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Lisa Klimas

I'm a 35 year old microbiologist and molecular biologist with systemic mastocytosis, Ehlers Danlos Syndrome, Postural Orthostatic Tachycardia Syndrome, Adrenal Insufficiency, and an assortment of other chronic health issues. My life is pretty much a blast.

Explain the tests: Complete blood count (CBC) with differential and platelets (Part One)

A complete blood count (CBC), also called full blood count (FBC) in some countries, is one of the most frequently ordered diagnostics.  A CBC quantifies and describes the types of cells found in the blood.  These cells include white blood cells (WBC, also called leukocytes), red blood cells (RBC, also called erythrocytes) and platelets (also called thrombocytes).

There are two commonly methods for counting blood cells, automated and manual.

In automated counting, the cells are counted by a machine called a flow cytometer.  Flow cytometers identify cells by shining a laser through a sample of the blood and using the way the light bounces off the cells to determine what kind of cells they are.   This bouncing of light is called scatter.  Flow cytometers measure forward scatter determines the diameter of a cell.  Side scatter determines granularity, how many granules are inside the cell. While this method is generally quite precise, if a cell is not shaped normally, the flow cytometer may count it incorrectly.

In manual counting, the blood is diluted and placed into a special chamber with grid lines called a hemocytometer.  The chamber is viewed under a microscope and the cells are counted by eye.  As someone who has counted lots of cell suspensions by eye, it can be hard to be exact.  This method works for red and white blood cells.

To evaluate abnormality in cell shape, a blood smear is made from the original blood sample.  A smear slide is made by smearing a thin layer of blood onto a glass slide.  Once the blood is dried on the slide, stains are then used to colorize the cells to make them easier to see and distinguish.  Giemsa is a commonly used stain for this purpose (fun fact: mast cells can be visualized with Giemsa stain).  Other stains can also be used. This method allows abnormalities in shape of red and white cells to visualized.

 

A CBC usually includes the following tests:

Total white blood cell count

  • The count of all white blood cells in a volume of blood;
  • Unit is cells/liter

Total red blood cell count

  • The count of all red blood cells in a volume of blood
  • Unit is cells/liter

Hemoglobin (Hb)

  • The amount of hemoglobin in a volume of blood
  • Unit is grams/deciliter

Hematocrit (Hct; also called packed cell volume, PCV)

  • The portion of a volume of blood that is red blood cells
  • Unit is percentage

Mean corpuscular volume (MCV)

  • The volume occupied by red blood cells in a volume of blood
  • Identifies if red cells are the right size
  • Unit is femtoliters/cell

Mean corpuscular hemoglobin (MCH)

  • The average hemoglobin in a red blood cell in a volume of blood; the amount of hemoglobin divided by the red blood cell count; mass of hemoglobin divided by number of red blood cells in a volume of blood; unit is picograms/cell
  • Mean corpuscular hemoglobin concentration (MCHC): the average concentration of hemoglobin in a volume of red blood cells; determines size of red cells; hemoglobin divided by hematocrit; unit is grams/liter

Red blood cell distribution width (RDW)

  • The amount of variation in the size of red cells
  • Can only be high or normal
  • High RDW means red cells show a wide range of size

Reticulocyte count

  • The amount of new red cells in a volume of blood
  • Unit is percentage

 

A CBC with differential and platelets will include the following tests:

Neutrophil count

  • The count of neutrophils in a volume of blood
  • Neutrophils are inflammatory cells that fight infections and initiate inflammatory response
  • Unit is cells/liter

Lymphocyte count

  • The count of lymphocytes in a volume of blood
  • B cells, T cells and NK cells are lymphocytes that detect pathogens in different ways
  • Unit is cells/liter

Monocyte count

  • The count of monocytes in a volume of blood
  • Monocytes respond to inflammatory signals and develop into specialized tissue cells
  • Unit is cells/liter

Eosinophil count

  • The count of eosinophils in a volume of blood
  • Eosinophils fight parasites and participate in allergic response
  • Unit is cells/liter

Basophil count

  • The count of basophils in a volume of blood
  • Basophils fight parasites and participate in allergic response
  • Unit is cells/liter

Platelet count

  • The count of plateletsin a volume of blood
  • Platelets stop bleeding
  • Unit is platelets/liter

Mean platelet volume (MPV)

  • The volume occupied by platelets in a volume of blood
  • Identifies if platelets are the right size
  • Unit is femtoliters/platelet

How to travel with mast cell disease

My travel tips:

