means I am immediately in a bad mood.

I don’t know how obvious this is to people who know me online, but my interpersonal skills are not always great. I do not understand a lot of social subtext. I am socially awkward by nature. About ten years ago, I picked someone I thought was graceful and kind and modeled my behavior in certain situations after them. I do a good job of anticipating situations before they happen so I practice what I will say and do ahead of time. But I am not good at social interactions naturally. It is a learned skill. And when I am very frustrated, it becomes more of a struggle.

My normal course of action when I am upset would be to just shut off my phone and retreat to my apartment for a few days of being alone. Except I can’t do that because people will think I’m dead and unfortunately, they could be right. I don’t have the luxury of being by myself for days because if something bad happens to me, I need someone to find me. How shitty of a realization is that.

And I depend on people to help me with basic life things, and they deserve for me to be nice and not be an asshole. Also I deserve room to have feelings and deal with them in a way that is helpful for me, except I can’t do that right now. Hopefully not forever, but maybe. I dream of going away somewhere by myself for three days.

And it is embarrassing and it makes me so mad but if my poor parents don’t wake me up in the morning and I miss my pills, I’ll be calling the good folks at 911 to take me to the Brigham before nightfall. So I can’t just go be mad for a few days and get over it because it is not safe for me. It makes everything much more stressful than it needs to be, for me, and for all the people involved in my care.

I feel like if I could ragequit one thing in my life, I would feel better. I realize that sounds dumb, but if I could just like change ANYTHING or get rid of SOMETHING, I think I would feel less frustrated. But there’s literally nothing I can change and still be safe. I can’t change anything or do anything different than I am right now and still function.

I miss independence. I might miss it more than anything else. I might miss it more than not pooping into a bag.

So for now I’m just trying to get through every day without being an asshole to everyone I care about. In the meantime when I get angry, I wiggle my tooth and hope it doesn’t fall out.




Mast cells in nerve pain

Mast cells are heavily involved in the generation and sensation of pain. The role of mast cells in neurogenic pain (also called nerve pain or neuropathy) is well established and is responsible for a number of painful conditions.

Pain is transmitted like this:

  1. You first feel the pain in nerve endings called nociceptors.
  2. These nerve endings and capillaries in the nearby tissue form a “pain unit” that sends pain signals.
  3. Mast cells are often found close to these nerve endings and capillaries. They release mediators like prostaglandins, histamine and bradykinin.
  4. Nociceptors release mediators like substance P, VIP and CRH, which activate mast cells.
  5. Mast cells then release mediators that increase permeability of the vessels and sensitize the nociceptors. This cycle, in which the nerve endings activate mast cells and the mast cells activate the nerve endings, is called a positive feed back loop. The end result is neurogenic inflammation, or inflammation caused by nerves.

Mast cells can communicate with nerve endings in a number of ways. The first way is by releasing mediators, which may bind to receptors on the nerve cells. A second way is by mast cells sticking to nerve cells through molecules like CADM-1 and N-cadherin; they are able to send signals when their membranes are touching. A third way is by the nerve cells ingesting mediators released by mast cells. These mediators are then transported to other nerve cells, where it can affect which genes are turned on and used.

Mast cells also draw other immune cells to the site of inflammation, like neutrophils and T cells. These cells also release mediators that increase pain, forming another positive feedback loop. The result is that inflammation can spread beyond the initial site of pain, causing a secondary, larger pain response. Hyperalgesia is an exaggerated pain response that is more severe than expected based upon the injury. Mast cells are thought to be directly involved in hyperalgesia and histamine is thought to cause this heightened pain sensation.

Chronic pain has been associated with mast cell degranulation. Degranulation close to colonic nerves is correlated with abdominal pain in IBS patients. Tryptase and histamine can also activate enteric nerves, causing the nerves to be oversensitive. Esophageal pain is also a function of mast cell degranulation.

The specific mechanism of bladder pain due to interstitial cystitis is not clear. However, mast cells are often elevated in IC patients, and contribute to inflammation. It is thought that activation of bladder nerves causes release of substance P by local nerve endings, which activates mast cells.

Overly sensitive and painful skin is sometimes a function of mast cells as well. A significant increase in mast cells has been found in the dermis of fibromyalgia patients. Chronic granulomatous inflammation of the skin causing pain has also been found to be from degranulation of mast cells.



Heron, Anne, Dubayle, David. 2013. A focus on mast cells and pain. Journal of Neuroimmunology 264 (2013) 1–7.