1. If you stopped traveling for health reasons, talk to your health providers when you want to start again. If you would receive emergency care at another hospital, it’s important to discuss exactly what that should look like.
2. Get fit to fly letters that detail what medications you need to carry onboard with you and emergency protocols on letterhead from your doctor. If possible, get multiple originals (with original signatures) rather than an original and copies. If traveling abroad, it is helpless to have them notarized.
3. Always carry rescue medications, emergency protocol and “Greatest Hits” sheet listing your diagnoses, daily meds, rescue meds, and any special precautions. You should do this everywhere, but it is especially important if you are traveling. If you take over the counter meds, they should be listed as well.
4. Make sure that it is legal to transport all of your medications to the destination. Some medications are illegal in certain countries, regardless of whether or not it is for your personal medical use. Of note, diphenhydramine (Benadryl) is illegal in some countries.
5. Find out if your medications are available at your destination. If they aren’t, identify an alternative.
6. Call the airline directly to describe your needs. Many airlines have seats with more space (bulkhead) that are preferentially given to people with medical issues so you have more room for meds/supplies. If you have need to use medical equipment during flight (like an infusion pump), tell them when you call and have the model number/serial number handy. Airlines will refrigerate medication for you if you tell them in advance.
7. If you are triggered by standing for long periods of time, lifting your carry-on, walking, etc, ask for a wheelchair to meet you at check-in and take you to the gate. In my experience, if you have a ton of meds/liquids with you, going through security is easier if are in a wheelchair.
8. Get to the airport early. I always go at least an hour before recommended. If you have made requests for assistance (like a wheelchair), you will not be able to check-in online.
9. Expect to have to tell your story at the check-in counter to at least one employee and their supervisor. Even with the notes added when you called the airline, you may still get push back when you check in. This most often occurs in the form of restrictions applying to your carry-on.
10. Remind them that you are allowed to bring extra luggage onboard if it contains medication/medical supplies. I infuse while flying so I have to wear a backpack at all times that holds the bag attached to my port line. Sometimes, they will count this backpack as one of my carry-on items and say I can only bring one more piece aboard. Again, you are allowed to bring extra luggage aboard if it contains medication.
11. Be reasonable with the extra luggage. Only bring aboard what you really need. When I flew to and from Hong Kong, I had a carry-on packed with all my meds in labeled containers, supplies to access/dress my port, and three days worth of IV bags and supplies to spike and remove air from IV bags. This would be enough that in an emergency where everything else was lost, I would have enough IV meds/supplies to fly home.
12. Pack medical supplies in hard shell luggage so that things don’t get crushed or broken.
13. Pack everything you need for the day in a separate bag and keep it in your purse. This is much easier than getting the luggage down in flight.
14. Bring safe foods. Do not expect to be able to eat on the airplane if you have severe food issues. You are allowed to bring some foods through security.
15. Expect that going through security will be time consuming. It will be. If you have medical implants/devices like central lines or ostomies, tell them before you go through the metal detector.
16. They will definitely pat you down, open your luggage and swab everything for explosives. Show them the letter stating that you need to bring these medications/supplies onboard.
17. When you arrive at the gate, ask at the counter to board early.
18. If you are sitting in the bulkhead row (no seats right in front of you) and you have an infusion pump/backpack, tell the flight attendant when you board. What happens next depends on the flight crew. Sometimes they will want you to switch seats for take off and landing since you can’t stow the backpack under the seat. Sometimes they will let you hold the backpack like a baby. Sometimes they will let you buckle it into the seat next to you.
19. If your pump will be on during take off and landing, if the flight attendant asks about it, tell them that you spoke to the airline previously and that it is medically necessary. It is safe for the pump to be on during take off and landing.
20. Hydrate like it is your job. Flying is seriously dehydrating and can really exacerbate GI motility issues.
21. I premed 24 hours and 1 hour before the flight with steroids, diphenhydramine, ranitidine and montelukast, just like for before surgery. I am most reactive during take off and landing, so I am careful to premed with enough time for the drug to be active during these times.
22. If my flight is longer than the window of these medications (3-4 hours), I medicate again an hour before landing. Please check with your doctor to determine what is the best medication protocol for you to provide additional coverage for flying.
23. I infuse IV fluids while flying as it helps stabilize my blood pressure.
24. I take extra diphenhydramine (Benadryl) for at least two days after flying. I also do a short taper to get down to my baseline steroid dose (I have adrenal insufficiency).
25. I take extra stool softener for a few days before flying and a few days after to avoid worsening GI issues from dehydration.
26. Call the hotel before you book to discuss options for food and cleaning supplies, and anything extra you may need, like a refrigerator or safe. If you will be eating primarily at the hotel, speak with the Food and Beverage manager to identify some safe options for you prior to arrival.
27. Plan around your need to sleep. Flying is very triggering and you will likely need a lot of sleep to recover. Plan some days (or at least parts of days) with empty blocks of time for you to nap and rest as needed. About 1/3 of the days I spent in Asia were spent sleeping or awake but in bed.
28. If I am traveling domestically, I often ship supplies/meds to my destination so I don’t have to worry about carrying everything/luggage getting lost. You can ship medication to yourself in the US as long as you are the end user. For example, when I visited my friend Christen, I sent a package to Lisa Klimas c/o Christen [Christen’s last name]. Having done this with multiple operators, my best experience has been with the USPS. They were half as expensive as UPS or FedEx and the only operator to deliver the package on time (I ship overnight because I have refrigerated meds).
29. Discuss with your doctor whether it is appropriate to bring antibiotics/antivirals with you on your trip in case you develop an infection.
30. Identify a hospital at your destination in case you have an emergency.
31. If possible, have a copy of your doctor’s letter translated into the local language.
32. Try to be patient. Some days I am just so tired of fighting about shit with airlines but if you can stay patient, the likelihood of things working out better increases. It’s one thing to let a sick person fly, it’s another thing to let a sick and hysterical person fly.
33. If the flight crew is uncomfortable with you flying, they can refuse to let you on the plane. This is where having a fit to fly letter is very important. Emphasize that it is safe for you to fly and that if you have a severe reaction, you are capable of managing it on your own. If you are NOT capable of managing a bad reaction alone, I urge you not to fly alone.
34. Wear a watch that displays local time at your place of departure so that your med schedule doesn’t get blown up. If the time difference is substantial, you may need to take an extra med dose in the first 24 hours to align your nighttime meds with your new nighttime and morning meds for your new morning. Check with your doctor on how to manage this.
35. Have fun! Enjoy your trip.

Immunoglobulin free light chains: A possible link between autoimmune disease and mast cell activation

An antibody (also called an immunoglobulin) is shaped like a Y.  The base of the Y is called the Fc region.  The arms of the Y are made of pieces called light chains and heavy chains.  Light chains (described as K or λ) have variable sequences that allow the complete antibody to stick to specific things, like bacteria or allergens.  Light chains are part of how your body fights infections and responds to allergens.  Importantly, free light chains do not work as antibodies.  They are not able to stick to the target the way the total antibody can.

Antibodies are made by white blood cells called plasma cells, which are B cells that circulate and release antibodies as needed.  When producing antibodies, B cells normally make more light chains than heavy chains.  Only about 60% of the light chains made are needed to produce antibodies.  The rest of the light chains are released into plasma and are present there for 2-6 hours, until they are cleared by kidneys.  Light chains that are released into plasma are called immunoglobulin free light chains, shortened as Ig-fLCs.

Another way Ig-fLCs are formed is when they antibody is bound and degraded by a cell.  Antibodies bind things like allergens.  Once they bind allergens (or something else), the antibodies can then bind to receptors on the outside of cells to tell the cells what they found.  Once the antibody is bound to the receptor, it can be partially broken down.  However, light chains are not damaged in this process, and they may be released back into serum.

Ig-fLCs are the subject of ongoing research in various disease models.  Ig-fLC elevation has been linked to a number of inflammatory conditions, including autoimmune diseases.  Systemic lupus erythematosus (SLE) patients demonstrate a significant elevation of Ig-fLCs in urine 4-8 weeks prior to a symptomatic flare.  SLE is an antibody driven disease and the extra Ig-fLCs may be produced as a byproduct of making more autoantibodies in advance of a flare.  In this capacity, it would demonstrate hyperactivity of the B cells that make the autoantibodies.

Ig-fLCs were also found to be elevated in 1/3 patients with rheumatoid arthritis and 1/5 patients with systemic sclerosis.  A number of cancers also induce elevation of Ig-fLCs.

Ig-fLCs are involved in a number of allergic processes.  In allergic asthma animal models, Ig-fLCs have been found to induce bronchoconstriction and acute mast cell degranulation.  Using an experimental light chain antagonist can prevent this reaction.  Κ light chains are elevated in serum of asthmatics, regardless of whether or not the asthma is atopic is nature. λ light chains are not elevated in this population.

Ig-fLCs are also involved in other allergic mouse models, including contact dermatitis, food allergy and inflammatory bowel disease.  In these models, the Ig-fLCs can sensitize mast cells to allergens so that exposure to the allergen causes mast cell activation and degranulation.

Ig-fLCs have also been implicated in mast cell dependent colitis and inflammatory bowel diseases such as ulcerative colitis and Crohn’s.  It is believed that antigen specific Ig-fLC sensitizes mast cells to cause activation and degranulation.  This is especially important because it describes a mechanism that occurs in the absence of IgE.  Serum κ and λ light chains are elevated in Crohn’s models and using an experimental blocker prevents these bowel symptoms.  Research has indicated that the IgE, IgG and paired Ig-like receptor A receptors are not involved in binding Ig-fLCs in these models.

Many mast cell patients have a primary inflammatory condition, such as IBD or autoimmune disease.  Mast cell activation via Ig-fLCs is, to me, the most plausible explanation for this relationship.  Currently, mast cell activation by Ig-fLCs has not been demonstrated in humans, though present in many animal models.  However, Ig-fLC correlation to autoimmune diseases such as lupus has been shown in humans.

References:

Kraneveld A, et al. Elicitation of allergic asthma by immunoglobulin free light chains. PNA 2005: 102(5); 1578-1583.

Thio M, et al. Antigen binding characteristics of immunoglobulin free light chains: crosslinking by antigen is essential to induce allergic inflammation. PLoS One 7(7): e40986.

Rijnierse A, et al. Ig-free light chains play a crucial role in murine mast cell-dependent colitis and are associated with human inflammatory bowel diseases. J Immunol 2010; 185:653-659.

Gottenberg JE, et al. Serum immunoglobulin free light chain assessment in rheumatoid arthritis and primary Sjogren’s syndrome. Ann Rheum Dis 2007; 66:23-27.

Aggarwal R, et al. Serum free light chains as biomarkers for systemic lupus erythematosus disease activity. Arthritis Care and Research 2011: 63(6): 891-898.

River stones

The day I was diagnosed, I left the hospital holding a piece of scrap paper with notes all over it. I occasionally come across it again while looking for reports in my massive collection of medical documentation. The paper is soft along the folds, but the ink is still bright. Words jotted down haphazardly surround a crude drawing of a mast cell heavy with granules. Words to explain my disease and its accompanied wreckage.

These words meant more than too many mast cells, too much activation. They meant the pain and stress of being sick. They meant all the things I had lost. They meant fear and loneliness. They meant desperation and need for validation. They meant that this was real and that meant that it wouldn’t go away. The words were arbitrary. They had no power on their own. They had power because of what they represented in my mind.

In the weeks that followed diagnosis, I said the words out loud when I was home alone. I turned them over in my mouth until the edges were smoothed, the jaggedness smoothed like a river stone.

I arrived in Beijing on Tuesday afternoon. It was cold and raw there, the kind that makes every movement feel heavy and dully painful. The city was overlaid with soft fog, fluffy and moist. It looked sleepy. Our wonderful tour guide apologized for the poor visibility but I liked it, this ethereal dressing. In fairy tales, that’s where magic happens.

On Thursday morning, we went to the Mutianyu portion of the Great Wall. We walked up to a cable car that delivered us into the heavy mountain fog. We made a short climb up slick stone steps to reach the wall, visible only in glimpses through this wet cover.

The shrouding was so complete that I could almost believe that if I stepped off the wall into the fog, I just might disappear. We were high above the world. We were in the sky.

There was a sharpness to walking through the mist in this place that had borne witness to eons of man. I can’t find the right words to express how it felt to walk along the Great Wall. If let down was a positive feeling, it might feel like that. I was awestruck by this experience. It could not have been more amazing for me. It feels like putting down something I carried for so long that my body began to accept it as its own. It is the knowledge that after so long, I will never again see the Great Wall for the first time because I already did.

I saw the Great Wall after years of doubting I would see it at all. I did this impossible thing. I wanted to cry tears laden with the salt of all the impossible things I had hoped for in that place where it seemed the very mountains were crying, too. Hope is the only way forward, but it can be so, so heavy.

Our tour guide explained the function of the Wall, its amazing length and structure. It was designed to prevent invaders from returning, watchtowers manned with sentries. It surprised me that the mountains themselves weren’t enough protection without the wall. I’m not sure that the wall was ever any better than the mountains alone. But the people believed it did and that made them better. Maybe it gave them hope.

A lot has changed since I was diagnosed. The words I smooth are different now. They are still painful. But if I think of the coolness of the stone, the feeling of another world encroaching, the realization that dreams come true, maybe when I say these words, they can mean that, too.

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Just before waking

For most of my life, I have seen things in that creeping inertia toward sleep. Figures made of vibrating inkiness would move towards me until I screamed and jumped in the moment before we touched. I would shake my head from side to side and rub my eyes like an incredulous cartoon character while my pounding heart slowed.

The shapes I saw never existed outside of that thin slip of time that bounded waking from sleep, but logic is not enough. It didn’t matter that I knew that these were hallucinations. The panic was real.

From the moment I decided to visit China, I was panicking. I fretted about bringing medications, transporting IV bags, getting medical notes, dealing with the airline, the weather. Everything was a variable I could not control. The mental invention I could muster to frame worst case scenarios was impressive. Every obstacle brought fresh waves of anxiety until I believed I may never get there. I worried and worried and worried.

By the day I was set to fly to China, my fear had reached fever pitch. What if the airline staff wouldn’t let me carry my supplies onboard? What if I need an epipen? What if my port clots off? What if I can’t reaccess my port? What if all my IV bags pop? What if I have a severe reaction during the sixteen hour flight?

I had actual nightmares that I would arrive in China to discover all of my medication bottles were empty. In the half slumber just before waking, vignettes of my illness destroying this trip paraded before my eyes.

Late on November 2, I went to Logan Airport with my new matching luggage and checked in for my flight to Hong Kong. As anticipated, there was some trouble with getting approval to bring my critical supplies and meds as my carry-on luggage. Lots of calling supervisors and discussions. At last, a supervisor walked over to us. In his hand was the printout summarizing my health conditions and necessary accommodations. I could bring this small piece of luggage onboard with me.

Things went much better from that point. A wheelchair was brought to transport me to the gate. TSA gave me no trouble. I boarded the plane first to get medicated and settled. A flight attendant came over, holding a copy of my medical approval form.

“It says you have ‘mas-to-cy-tro-sis’, this is right?” she asked warmly.

“Yes, that’s me,” I said, fighting with my infusion pump.

“This word does not mean anything to me. How can we help you during this flight?”

“I’m fine, I can handle everything myself.” And I was fine and I could handle everything myself. I manage my disease everyday. There was never anything to fear.

After we took off, I laid back and fell asleep for nine hours. I flew over the North Pole and landed in Hong Kong without any trouble.

I have been in Hong Kong for five days. I am very tired. I am very sore from the flight. I am reacting mildly. It is hot and hazy here, the air like droplets of lead weighing everything down. I can eat almost nothing that wasn’t prepared at the house and need to nap every afternoon on top of sleeping 10-12 hours a night.

But I am here. I made it to Asia. I have seen the Star Ferry and the Peak, the bustling central area and the sun blazing through the fog over the South China Sea.

The nightmare is not that I would be sick in China because I am sick and will always be sick and being in China won’t change that. The nightmare is that I would wait so long to be “healthy” that I would never experience the blinding joy of going to the other side of the world. The nightmare is that my disease would prevent me from living a life of wonder and meaning.

You don’t need a good reason to pursue your dreams. It doesn’t have to be logical or convenient. You don’t need a plan. You just need to decide that you want things to be different and believe that they can be.

In a season when it feels like I have lost so much, I can no longer be controlled by these nightmares. And even when I’m queasy and sore, I am happy in those quiet moments just before waking.

Reading list: Papers to better understand mast cells and mast cell disease (Part 4)

Mast cells and eosinophils

  • Elishmereni M, Alenius HT, Bradding P, Mizrahi S, Shikotra A, Minai-Fleminger Y, et al. Physical interactions between mast cells and eosinophils: a novel mechanism enhancing eosinophil survival in vitro. Allergy 2011;66:376–385.
  • Elishmereni M, Bachelet I, Nissim Ben Efraim AH, Mankuta D, Levi-Schaffer F. Interacting mast cells and eosinophils acquire an enhanced activation state in vitro. Allergy 2013; 68: 171–179.
  • Minai-Fleminger Y, Elishmereni M, Vita F, Soranzo MR, Mankuta D, Zabucchi G et al. Ultrastructural evidence for human mast cell-eosinophil interactions in vitro. Cell Tissue Res 2010; 341: 405–415.
  • Puxeddu I, Ribatti D, Crivellato E, Levi- Schaffer F. Mast cells and eosinophils: a novel link between inflammation and angiogenesis in allergic diseases. J Allergy Clin Immunol 2005; 116: 531–536.