Parada, C.A., Tambeli, C.H., Cunha, F.Q., Ferreira, S.H., 2001. The major role of peripheral release of histamine and 5-hydroxytryptamine in formalin-induced nociception. Neuroscience 102, 937–944.

Theoharides, T.C., Kempuraj, D., Sant, G.R., 2001. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 57, 47–55.

Theoharides, T.C., Donelan, J., Kandere-Grzybowska, K., Konstantinidou, A., 2005. The role of mast cells in migraine pathophysiology. Brain Res. Brain Res. Rev. 49, 65–76.

Gao, G., Ouyang, A., Kaufman, M.P., Yu, S., 2011. ERK1/2 signaling pathway in mast cell activation-induced sensitization of esophageal nodose C-fiber neurons. Dis. Esophagus 24, 194–203.

What do all these words mean? (Part 1)

What is a neoplasm?

A neoplasm is an abnormal growth of cells. Systemic mastocytosis is a neoplasm because your body makes too many mast cells. Cancers are all neoplasms, but not all neoplasms are cancers. SM is not cancer.


What is a myeloproliferative neoplasm (MPN)?

Myelo- means “related to granulocytes”, cells that store chemicals in granules. Mast cells are a type of granulocyte.

Proliferative means “cell growth”.

So together you have “growth of too many granulocytes”.


What are receptors?

Receptors are proteins on the outside of cells. They have very unique and specific shapes, but it is easier to think of them as being shaped by cups. Only very specific molecules fit into these cups. When the molecule is in the receptor, the cell knows to do something. What this something is varies a lot from receptor to receptor.

For example, when an IgE antibody binds to the IgE receptor on a mast cell, the mast cell degranulates. However, not any molecule would be able to bind in the IgE receptor and cause this action.


What are antibodies?

These are large proteins that help the immune system identify and destroy things like bacteria and viruses. Sometimes your body mistakenly makes antibodies to things inside the body. This causes autoimmune disease.

In labs, antibodies are very useful. There are ways to make antibodies to almost anything in the lab. Using these lab made antibodies, scientists are able to test for specific structures that tell us what cells are present in a sample and how the cells are working.


What are immunoglobulins?

They are the same as antibodies.


What does CD mean? Like in CD117?

CD means “cluster of differentiation”. This means that it is a protein or group of proteins on the surface of a cell that is recognized by an antibody. This means that in a lab, if I use an antibody called “ABC123” and it binds to a specific protein on the outside of cells, that protein will be called “CD-ABC123”.

Over time, as we learn more about “CD-ABC123”, we may realize that this protein is made by a gene called “Wow”. So some people will call it “Wow” and some will continue to call it “CD-ABC123”, which can be confusing. Generally speaking, scientists who work with antibody testing usually use the “CD-ABC123” name and doctors use the “Wow” name. However, both names are still correct.

Receptors are often given “CD” names, but not all “CD” molecules are receptors. Some “CD” molecules are on the outside of cells to do other things, like help cells stick to other cells.


What is CKIT?

CKIT is a receptor that is found on all mast cells, whether or not a person has mast cell disease. The CKIT receptor is also called CD117. They are the same thing. CKIT is sometimes also called KIT. They are also the same thing.

The molecule that fits in the CKIT receptor is called stem cell factor (SCF). When SCF binds the CKIT receptor, it tells the mast cell to stay alive much longer than it is supposed to. It also starts a process that tells mast cells to make more mast cells.


CKIT (CD117) is only found on mast cells?

No, other normal cells have CKIT (CD117) on their surface. Epithelial cells in the skin, breast and some parts of the brain express CD117. Some stem cells in the bone marrow and melanocytes also express CD117. Smooth muscle and fibroblasts do not express CD117. This is important because smooth muscle and fibroblasts are often found close to the cells we might be looking for that may be positive for CD117.

However, when found on cells that don’t normally express CD117, it can be a sign of cancer – but ONLY if these cell types don’t normally have CD117 on their surfaces. Examples of cancers that express CD117 include angiosarcoma and Ewing sarcoma.

Mast cells in vascular disease: Part 1

Atherosclerosis is a very specific type of artery hardening that occurs due to accumulation of white blood cells and their inflammation of the vessel. Atherosclerosis can cause heart attacks, formation of blood clots and obstruction of major vessels. There are a number of risk factors, including tobacco smoking, high LDL cholesterol, diabetes, vitamin B6 deficiency, high C reactive protein, and many others.

Atherosclerosis is now known to be an immunoinflammatory condition, one which results from inflammation mediated by immune cells. In recent years, mast cells have been found to play an important role in the formation of atherosclerotic lesions, progression and destabilization of the lesion, which in turn causes the more significant clinical effects. In 2004, 66% of men and 47% of women in the US had heart attack or sudden cardiac death as their first symptom of atherosclerotic heart disease.

Endothelial cells line the blood vessels and form the endothelium. In atherosclerotic plaques, monocytes from the blood burrow into the endothelium. They turn into macrophages, a different kind of cell. These macrophages eat certain kinds of cholesterol and start a cycle in inflammation in the vessel wall. Platelets then stick to the inflamed places.

Mast cells are known to have a number of behaviors that affect plaque pathology. Mast cells near plaques release tryptase, which activates endothelial cells through the PAR-2 receptor. This causes a series of events that produces platelet activating factor (PAF). PAF increases the permeability and contraction of the nearby smooth muscle, which can lead to vascular events.

Increased densities of mast cells have been found in the tissue layer overlaying plaques that ruptured. It has been hypothesized that mast cell released histamine could cause coronary spasm, making the plaque more likely to rupture. In a study that looked at 44 autopsy samples of aorta with atherosclerotic lesions, there was a direct correlation found between levels of tryptase and chymase, the amount of collagen in the plaque, and the size of the endothelium involved.

Mast cells that store basic fibroblast growth factor (bFGF) are found in small vessels inside plaques. Histamine may cause leakage from those tiny vessels, which can further make the plaque more likely to rupture.   In histamine deficient mice, the plaque area was reduced in size, and expression of genes for NF-kB, matrix metalloproteinases (MMPs), and inflammatory cytokines involved in plaque progression. Histamine is also involved in acute coronary vasospasm that may result in heart attack; this is called Kounis Syndrome.



Simon Kennedy, Junxi Wu, Roger M. Wadsworth, Catherine E. Lawrence, Pasquale Maffia. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53–65.

Ramalho, L. S., Oliveira, L. F., Cavellani, C. L., Ferraz, M. L., de Oliveira, F. A., Miranda Corrêa, R. R., et al. (2012). Role of mast cell chymase and tryptase in the progression of atherosclerosis: study in 44 autopsied cases. Ann Diagn Pathol 17, 28–31.

Lappalainen,H., Laine, P., Pentikäinen,M. O., Sajantila,A.,& Kovanen, P. T. (2004).Mast cells in neovascularized human coronary plaques store and secrete basic fibroblast growth factor, a potent angiogenic mediator. Arterioscler Thromb Vasc Biol 24, 1880–1885.

Kounis, N. G., Mazarakis, A., Tsigkas, G., Giannopoulos, S., & Goudevenos, J. (2011). Kounis syndrome: a new twist on an old disease. Future Cardiol 7, 805–824.

Effects of Platelet Activating Factor (PAF) in asthma and anaphylaxis

PAF is released by many different cells, including eosinophils, mast cells, neutrophils, monocytes, macrophages and endothelial cells. PAF receptors are expressed by platelets, monocytes, mast cells, neutrophils, and eosinophils. T and B cells do not express PAF receptors, but PAF can stimulate them to migration of these cells. PAF receptors are found to be increased in eosinophils of asthma patients. PAF receptors are also elevated in lungs of asthmatic patients. PAF can activate mast cells and basophils, causing histamine release. One study proposed the PAF activation of basophils may play a role in aspirin sensitivity in asthma patients.

PAF is most well known for its effects on the airway. It causes constriction of the airway and can affect the way oxygen is brought into the lungs. However, it also has many other effects in the body, many of which affect anaphylaxis and severity thereof.

PAF activates eosinophils and neutrophils to degranulate. It also causes leukotriene C4 production by activated eosinophils in asthma patients, but not in normal patients. A PAF inhibitor has been observed to prevent eosinophil migration and leukotriene C4. Another PAF inhibitor was able to inhibit eosinophil activation by PAF. In activated neutrophils in asthma patients, PAF causes an increase in secretion of leukotriene B4 and increased 5-lipoxygenase activity.

PAF is a powerful signal for eosinophils to migrate toward the cell releasing PAF, and may be involved in inflammation resulting in eosinophilic infiltration. PAF can cause eosinophilic movement across endothelium and into airway. This behavior is increased during asthma attacks and can be minimized with steroids.