Allergic to infections

  • Abraham S. N, St John A. L. (2010). Mast cell-orchestrated immunity to pathogens. Rev. Immunol. 10440–452.
  • Dietrich N., Rohde M., Geffers R., Kroger A., Hauser H., Weiss S., Gekara N. O. (2010). Mast cells elicit proinflammatory but not type I interferon responses upon activation of TLRs by bacteria. Natl. Acad. Sci. U.S.A.1078748–8753
  • Fehrenbach K., Port F., Grochowy G., Kalis C., Bessler W., Galanos C., Krystal G., Freudenberg M., Huber M. (2007). Stimulation of mast cells via FcvarepsilonR1 and TLR2: the type of ligand determines the outcome. Immunol.442087–2094.
  • Gilfillan A. M., Tkaczyk C. (2006). Integrated signalling pathways for mast-cell activation. Rev. Immunol.6218–230.
  • McCurdy,J.D., Olynych,T.J., Maher, L. H.,and Marshall, J.S.(2003). Cutting edge: distinct Toll-like receptor2 activators selectively induce different classes of mediator production from human mast cells. Immunol. 170, 1625–1629.
  • Medina-Tamayo, J., Ibarra-Sanchez, A., Padilla-Trejo,A., and Gonzalez- Espinosa, C. (2011). IgE-dependent sensitization increases responsiveness to LPS but does not modify development of endotoxin tolerance in mast cells. Res. 60, 19–27.
  • Qiao,H., Andrade,M.V., Lisboa,F. A., Morgan,K., and Beaven, M. A. (2006).FcepsilonR1 and toll-like receptors mediate synergistic signals to markedly augment production of inflammatory cytokines in murine mast cells.Blood 107, 610–618.
  • Sandig H, Bulfone-Paus S. TLR signaling in mast cells: common and unique features. Front Immunol. 2012; 3: 185.
  • Varadaradjalou, S., Feger, F., Thieblemont, N., Hamouda, N.B., Pleau, J. M., Dy,M., and Arock, M. (2003). Toll-like receptor 2 (TLR2) and TLR4 differentially activate human mast cells. J. Immunol. 33, 899–906.
  • Yoshioka,M., Fukuishi,N., Iriguchi,S., Ohsaki, K., Yamanobe,H., Inukai, A., Kurihara,D., Imajo,N., Yasui, Y., Matsui, N., Tsujita, T., Ishii, A., Seya,T., Takahama,M., and Akagi, M. (2007). Lipoteichoicacid down- regulates FcepsilonRI expressionon human mast cells through Toll-like receptor2. Allergy Clin. Immunol. 120, 452–461.

Interactions with B and T cells

  • Brill, A., Baram, D., Sela, U., Salamon, P., Mekori, Y. A., and Hershkoviz, R. Induction of mast cell interactions with blood vessel wall components by direct contact with intact T cells or T cell membranes in vitro. Exp. Allergy 2004; 34, 1725–1731.
  • Gri, Giorgia, et al. Mast cell: an emerging partner in immune interaction. Front. Immunol., 25 May 2012.

Mast cells in wound healing

  • Douaiher, Jeffrey, et al. Development of Mast Cells and Importance of Their Tryptase and Chymase Serine Proteases in Inflammation and Wound Healing Advances in Immunology, Volume 122 (2014): Chapter 6.
  • Westerberg CM, et al. Differentiation of mast cell subpopulations from mouse embryonic stem cells. Journal of Immunological Methods 382 (2012) 160–166.

Exercise

  • Baek HS, et al. Leptin and urinary leukotriene E4and 9α,11β-prostaglandin F2 release after exercise challenge. Volume 111, Issue 2, August 2013, Pages 112–117
  • Graham P, Kahlson G, Rosengren E. Histamine formation in physical exercise, anoxia and under the influence of adrenaline and related substances. Physiol., 172, 174—188 (1964).
  • Hahn AlG., et al. Histamine reactivity during refractory period after exercise induced asthma. Thorax 1984; 39: 919-923.
  • McNeill RS, Nairn JR, Millar JS, Ingram CG.Exercise-induced asthma. Q J Med 1966; 35: 55-67.
  • Niijima-Yaoita F, et al. Roles of histamine in exercise-induced fatigue: favouring endurance and protecting against exhaustion. Biol Pharm Bull 2012; 35; 91-97.
  • Schoeffel, Robin E., et al. Multiple exercise and histamine challenge in asthmatic patients. Thorax, 1980, 35, 164-170.
  • Teal S. Hallstrand, Mark W. Moody, Mark M. Wurfel, Lawrence B. Schwartz, William R. Henderson, Jr., and Moira L. Aitken. Inflammatory Basis of Exercise-induced Bronchoconstriction. American Journal of Respiratory and Critical Care Medicine, Vol. 172, No. 6 (2005), pp. 679-686.

Circadian rhythm of mast cells

  • 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.
  • Baumanna A, et al. IgE-dependent activation of human mast cells and fMLP-mediatedactivation of human eosinophils is controlled by the circadian clock. Molecular Immunology 64 (2015) 76–81.
  • 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.
  • Nakamura Y, et al. Circadian regulation of allergic reactions by the mast cell clock in mice. J Allergy Clin Immunol 133 (2014) 568-575.
  • 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. 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.

Microbial effects on mast cell behavior

  • Choi HW, Abraham SN. Mast cell mediator responses and their suppression by pathogenic and commensal microorganisms. Molecular Immunology 63 (2015) 74–79.
  • 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. Cell Biol. 158, 401–408.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

Reading list: Papers to better understand mast cells and mast cell disease

Prostaglandin E2

  • Legler DF, et al. Prostaglandin E2 at new glance: Novel insights in functional diversity offer therapeutic chances. The International Journal of Biochemistry & Cell Biology 42 (2010) 198–201.
  • Ricciotti E, FitzGerald GA. Prostaglandins and Inflammation.Arterioscler Thromb Vasc Biol. 2011; 31: 986-1000.
  • Torres R, Picado C, de Mora F. The PGE2–EP2–mast cell axis: An antiasthma mechanism. Molecular Immunology 63 (2015) 61–68

Prostaglandin D2

  • Bochenek G et al. Plasma 9a,11b-PGF2, a PGD2 metabolite, as a sensitive marker of mast cell activation by allergen in bronchial asthma. Thorax 2004; 59: 459–464.
  • Dishy V, et al. Effects of Aspirin When Added to the Prostaglandin D2 Receptor Antagonist Laropiprant on Niacin-Induced Flushing Symptoms. Journal of Clinical Pharmacology, 2009; 49: 416-422
  • Matsuoka T, Hirata M, Tanaka H, Takahashi Y, Murata T, Kabashima K, Sugimoto Y, Kobayashi T, Ushikubi F, Aze Y, Eguchi N, Urade Y, Yoshida N, Kimura K, Mizoguchi A, Honda Y, Nagai H, Narumiya S. Prostaglandin D2 as a mediator of allergic asthma. Science. 2000;287: 2013–2017.
  • Ricciotti E, FitzGerald GA. Prostaglandins and Inflammation.Arterioscler Thromb Vasc Biol. 2011; 31: 986-1000.

Platelet activating factor

  • 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.
  • 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.
  • Vadas P, et al. 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.

Sphingosine-1-phosphate

  • Allende ML, Proia RL. Sphingosine-1-phosphate receptors and the development of the vascular system. Biochim Biophys Acta. 2002; 1582: 222–227.
  • Olivera A, Eisner C, Kitamura Y, et al. Sphingosine kinase 1 and sphingosine-1-phosphate receptor 2 are vital to recovery from anaphylactic shock. J Clin Invest. 2010.
  • Olivera A, Rivera J. An emerging role for the lipid mediator sphingosine-1-phosphate in mast cell effector function and allergic disease. Adv Exp Med Biol. 2011; 716: 123–142.