PAF injected into the skin causes a biphasic reaction with immediate hiving, then a delayed redness and pain reaction that causes eosinophilic infiltration. PAF also increases IL-6 production by macrophages, activates IL-4 production by T cells, and enhances IL-6 production by mononuclear cells in peripheral blood.

PAF has been heavily linked to asthma. One study found higher levels of PAF as well as lower level of the enzyme that inactivates PAF in plasma of asthmatic adults both during attacks and the rest of the time. When exposed to allergens, PAF level in blood rapidly increases. The large increases in PAF level upon exposure were ameliorated upon successful allergen immunotherapy (also known in the US as “allergy shots”).

PAF induced bronchoconstriction does not affect histamine release and is not alleviated by H1 receptor antihistamines. Inhaling PAF does not change plasma histamine level in asthmatics. Leukotrienes may behave as secondary mediators of PAF action. Zileuton attenuated systemic and respiratory effects of PAF, including airway constriction and changes in neutrophil behavior.

PAF level, and the level of the enzyme that metabolizes it, PAF-acetylhydrolase, is directly correlated to severity of anaphylaxis. Patients with grade I anaphylaxis have 2.5x as much PAF as controls; grade II, 5x; and grade III, 10x. PAF blockers are being investigated for use in this context. Rupatadine is available in some countries, and has H1 antihistamine and PAF blocking activity.

The exact nature of PAF’s activity in anaphylaxis is unclear. It has been shown to cause mast cell degranulation and increased production and release of prostaglandin D2. It can also amplify the response to IgE, making the allergic reaction worse. However, these effects were not seen in skin mast cells for unknown reasons. The source of PAF that acts on mast cells in anaphylaxis is unknown, but is thought to be at least partially from mast cells themselves.



Kasperska-Zajac, Z. Brzoza, and B. Rogala. Platelet Activating Factor as a Mediator and Therapeutic Approach in Bronchial Asthma. Inflammation, Vol. 31, No. 2, April 2008.

Peter Vadas, M.D., Ph.D., Milton Gold, M.D., Boris Perelman, Ph.D., Gary M. Liss, M.D., Gideon Lack, M.D., Thomas Blyth, M.D., F. Estelle R. Simons, M.D., Keith J. Simons, Ph.D., Dan Cass, M.D., and Jupiter Yeung, Ph.D. Platelet-Activating Factor, PAF Acetylhydrolase, and Severe Anaphylaxis. N Engl J Med 2008; 358:28-35.

Vadas P, Gold M, Liss G, Smith C, Yeung J, Perelman B. PAF acetylhydrolase predisposes to fatal anaphylaxis. J Allergy Clin Immunol 2003;111: S206-S206.

Kajiwara N, Sasaki T, Bradding P, Cruse G, Sagara H, Ohmori K, Saito H, Ra C, Okayama Y. Activation of human mast cells through the platelet-activating factor receptor. J Allergy Clin Immunol. 2010 May; 125(5): 1137-1145.

Anti-inflammatory properties of H1 antihistamines

H1 antihistamines are also known to have anti-inflammatory properties. Some studies show that H1 antihistamines prevent histamine release, which is actually independent of the ability to bind H1 receptors. This effect is thought to occur by interfering with calcium activity on the cell membrane, which may be important in signaling to a cell to release histamine. However, other studies say the amount by which histamine release is reduced is not significant clinically.

H1 antihistamines have also been observed to reduce eosinophil accumulation near allergic sites. This may be due to the ability of H1 antihistamines to interfere with activation of a molecule called NF-kB. This molecule is important in production of inflammatory cytokines. NF-kB can be activated by several inflammatory molecules, including histamine and TNF. Low concentrations of cetirizine and azelastine have been shown to result in lower levels of NF-kB while also inhibiting the production of IL-1b, IL-6, IL-8, TNF and GM-CSF.

Bradykinin is a mediator released by mast cells that causes inflammation, pain and edema. H1 antihistamines such as chlorpheniramine and cetirizine have been reported to inhibit bradykinin induced formation of hives, which may mean that bradykinin triggers hitamine release, which in turn participates in hive formation. However, in testing, the amount of histamine found in these reactions was minimal. This implies that H1 antihistamines may be able to inhibit bradykinin action in another way. H1 antihistamines have also inhibited weal and flare responses by methacholine and platelet activating factor (PAF).


Church, Diana S., Church, Martin K. Pharmacology of antihistamines. World Allergy Organization Journal 2011, 4 (Suppl 3): S22-S27.