Leptin

  • Altintas et al. Leptin deficiency-induced obesity affects the density of mast cells in abdominal fat depots and lymph nodes in mice. Lipids in Health and Disease 2012, 11:21
  • Baatar D, Patel K, Taub DD. The effects of ghrelin on inflammation and the immune system. Mol Cell Endocrinol. 2011 Jun 20; 340(1): 44-58.
  • Fernández-Riejos P, et al. Role of Leptin in the Activation of Immune Cells. Mediators of Inflammation, Volume 2010 (2010), Article ID 568343, 8 pages.
  • Hirayama T, et al. Ghrelin and obestatin promote the allergic action in rat peritoneal mast cells as basic secretagogues. Peptides. 2010 Nov;31(11):2109-13
  • Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007 Jan; 8(1): 21-34.
  • Taildeman J, et al. Human mast cells express leptin and leptin receptors. Histochem Cell Biol. 2009 Jun; 131(6): 703-11.

Heparin and bradykinin

  • Brunnée T, et al. Mast cell derived heparin activates the contact system: a link to kinin generation in allergic reactions. Clin Exp Allergy. 1997 Jun;27(6):653-63.
  • Kaplan AP,Ghebrehiwet B. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol. 2010 Aug; 47(13):2161-9
  • Oschatz C, et al. Mast cells increase vascular permeability by heparin-initiated bradykinin formation in vivo. Immunity. 2011 Feb 25; 34(2):258-68.

Mast cell mutations

  • Akin C, et al.. A novel form of mastocytosis associated with a transmembrane c- Kit mutation and response to imatinib. Blood, 103 (2004), pp. 3222–3225
  • Chan EC, et al. Mastocytosis associated with a rare germline KIT K509I mutation displays a well-differentiated mast cell phenotype. J Allergy Clin Immunol, 134 (2014), pp. 178–187
  • Damaj, G., Joris, M., Chandersris, O., Hanssens, K., Soucie, E., Canioni, D., et al., 2014.ASXL1 but not TET2 Mutations Adversely Impact Overall Survival of PatientsSuffering Systemic Mastocytosis with Associated Clonal Hematologic Non-Mast-Cell Diseases. PLoS ONE 9 (1), e85362.
  • de Melo Campos, J.A. Machado-Neto, A.S.S. Duarte, R. Scopim-Ribeiro, F.F. de Carvalho Barra, J.Vassallo,et al.Familial mastocytosis: identification of KIT K509I mutation and its in vitro sensitivity to imatinib, dasatinib and PK412. Blood, 122 (2013), p. 5267
  • Escribano, R. Nunez-Lopez, M. Jara, A. Garcia-Montero, A. Prados, C. Teodosio,et al. Indolent systemic mastocytosis with germline D816 V somatic c-kit mutation evolving to an acute myeloid leukemia. J Allery Clin Immunol, 117 (Suppl.) (2006), p. S125
  • Hanssens K., et al. SRSF2-P95 Hotspot Mutation is Highly Associated with Advanced Forms of Mastocytosis and Mutations in Epigenetic Regulator Genes. Haematologica 2013 [Epub ahead of print.]
  • Hartmann, E. Wardelmann, Y. Ma, S. Merkelbach-Bruse, L.M. Preussenr, C. Woolery,et al. Novel germline mutation of KIT associated with familial gastrointestinal stromal tumors and mastocytosis. Gastroenterology, 129 (2005), pp. 1042–1046
  • Molderings GJ et al. Familial occurrence of systemic mast cell activation disease. PLoS One, 8 (2013), p. e76241
  • Molderings GJ et al. The genetic basis of mast cell activation disease – looking through a glass darkly. Critical Reviews in Oncology/Hematology 2014.
  • Schwaab, J., Schnittger, S., Sotlar, K., Walz, C., Fabarius, A., Pfirrmann, M., et al., 2013.Comprehensive mutational profiling in advanced systemic mastocytosis. Blood122 (October (14)), 2460–2466.
  • Schwaab, Juliana, et al. Comprehensive mutational profiling in advanced systemic mastocytosis. Blood 2013, 122 (14): 2460-2466.
  • Sotlar, Karl, et al. Systemic mastocytosis associated with chronic idiopathic myelofibrosis. J Mol Diagn Jan 2008; 10(1): 58-66.
  • Soucie, E., Brenet, F., Dubreuil, P. Molecular basis of mast cell disease. Molecular Immunology 63 (2015) 55-60.
  • Soucie, E., Hanssens, K., Mercher, T., Georgin-Lavialle, S., Damaj, G., Livideanu, C.,et al., 2012. In aggressive forms of mastocytosis. TET2 loss cooperates with c-KITD816V to transform mast cells. Blood 2012; 24: 4846–4849.
  • Speight RA, et al. Rare germline mutation of KIT with imatinib-resistant multiple GI stromal tumors and mastocytosis. J Clin Oncol, 31 (2013), pp. e245–e247
  • Zhang LY, et al. A novel K5091 mutation of KIT identified in familial mastocytosis – in vitro and in vivo responsiveness to imatinib therapy. Leukemia Res, 30 (2006), pp. 373–378

Complement C3a

  • Ali H. Regulation of human mast cell and basophil function by anaphylatoxins C3a and C5a. Immunology Letters 128 (2010) 36–45.
  • Erdei et al. Regulation of mast cell activation by complement-derived peptides. Immunology Letters 92 (2004) 39–42.
  • Theoharides TC, et al. Mast cells and inflammation. Biochimica et Biophysica Acta 1822 (2012) 21–33.
  • Woolhiser MR, et al. Activation of human mast cells by aggregated IgG through FcγRI: additive effects of C3a, Clin. Immunol. 110 (2004) 172–180.

Role of mast cells in  vaginal pain

  • Graziottin A. Mast cells and their role in sexual pain disorders in: Goldstein A. Pukall C. Goldstein I. (Eds), Female Sexual Pain Disorders: Evaluation and Management, Blackwell Publishing 2009, p. 176-179.
  • Harlow BL, et al. Allergic Reactions and Risk of Vulvodynia.Ann Epidemiol. Nov 2009; 19(11): 771–777.
  • Reed BD, et al. Relationship Between Vulvodynia and Chronic Comorbid Pain Conditions. Obstet Gynecol. Jul 2012; 120(1): 145–151.

Regulation of mast cells by IgE and stem cell factor (SCF)

  • Cruse, G., Bradding, P. Mast cells in airway dieases and institial lung disease. Eur J Pharmacol (2015).
  • Gilfillian, A.M., Beaven, M.A. Regulation of mast cell responses in health and disease. Crit Rev Immunol 2011, 31, 475-529.
  • River, K., Gilfillian, A.M. Molecular regulation of mast cell activation. J Allergy Clin Immunol 2006, 117, 1214-1225.

Reading list: Papers to better understand mast cells and mast cell disease (continued)

Bone aspects of mast cell disease

  • Barete S, Assous N, de Gennes C, Granpeix C, Feger F, Palmerini F, et al. Systemic mastocytosis and bone involvement in a cohort of 75 patients. Ann Rheum Dis 2010;69:1838–41.
  • Biosse-Duplan M, Baroukh B, Dy M, de Vernejoul MC, Saffar JL. Histamine promotes osteoclastogenesis through the differential expression of histamine receptors on osteoclasts and osteoblasts.Am J Pathol. 2009;174(4):1426-1434.
  • Brumsen C, Papapoulos SE, Lentjes EG, Kluin PM, Hamdy NA. A potential role for the mast cell in the pathogenesis of idiopathic osteoporosis in men. Bone. 2002 Nov;31(5):556-61.
  • Dobigny C, Saffar JL. H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: evidence obtained by using receptor antagonists in a rat synchronized resorption model. J Cell Physiol. 1997 Oct;173(1):10-8.
  • Escribano L, Alvarez-Twose I, Sanchez-Munoz L, Garcia-Montero A, Nunez R, Almeida J et al. Prognosis in adult indolent systemic mastocytosis: a long-term study of the Spanish network on mastocytosis in a series of 145 patients. J Allergy Clin Immunol 2009;124:514–521.
  • Kushnir-Sukhov NM, Brittain E, Reynolds JC, Akin C, Metcalfe DD. Elevated tryptase levels are associated with greater bone density in a cohort of patients with mastocytosis. Int Arch Allergy Immunol. 2006;139(3):265-70. Epub 2006 Jan 30.
  • Matito A, Morgado JM, Álvarez-Twose I, Laura Sánchez-Muñoz, Pedreira CE, et al. (2013) Serum Tryptase Monitoring in Indolent Systemic Mastocytosis: Association with Disease Features and Patient Outcome. PLoS ONE 8(10): e76116. doi:10.1371/journal.pone.0076116
  • Nicolas Guillaume, et al. Bone Complications of Mastocytosis: A Link between Clinical and Biological Characteristics. The American Journal of Medicine (2013) 126, 75.e1-75.e7
  • Pardinini A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage). April 18, 2013; Blood: 121 (16.)
  • Reinacher-Schick, S. Petrasch, B.J. Longley, C. Teschendorf, U. Graeven, W. Schmiegel. c-Kit mutation and osteopetrosis-like osteopathy in a patient with systemic mast cell disease. Ann Hematol, 77 (1998), pp. 131–134
  • Rossini M, et al. Bone mineral density, bone turnover markers and fractures in patients with indolent systemic mastocytosis. Bone 49 (2011) 880–885.
  • Sánchez-Muñoz L, et al. Evaluation of the WHO criteria for the classification of patients with mastocytosis. Modern Pathology (2011) 24, 1157–1168.
  • Theoharides TC, Boucher W, Spear K. Serum interleukin-6 reflects disease severity and osteoporosis in mastocytosis patients. Int Arch Allergy Immunol 2002;128: 344–50.
  • Valent P, Sperr WR and Akin C. How I treat patients with advanced systemic mastocytosis. December 23, 2010; Blood: 116 (26.)
  • van der Veer, W. van der Goot, J. G. R. de Monchy, H. C. Kluin-Nelemans, J. J. van Doormaal. High prevalence of fractures and osteoporosis in patients with indolent systemic mastocytosis. Allergy 67 (2012) 431–438.

Mast cells in respiratory disease

  • Anand P, et al. Mast cells: an expanding pathophysiological role from allergy to other disorders. Naunyn-Schiedeberg’s Arch. Pharmacol. 2012 May.

Mast cells in renal and urinary disease

  • Blank U., et al. Mast cells and inflammatory kidney disease. Immunol Rev 2007, 217: 79-95.
  • Holdsworth SR, Summers SA.  Role of mast cells in progressive renal disease.  J. Am. Soc. Nephrol. 2008 Dec; 19(12):2254-2261.
  • Kempuraj D, Theoharides TC, et al.  Increased numbers of activated mast cells in endometrial lesions positive for corticotropin-releasing hormone and urocortin.  Am. J. Reprod. Immunol. 2004; 52:267-275.
  • Madjene LC., et al. Mast cells in renal inflammation and fibrosis: Lessons learnt from animal studies. Molecular Immunology 63 (2015) 86-93.
  • Sant, Grannum R., Kempuraj , Duraisamy, Marchand , James E., Theoharides, Theoharis C. The mast cell in interstitial cystitis: role in pathophysiology and pathogenesis.  2007.  Urology 69 (Suppl 4A): 34-40.
  • Summers, SA., et al. Mast cell activation and degranulation promotes renal fibrosis in experimental unilateral ureteric obstruction. Kidney Int 2012.

Mast cells in cardiovascular disease

  • Afrin, Lawrence B. Presentation, diagnosis and management of mast cell activation syndrome.  2013.  Mast cells.
  • Biteker M.  Current understanding of Kounis Syndrome.  Expert Rev Clin Immunol 2010 Sep;6(5):777-88.
  • Bot I, et al. Mast cells: Pivotal players in cardiovascular diseases. Current Cardiology Reviews, 2008, 4, 170-178.
  • Glowacki J, Mulliken JB. Mast cells in hemangioma and vascular malformations. Pediatrics 1982; 70(1):48-51.
  • Guo, T., Chen,W. Q., Zhang, C., Zhao, Y. X., & Zhang, Y. (2009). Chymase activity is closely related with plaque vulnerability in a hamster model of atherosclerosis. Atherosclerosis 207, 59–67.
  • Kennedy S, et al. Mast cells and vascular diseases. Pharmacology & Therapeutics 138 (2013) 53–65.
  • Kolck UW, Alfter K, Homann J, von Kügelgen I, Molderings GJ. Cardiac mast cells: implications for heart failure. JACC 2007 Mar 13; 49(10):1106-1108.
  • Kounis, N. G., Mazarakis, A., Tsigkas, G., Giannopoulos, S., & Goudevenos, J. (2011). Kounis syndrome: a new twist on an old
  • 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.
  • Meléndez, G. C., Li, J., Law, B. A., Janicki, J. S., Supowit, S. C., & Levick, S. P. (2011). Substance P induces adverse myocardial remodelling via a mechanism involving cardiac mast cells. Cardiovasc Res 92, 420–429.
  • Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J. Hematol. Oncol.2011; 4:10-17.
  • 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.
  • Ribatti D, Crivellato E. Mast cells, angiogenesis, and tumour growth. Biochim. Biophys. Acta Mol. Basis Dis. 2012 Jan; 1822(1): 2-8.

Miscellaneous considerations for studying mast cell disease

  • Butterfield JH, Li C-Y. Bone marrow biopsies for the diagnosis of systemic mastocytosis: is one biopsy sufficient? Am. J. Clin. Pathol. 2004; 121:264-267.
  • Sur R. Cavender D. Malaviya R. Different approaches to study mast cell functions. Int. Immunopharmacol. 2007 May; 7(5):555-567.

Role of mast cells in pain

  • Barbara G, et al. Mast Cell-Dependent Excitation of Visceral-Nociceptive Sensory Neurons in Irritable Bowel Syndrome. Gastroenterology 2007; 132 (1): 26–37.
  • Ferjan, F. Erjavec. Changes in histamine and serotonin secretion from rat peritoneal mast cells caused by antidepressants. Inflammation Research 1996, Volume 45, Issue 3, pp 141-144.
  • Gao, G., Ouyang , Kaufman MP, Yu S. ERK1/2 signaling pathway in mast cell activation-induced sensitization of esophageal nodose C-fiber neurons. Dis. Esophagus 2011; 24, 194–203.
  • 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., Donelan, J., Kandere-Grzybowska, K., Konstantinidou, A. The role of mast cells in migraine pathophysiology. Brain Res. Rev.2005; 49, 65–76.
  • Theoharides, T.C., Kempuraj, D., Sant, G.R. Mast cell involvement in interstitial cystitis: a review of human and experimental evidence. Urology 2001; 57, 47–55.
  • Wang B. et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology, vol. 126, no. 3, pp. 693–702, 2004.
  • Wang B. et al. Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology, vol. 132, no. 1, pp. 26–37, 2007.
  • Xinning Li, MD; Keith Kenter, MD; Ashley Newman, BS; Stephen O’Brien, MD, MBA. Allergy/ Hypersensitivity Reactions as a Predisposing Factor to Complex Regional Pain Syndrome I in Orthopedic Patients. Orthopedics 2014: Volume 37 · Issue 3: e286-e291

Mast cells in metabolic syndrome: hypertension, obesity and atherosclerosis

  • Chinellato I, Piazza M, Sandri M, Peroni DG, Cardinale F, Piacentini GL, Boner AL.  Serum vitamin D levels and exercise-induced bronchoconstriction in children with asthma.  Eur Respir J. 2011; 37(6): 1366-70.
  • Melander A, Owman C, Sundler F.  TSH-induced appearance and stimulation of amine-containing mast cells in the mouse thyroid.  Endocrinology 1971; 89: 528–533.