Leurs, R., et al. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clinical and Experimental Allergy 32 (2002): 489-498.

Pharmacology of H1 antihistamines

H1 receptors are a type of G-protein-coupled-receptors (GPCRs), and exist in two different conformational states. A conformation is a shape, and the way a receptor is shaped affects its activity. One of the H1 receptor conformations makes it active, so it is effectively the “on” position. The other makes it inactive, so it is effectively the “off” position.

When histamine binds to the H1 receptor, it keeps the receptor in the “on” position. This causes many things to occur. If too many H1 receptors are bound in the “on” position for too long, it can cause airway constriction, difficulty breathing, dilation of blood vessels, hiving, pain and itching, among other symptoms.

In pharmacology, two terms are used to describe the effect a substance has when it binds to a receptor. An agonist fully activates the receptor it binds to. Histamine is an agonist of the H1 receptor because when it binds the receptor, it activates it and thus turns it on. An antagonist binds the receptor but doesn’t turn it on (which is not the same as turning it off). By the antagonist binding the receptor, it prevents histamine from binding there are turning it on.

The medications we use to mediate H1 receptor actions, like diphenhydramine or cetirizine, are often called H1 antagonists, but this is a misnomer. All known medications that act on H1 receptors are more correctly classed as H1 reverse agonists, which is a trickier concept. Basically this means that when these medications bind the H1 receptor, they turn it off. In turn, this prevents a series of actions that are executed by the action of histamine.

First generation H1 antihistamines have a wide ranging group of effects. I have described receptors in the past as being like locks, and the substances that bind them (called ligands) are like keys. In this analogy, first generation H1 antihistamines like diphenhydramine would be like a master key. They are capable of binding to many receptors, including muscarinic, serotonin and a-adrenergic receptors. They also cross the blood-brain barrier. Histamine is an important neurotransmitter with a lot of activity of the brain. By crossing into the brain, these first generation H1 antihistamines can interfere with the sleep-wake cycle, learning, memory, fluid balance, regulation of body temperature, regulation of the cardiovascular system, and stress release of ACTH and b-endorphin from the pituitary.

During the day, first generation H1 antihistamines often cause sleepiness, sedation, drowsiness, fatigue and impaired concentration and memory, even at recommended doses. At night, they delay the onset and reduce the duration of REM sleep. This in turn causes a lower quality sleep, with decreases in attention, vigilance and working memory still observable in the morning.

Second generation H1 antihistamines have largely dealt with the issues present in first generation formulations. Unlike first generation medications, they bind with excellent specificity to the H1 receptor, rather than binding promiscuously. They demonstrate very limited penetration of the blood brain barrier so there is little associated sedation. Desloratadine in the most potent antihistamine, followed by levocetirizine and then fexofenadine.

H1 antihistamines are universally well absorbed with the exception of fexofenadine, which relies on a unique transport mechanism that can be more variable. Studies have shown that in adults, the maximum inhibition of allergic response occurs about four hours after taking levocetirizine, fexofenadine or desloratadine. Loratadine requires metabolism to release the active portion of the molecule, and thus can take hours longer to become efficacious. Fexofenadine has a shorter duration of action at about 8.5 hours, compared to 19 hours for cetirizine at a typical dose.


Church, Diana S., Church, Martin K. Pharmacology of antihistamines. World Allergy Organization Journal 2011, 4 (Suppl 3): S22-S27.

Leurs, R., et al. H1-antihistamines: inverse agonism, anti-inflammatory actions and cardiac effects. Clinical and Experimental Allergy 32 (2002): 489-498.

Circadian rhythm of mast cells

The circadian clock (also called circadian rhythm) regulates many physiological activities including the sleep-wake cycle, metabolism, digestion and immune processes. It is essentially a system that tells cells in the body what to do based on a 24 hour cycle, which can be influenced by such things as light cues, sleep and medication. Many cell types in the body have been shown to maintain their own internal circadian clocks and to change their behavior based upon time. Mast cells and eosinophils have been shown to maintain their own internal clocks.

On a cellular level, the circadian clock is maintained by the expression of clock genes. Inside the cell, a protein called CLOCK attaches to another protein (BMAL1) and they initiate expression of several genes that regulate circadian rhythm in the cell. These genes are called Period 1, Period 2, Period 3, Cryptochrome 1 and Cryptochrome 2. The proteins made by those genes regulate the expression of other genes based upon time.

An interesting facet of allergic disease is the well established variation in symptom severity depending on the time of day. This is seen in a variety of allergic conditions, such as asthma and atopic dermatitis. Allergic symptoms, including those that affect pulmonary function, are worse between midnight and morning, with a ramping up of symptoms seen around 10pm. This worsening overnight often results in sleep disruptions and “morning attacks”, which affect rest and result in decreased quality of life for patients. This has been verified repeatedly both through mouse studies and in reports of human patients.

Circadian rhythm has been shown to affect mediator release in mast cells, and this has been shown to be regulated by the five genes listed above. If even one of those genes are mutated, the mediator release becomes uniform and does not shown the peaks and lows observed normally. Both tryptase and plasma histamine levels have been observed to have lower levels in the afternoon and to peak at night. A marker associated with degranulation (b-hexosaminidase) showed the same pattern.

There is currently no information available on how mast cells tell time in relation to the rest of the body, though it is thought that mast cells receive molecular signals that “start the clock”. Importantly, in mice that have had their adrenal glands removed, mast cells do not shown circadian rhythms in mediator release. This indicates that the signal that “starts the clock” comes to mast cells from the adrenal glands. Corticosterone is being investigated as the possible signal, as it has been shown to induce expression of at least two clock genes, Period 1 and Period 2.



Silver, A.C., Arjona, A., Hughes, M.E., Nitabach, M.N., Fikrig, E., 2012. Circadian expres-sion of clock genes in mouse macrophages, dendritic cells, and B cells. BrainBehav. Immun. 3, 407–413.

Smolensky, M.H., Lemmer, B., Reinberg, A.E., 2007. Chronobiology and chronother-apy of allergic rhinitis and bronchial asthma. Adv. Drug Deliv. Rev. 9–10,852–882.

Baumann, A., Gonnenwein, S., Bischoff, S.C., Sherman, H., Chapnik, N., Froy, O.,Lorentz, A., 2013. The circadian clock is functional in eosinophils and mast cells. Immunology 4, 465–474.

Burioka, N., Fukuoka, Y., Koyanagi, S., Miyata, M., Takata, M., Chikumi, H., Takane, H.,Watanabe, M., Endo, M., Sako, T., Suyama, H., Ohdo, S., Shimizu, E., 2010. Asthma: chronopharmacotherapy and the molecular clock. Adv. Drug Deliv. Rev. 9–10,946–955.

Cermakian, N., Lange, T., Golombek, D., Sarkar, D., Nakao, A., Shibata, S., Mazzoccoli, G., 2013. Crosstalk between the circadian clock circuitry and the immune system.Chronobiol. Int. 7, 870–888.

IgE-dependent activation of human mast cells and fMLP-mediatedactivation of human eosinophils is controlled by the circadian clockAnja Baumanna, Katharina Feilhauerb, Stephan C. Bischoffa, Oren Froyc, Axel Lorentza. Molecular Immunology 64 (2015) 76–81.

Yuki Nakamura, et al. Circadian regulation of allergic reactions by the mast cell clock in mice. J Allergy Clin Immunol 133 (2014) 568-575.


Real talk about ostomies

I was driving around the internet at 130 in the morning as you do when I came across a petition on change.org. The petition is asking the CDC to stop airing an ad in which a smoker develops colon cancer and discusses wearing a colostomy bag. Here are some quotes from the salient portions:

“In this ad she refers to having to wear a colostomy bag for a year which is “smelly” and because she fears leaks she doesn’t leave her home. This may or may not deter people from smoking, but in the meantime, unnecessarily sheds negative light on people with ostomies.”

“The negative stigma that is spread by this ad is itself a health threat. Fear of being stigmatized, including the extreme negative body image that our society has placed on those with ostomies…”

“…it sends the wrong message to the general public, at a time when those of us who have permanent ostomies are trying to educate others about this condition.”

I have a lot of feelings about this.

The first is that yes, I agree that ostomies are stigmatized. I think this is less of a problem than it was years ago, but ostomies are still not very common and people are unfamiliar with them. It changes the way you look at your body and makes the process of waste elimination a very graphic part of your daily life. It is difficult for many people, and many people elect not to get ostomies because of that.

However, I completely disagree with this idea that ostomies are totally palatable, because that is simply not the case. I feel like this petition is saying that this woman is being dishonest in portraying the colostomy bag as being smelly or leaky. The fact is that they often are. And while I agree that ostomies shouldn’t be stigmatized as they are medically necessary for many of us, I don’t agree that we should gloss over the realities of living with ostomies in order to get there.