 

  • Siebler T, Robson H, Bromley M, Stevens DA, Shalet SM, Williams GR.  Thyroid status affects number and localization of thyroid hormone receptor expressing mast cells in bone marrow.  2002; 30(1): 259-66.
  • Zhang J, Shi GP. Mast cells and metabolic syndrome. Biochim. Biophys. Acta 2012 Jan, 822(1):14-20.

Effects of sex hormons and pregnancy on mast cells

  • Jensen F, Woudwyk M, Teles A, Woidacki K, Taran F, Costa S et al. (2010). Estradiol and progesterone regulate the migration of mast cells from the periphery to the uterus and induce their maturation and degranulation. PLoS One2010; 5: e14409.
  • Matito, A., et al. Clinical Impact of Pregnancy in Mastocytosis: A Study of the Spanish Network on Mastocytosis (REMA) in 45 Cases.  Int Arch Allergy Immunol 2011;156:104-111.
  • Metcalfe, D. D., and Akin, C. (2001). Mastocytosis: molecular mechanisms and clinical disease heterogeneity.  Res. 25, 577–582.
  • Woidacki, K., Jensen, F., Metz, Zenclussen, A. (2013). Mast cells as novel mediators of reproductive processes.  Immunol.10.
  • Woidacki, K., Popovic, M., Metz, M., Schumacher, A., Linzke, N., Teles, A., et al. (2013). Mast cells rescue implantation defects caused by c-kit deficiency. Cell Death Dis.4, e462.

H1 antihistamines

  • 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.

Natural mast cell stabilizers

  • Bheekha-Escura, Roy, et al. Pharmacologic regulation of histamine release by the human recombinant histamine-releasing factor. May 1999; 103(5): 937-943.
  • Finn, DF, Walsh, JJ. Twenty-first century mast cell stabilizers. J Pharmacol 2013 Sep; 170(1): 23-37.
  • Hong J, et al. Suppression of the antigen-stimulated RBL-2H3 mast cell activation by Artekeiskeanol A. Planta Med 2009 Nov; 75(14): 1494-1498.
  • Kim DY, et al. Emodin attenuates A23187-induced mast cell degranulation and tumor necrosis factor-a secretion through protein kinase C and IkB kinase 2 signaling. Eur J Pharmacol 2014 Jan 15; 723: 501-506.
  • Kim M, et al. Gnetin H isolated from Paeonia anomala inhibits FceRI-mediated mast cell signaling and degranulation. J Ethnopharmacol 2014 Jul 3; 154(3): 798-806.
  • Kishiro S, et al. Selinidin suppresses IgE-mediated mast cell activation by inhibiting multiple steps of Fc epsilonRI signaling. Biol Pharm Bull 2008 Mar; 31(3): 442-448.
  • Kritas SK, et al. Luteolin inhibits mast cell-mediated allergic inflammation. J Biol Regul Homeost Agents 2013 Oct-Dec; 27(4): 955-959.
  • Lee, YS, et al. Homoisoflavonone prevents mast cell activation and allergic responses by inhibition of Syk signaling pathway. Allergy 2014; 69: 453-462.
  • Lu Y, et al. Emodin, a naturally occurring anthraquinone derivative, suppresses IgE-mediated anaphylactic reaction and mast cell activation. Biochem Pharmacol 2011 Dec 1; 82(11): 1700-1708.
  • Moon PD, et al. Use of scopoletin to inhibit the production of inflammatory cytokines through inhibition of the IkappaB/NF-kappaB signal cascade in the human mast cell line HMC-1. Eur J Pharmacol 2007 Jan 26; 555(2-3): 218-225.
  • Park HH, et al. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Arch Pharm Res. 2008 Oct; 31(10): 1303-11.
  • Persia FA, et al. Hydroxytyrosol and oleuropein of olive oil inhibit mast cell degranulation induced by immune and non-immune pathways.  Phytomedicine. 2014 Sept 25; 21(11): 1400-1405.
  • Son JK, et al. Ginkgetin, a biflavone from Ginkgo biloba leaves, inhibits cyclooxygenases-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells. Biol Pharm Bull 2005 Dec; 28(12): 2181-4.
  • Theoharides TC, Kempuraj D, Iliopoulou BP. Mast cells, T cells, and inhibition by luteolin: implications for the pathogenesis and treatment of multiple sclerosis. Adv Exp Med Biol 2007; 601: 423-30.
  • Weng Z., et al. Quercetin is more effective than cromolyn in blocking human mast cell cytokine release and inhibits contact dermatitis and photosensitivity inhumans. PLoS One. 2012; 7(3): e33805.
  • Yang B, et al. Polydatin attenuated food allergy via store-operated calcium channels in mast cell. World J Gastroenterol 2013 Jul 7; 19(25): 3980-3989.
  • Yuan M, et al. Polydatin (PD) inhibits IgE-mediated passive cutaneous anaphylaxis in mice by stabilizing mast cells through modulating Ca2+ mobilization. Toxicol Appl Pharmacol 2012 Nov 1; 264(3): 462-469.
  • Zhang, T., et al. Mast cell stabilisers. Eur J Pharmacol (2015).

Reading list: Papers to better understand mast cells and mast cell disease

I get asked semi-regularly for literature recommendations.  This post (and the other posts marked “Reading list”) lists papers I have found helpful in understanding mast cell disease and the roles of mast cells in other diseases.

As a general rule of thumb, read the guidance documents first.  They give comprehensive overviews that include symptoms, diagnosis, treatment, statistics and so on.  Please keep in mind that at this time, there are multiple sets of diagnostic criteria for MCAS.  I have included papers here that represent the competing schools of thought on MCAS.

Enjoy!

 

Guidance documents: Overviews of mast cell diseases

  • Afrin, Lawrence B. Presentation, Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Mast Cells.
  • Akin C, Valent P, Metcalfe D. Mast cell activation syndrome: Proposed diagnostic criteria. Journal of Allergy and Clinical Immunology 2010: 126 (6): 1099–1104.e4
  • Bodemer C., Hermine O., Palmérini F., Yang Y., Grandpeix-Guyodo C., Leventhal PS., Hadj-Rabia S., Nasca L., Georgin-Lavialle S., Cohen-Akenine A., Launay JM., Barete S., Feger F., Arock M., Catteau B., Sans B., Stalder JF., Skowron F., Thomas L., Lorette G.Plantin P, Bordigoni P, Lortholary O, de Prost Y, Moussy A, Sobol H, Dubreuil P. Pediatric mastocytosis is a colonal disease associated with D816V and other activating C-KIT mutations. J Invest Dermatol 2010; 130:804–815.
  • Brockow, C. Jofer, H. Behrendt and J. Ring. Anaphylaxis in patients with mastocytosis: a study on history, clinical features and risk factors in 120 patients. Allergy 2008, 63 ( 2):, 226–232.
  • Cardet JC, Castells M, Hamilton MJ. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.
  • Carter et al. Assessment of clinical findings, tryptase levels, and bone marrow histopathology in the management of pediatric mastocytosis. J Allergy Clin Immunol 2015.
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  • Hauswirth, Alexander, et al. Response to therapy with interferon alpha-2b and prednisolone in aggressive systemic mastocytosis: report of five cases and review of the literature. 2004; Leuk Res 28 (3): 249-257.
  • Kettelhut BV., Metcalfe DD. Mastocytosis. J Invest Dermatol 1991; 96:115S–118S.
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  • Lim KH, Tefferi A, Lasho TL, et al.Systemic mastocytosis in 342 consecutive adults: survival studies and prognostic factors. Blood 2009; 113(23): 5727-5736.
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  • Mital A, Piskorz A, Lewandowski K, Wasag B, Limon J, Hellmann A. A case of mast cell leukaemia with exon 9 KIT mutation and good response to imatinib.Eur J Haematol 2011; 86(6):531-535.
  • Molderings GJ, Brettner S, Homann J, and Afrin LB. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011; 4: 10.
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  • Noack F, Sotlar K, Notter M, Thiel E, Valent P, Horny HP. Aleukemic mast cell leukemia with abnormal immunophenotype and c-kit mutation D816V.Leuk Lymphoma 2004; 45(11): 2295-2302.
  • Pardanani A. How I treat patients with indolent and smoldering mastocytosis (rare conditions but difficult to manage.) Blood 2013: 121 (16).
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  • Sperr, Wolfgang. Diagnosis, progression patterns and prognostication in mastocytosis. Expert Review of Hematology 2012: 5 (3): 261-274.
  • Uzzaman, Ashraf, et al. Pediatric-onset Mastocytosis: A long term clinical follow-up and correlation with bone marrow histopathology. Pediatr Blood Cancer. Oct 2009; 53 (4): 629-634.
  • Valent, Peter, et al. Aggressive systemic mastocytosis and related mast cell disorders: current treatment options and proposed response criteria. 2003; Leuk Res 27 (7): 635-41.
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Testing and diagnosis of mast cell disease

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  • Gordon JR, Galli SJ. Mast cells as a source of both preformed and immunologically inducible TNF-α/cachectin. Nature 1990 Jul 19; 346:274-276.
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  • Maclouf J, Corvazier E, Wang ZY. Development of a radioimmunoassay for prostaglandin D2 using an antiserum against 11-methoxime prostaglandin D2. Prostaglandins 1986 Jan; 31(1):123-132.
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  • Seidel H, Molderings GJ, Oldenburg J, Meis K, Kolck UW, Homann J, Hertfelder HJ. Bleeding diathesis in patients with mast cell activation disease. Thromb. Haemost. 2011 Nov; 106(5):987-989.
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Neurologic aspects of mast cell activation

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  • Rogers MP, et al. Mixed organic brain syndrome as a manifestation of systemic mastocytosis. Psychosom Med. 1986 Jul-Aug; 48(6):437-47.
  • Smith, Jonathan H, Butterfield, Joseph H, Pardanini, Animesh, DeLuca, Gabriele, Cutrer, F Michael. Neurologic symptoms and diagnosis in adults with mast cell disease.  Clinical Neurology and Neurosurgery 113 (2011) 570-574.

Gastrointestinal aspects of mast cell disease

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  • Lee, Jason K, et al.  Gastrointestinal manifestations of systemic mastocytosis.  World J Gastroenterol. 14(45): 7005-7008.

Mastocytic enterocolitis

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  • Hahn, Hejin P., Hornick, Jason L.  Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis.  American Journal of Surgical Pathology. Volume 31 (11). 2007.
  • Hamilton, Matthew J, et al.  Mast cell activation syndrome : A newly recognized disorder with systemic clinical manifestations.  2011, Vol 128, Issue 1, pp. 147-152.
  • Shriram Jakate, Mark Demeo, Rohan John, Mary Tobin, and Ali Keshavarzian (2006) Mastocytic Enterocolitis: Increased Mucosal Mast Cells in Chronic Intractable Diarrhea. Archives of Pathology & Laboratory Medicine: March 2006, Vol. 130, No. 3, pp. 362-367.

Raw

Summer packed up quickly. Humidity and too hot days were gone in an instant.  The days are short now, the last waves of golden autumn sun just barely shadows when I get home from work.  It was below freezing as I walked to work yesterday morning. Two nights ago, when I stepped outside, it smelled like snow.

I blinked and suddenly the ground was covered in dry leaves, the chorus of fall sung in deep musical gusts.  It really seems like just a moment ago I was eager for summer to end and now it has been gone for weeks.

This year’s autumn has been fraught with emotions.  I am having some big feelings these days and they are leeching from my other reservoirs: patience, kindness, love.   But mostly patience.  Loss of patience is where it shows the most.

We were so scared that Seth would die, and he didn’t but we still don’t really know how to feed him.  I read papers by the hundreds, make notes, send emails.  He is better but not good.  We still don’t have a good plan.  What happened with Seth felt immediate, traumatic. Like the pain of landing hard after falling, hands and knees stinging, blood seeping through the wounds.  Startling, alarming but survivable.

Then I picked up my phone and read a text telling me that my friend was having a bad reaction in an emergency room.  I relive that night constantly.  The back and forth, my let’s not panic attitude when we should have been panicking.  I am too used to this, I have seen us all be fine after so many panic-worthy episodes.  I am too used to us all being fine.  But we should have been panicking.  And by the time we understood what was happening, she had already had a stroke in her brainstem.

It feels so slow in my memory, like a parchment map being slowly unrolled.  By the time we knew where we were, it was too late.  There is this heavy sorrow inside of my heart that makes it hard to breathe.  We didn’t even know where we were and now she is locked inside of her body. It is suddenly the end of October and the sorrow doesn’t feel lighter. I am just learning to carry the weight.

Everything is a fight sometimes.  Every. Thing.  Insurance companies, doctors’ offices, hospitals and pharmacies all call to inform me about the ways in which bureaucracy and the broken American health care system is messing up my care again.  Not in a way that will kill me, just in a way that requires a patience I no longer have.  My eye has started twitching again when I have to explain something about my healthcare again to someone who has already heard it and was previously unmoved.

Someone called me today to say that they could waive part of my bill. I had a panic attack in a grocery store, because even receiving good news about my healthcare is too stressful right now.

I was medically cleared to fly to China by all relevant medical professionals but had to undergo a medical clearance by the airline since I needed to use an infusion pump during flight.  I filled out forms, provided notarized letters.  In their infinite wisdom, the airline decided it wasn’t safe for me to fly alone.

I paid a visit to my PCP’s office after having a mid-level nervous breakdown on the phone with a nurse about the fact that the airline may not let me go to China. I apologized for getting so upset.  While she wrote another letter for me, I told her that mast cell patients get labelled as psych patients a lot because we look fine until we are in liver failure or having a stroke. I told her about my friend.

She called the pharmacist working downstairs and he came up to notarize her letter.  After some back and forth, the airline relented and agreed I can fly with my pump.

My skin is burning this week. I am flushed a deep pink all over.  I realized today that I am reacting to my ketotifen after eighteen months of taking it every day without an issue.  More phone calls with my fingers pressing on my eyelid in a vain attempt to stop the twitching, heat creeping up the back of my neck.

Last week, some guy kept obstructing my path down the sidewalk in an attempt to make me donate to some charity.  When I finally maneuvered around him successfully, he made a snide comment.  I turned around and yelled at him.  Because get the fuck out of my way.

I am grieving and angry and impatient and raw and exposed.  In two weeks I will be in Hong Kong and it feels wrong that I am stable enough to travel to Asia, a sort of betrayal and survival’s guilt.