I have a colostomy. It was placed two years ago with the intention of being permanent. Due to some further complications, I am having my colostomy reversed, which may result in the later placement of a permanent ileostomy. The likelihood of my needing an ileostomy at some point is significant.

I use a two part pouching system. One part, called the wafer, is a ring that fits around the stoma and is adhesive, so it adheres directly to my skin. The second part is the colostomy bag, which has a ring that snaps into the ring on the wafer.

Colostomy bags are either disposable or reusable. With disposables, you throw the entire thing out and put on a new bag when you stool. I use reusable bags that can be emptied by unrolling the end of the bag, called the tail. The stool is then pushed out of the bag into the toilet while the bag is still snapped into the wafer and attached to your body. If your stool is really hard most of the time and doesn’t really come out of the bag well through the tail, you may end up removing the bag from the wafer and emptying it through the hole in the back, then reattaching the bag.

Ostomy suppliers make deodorant that you can put in the bag. It works okay. It doesn’t work great. If I am dressed, on an average day, you will not smell stool. If I am walking around naked, I might smell it. However, I find the deodorant is not very effective for gas. You cannot control gas when you have an ostomy in the same way that you cannot control stooling. So you can pass gas at any time and yes you can hear it and yes it smells. Another thing many people don’t realize is that the closer the end of your GI tract is to your stomach, the worse the stool smells. I can’t really think of an appropriate analogy, but suffice it to say that stool and gas smells much worse when you have an ostomy.

Disposables don’t tend to smell as much because there isn’t really enough time. Smell is more of an issue for people who use reusable bags. So why do people use them, right? Mostly insurance. Most insurances will pay for 20 reusable bags a month or 60 disposable bags. So either change the bag every day and a half or throw out the bag twice a day. What if you go to the bathroom more than twice a day? Most places won’t allow you to pay cash for more bags, so people who use disposables generally use larger bags to hold more stool, which is more visible and may smell if it is full.

Side note: You have not known fear until your insurance is refusing to approve your ostomy supplies and you won’t have anything to poop into in three days.

Ostomy pouching systems are pretty clever but they are not perfect, so they sometimes leak. One kind of leak is when stool doesn’t go into the bag completely when you stool and so some of it gets under the wafer and onto the skin. This is much worse for people with ileostomies where the stool is much more liquid, but it happens for colostomies, too. It happens at some point to everyone who has an ostomy. Stool on the skin can cause infections and also causes literal burns, which feel awesome and take forever to heal because you have to keep applying adhesive to the skin whether or not it is in bad shape. It’s a sucky situation.

The other kind of leak is when you poop so much that the force pushes the bag out of the seal the rings make and the stool literally leaks out. This mostly happens when you suddenly get diarrhea, like during anaphylaxis or a sudden onset bad mast cell reaction. This has happened to me a few times. It actually happened to me recently while I was on the train to work. I walked to a Starbucks and threw everything away and threw my tights away and cleaned myself up and went on with my day. But yes, if you have a colostomy, there is always a chance that you are going to poop on yourself on your way to work. And yes, that affects the decisions that I make regarding travel and transportation.

Pretending that people with ostomies don’t have these issues is both disingenuous and not helpful. I agree that all medically necessary things should be accepted by society but trying to convince people that ostomy bags don’t sometimes smell is not the way to do it. I hope someday insurance companies will stop being dumb about pouches and we will have better supply options or treatment options that don’t involve surgically created openings to the GI tract but you get what you get.

I live a very full life and having an ostomy has not prevented that. But it affects my life and it affects the lives of all ostomates. You shouldn’t be ashamed of your ostomy, and I am certainly not, but pretending that they don’t create gross or socially awkward situations is not progress. It is a different form of being closeted. So I do not support this petition. And I will not be signing it.


Mast cell inhibitory effects of some microorganisms

We have talked recently about how infections can activate mast cells and result in worsening of symptoms in mast cell patients. However, some organisms are actually able to decrease mast cell degranulation and secretion of mediators. Some of these organisms are highly pathogenic with dangerous infectious capabilities, but some are commensal bacteria that can be found in probiotics. These findings support a growing body of evidence that indicates that the changes in our commensal organisms in the last thirty years have contributed to the increased frequency of atopic disease in developed countries. Additionally, improved hygiene and public health have decreased the frequency of some infections, which may also contribute to allergic conditions.

Lactobacillus and Bifidobacteria have been found to directly inhibit mast cell degranulation. Lactobacillus reduces both mast cell degranulation and cytokine secretion by reducing the number of IgE receptors on mast cell surface. Expression of IL-8 and TNF-a are actively decreased, while expression of the anti-inflammatory IL-10 is increased. Bifidobacterium bifidum inhibit IgE activation of mast cells in similar ways.

Salmonella typhimurium is a frequent cause of foodborne illness. In the US, it is estimated to cause 1,000,000 illness events annually, resulting in 19,000 hospitalizations and 380 deaths. It causes diarrhea, fever and severe abdominal cramping that can last several days. A 2001 study found that Salmonella are able to avoid detection by neutrophils through inactivation of local mast cells. Specifically, Salmonella inject a protein known as SptP into the fluid inside mast cells. Following exposure to Salmonella, mast cells lost their ability to degranulate, even when exposed to IgE or strong antigens.

Yersinia pestis, which causes plague, can also suppress mast cell degranulation by injecting a similar protein called YopH. Several forms of commensal E. coli (which do not cause infection) have been found to exhibit similar suppression.

Some organisms can cause mast cells to lyse (burst) and thus die. Pseudomonas aeruginosa releases exotoxin A, which causes lysis of mast cells.

Infectious fungi, such as Aspergillus fumigatus, release a gliotoxin that suppresses mast cell degranulation as well as mediator secretion. Other fungal products that decrease mast cell activity include FK-506 from Streptomyces tsukubaensis and cyclosporine A from Tolypocladium inflatum. Cyclosporine A is often used as an immunosuppressive after organ transplant and also sees some use in treating inflammatory disorders.

Some nematodes (roundworms) are also able to block mast cell degranulation. Filarial nematodes release a molecule, ES-62, that blocks IgE activation of mast cells as well as inhibiting secretion of allergic inflammatory factors. This finding is notable as it provides a possible reason why allergic diseases occur less frequently in developing countries. Toxoplasma gondii, a parasitic protozoan that causes toxoplasmosis, also prevented mast cell degranulation.



Choi, H.W., Brooking-Dixon, R., Neupane, S., Lee, C.-J., Miao, E.A., Staats, H.F., Abraham, S.N., 2013. Salmonella typhimurium impedes innate immunity with a mast-cell-suppressing protein tyrosine phosphatase, SptP. Immunity 39,1108–1120.

Cornelis, G.R., 2002. Yersinia type III secretion: send in the effectors. J. Cell Biol. 158, 401–408.

Magerl, M., Lammel, V., Siebenhaar, F., Zuberbier, T., Metz, M., Maurer, M., 2008. Non-pathogenic commensal Escherichia coli bacteria can inhibit degranulation of mast cells. Exp. Dermatol. 17, 427–435.

Harata, G., He, F., Takahashi, K., Hosono, A., Kawase, M., Kubota, A., Hiramatsu, M.,Kaminogawa, S., 2010. Bifidobacterium suppresses IgE-mediated degranulationof rat basophilic leukemia (RBL-2H3) cells. Microbiol. Immunol. 54, 54–57.

Forsythe, P., Wang, B., Khambati, I., Kunze, W.A., 2012. Systemic effects of ingested Lactobacillus rhamnosus: inhibition of mast cell membrane potassium (IKCa)current and degranulation. PLoS One 7, e41234.

Oksaharju, A., Kankainen, M., Kekkonen, R.A., Lindstedt, K.A., Kovanen, P.T., Korpela,R., Miettinen, M., 2011. Probiotic Lactobacillus rhamnosus downregulates FCER1and HRH4 expression in human mast cells. World J. Gastroenterol. 17, 750–759.

Wesolowski, J., Paumet, F., 2011. The impact of bacterial infection on mast celldegranulation. Immunol. Res. 51, 215–226.

Niide, O., Suzuki, Y., Yoshimaru, T., Inoue, T., Takayama, T., Ra, C., 2006. Fungal metabolite gliotoxin blocks mast cell activation by a calcium- and superoxide-dependent mechanism: implications for immunosuppressive activities. Clin.Immunol. 118, 108–116.

Melendez, A.J., Harnett, M.M., Pushparaj, P.N., Wong, W.S., Tay, H.K., McSharry, C.P.,Harnett, W., 2007. Inhibition of Fc epsilon RI-mediated mast cell responses by ES-62, a product of parasitic filarial nematodes. Nat. Med. 13, 1375–1381.

Hae Woong Choi, Soman N. Abraham. Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms. Molecular Immunology 63 (2015) 74–79.