The Devil’s Arithmetic

When I was in grad school, I took immunology. I still have my textbook and refer to it sometimes, my crowded notes in the margins. The chapter on allergy and anaphylaxis is highlighted in green, somehow aggressively bright after eleven years.

It’s kind of amusing to recall this time in my life, before every mast cell activation pathway had been hammered into my brain. There’s also some black humor in reading about how IgE activation is the allergy pathway. You know, THE allergy pathway. This book doesn’t cover any other pathways. As if you cannot possibly be allergic to something without IgE.

That’s the problem, of course. This is what most healthcare providers or science majors learn in school. They learn about allergy and anaphylaxis, but they learn about the textbook description which invariably refers to IgE mediated food anaphylaxis. They learn about peanut allergy.

I don’t have a peanut allergy. I literally don’t have a single food allergy that displays the hallmark swelling/closing airway that people expect. But I have major food allergies, some bad enough to require epinephrine, IV Benadryl, Pepcid, Solu Medrol, Zofran and IV fluids.

The problem is not just that I’m allergic to some foods. It’s that I’m not always allergic to the same foods as I was the day before. Or the same medications. Or the same environmental exposures. My reactions on a given day are the cumulative product of the amount of irritation my mast cells have experienced in the previous day or two. There is always a running tally in my mind.

There are a lot of analogies and models used to describe mast cell attacks both to patients and to people who don’t have them. I have always thought of it as a bank. You make deposits and you make withdrawals. Like this:

For the sake of simplicity, let’s assume you have $100 in a bank account. Any activity that can cause mast cell activation has to be paid for. The cost is proportionate to the amount of activation. Getting a splinter: $2. Being hot: $10. Being in direct sunlight: $10. Standing up for 20 minutes while being hot in direct sunlight: $35. Cardiovascular exercise: $40. Arguing with your spouse: $60. Moderate pain experienced in your day to day life: $50. A painful medical procedure: $70. Mild cold: $40.

Some things are too costly to ever attempt.  Undercooked egg whites: $9000.  Massive bleach exposure: $7500.

You can make deposits into the bank with medications and physical changes. Getting enough sleep: $30. Wearing loose, comfortable clothes: $15. Doing orthostatic manuevers before standing up: $10. Taking baseline mast cell medications on your normal schedule: $50. Eating food that is warm but not hot: $15. Monitoring your exercise and stopping for breaks: $15. Wearing a cooling vest on a hot day: $20. Oral Benadryl: $25. IV Benadryl: $50. Steroids: $50.

So you have this running tally in your head all day long. When you start getting close to $100, you get stressed. You know you can’t afford to spend more than $100. Things that you could have done four hours ago safely are no longer safe. Things you could eat on a day spent relaxing at home inside with comfortable ambient temperature cannot be eaten if your apartment is too hot or if you are in a lot of pain.

You are constantly trying to avoid running out of dollars before you can get home and go to bed. Part of this is because you don’t want to trigger a physical reaction. Part of it is that this phenomenon – allergies as a function of circulating histamine/mast cell activation rather than IgE – is hard to explain briefly to people who don’t have this disease. So people will see you on a super crappy day only being able to eat one thing at a party and then four months later, when your body is much less inflamed, will see you eat three things at a party. And then it’s a thing, because these people invariably think that you are faking/being overdramatic as if somehow it is worth the effort to “pretend to have allergies.” WHO FUCKING DOES THAT?

Cost for being around someone who gives you shit for not always having the same restrictions: $75.

So everyday, you get $100. Except this is the US and our banks hate us so we have overdraft. This means that you can spend more money than you have but then they charge a steep fee and so the next day, you don’t have $100. You have maybe $30 dollars. After overspending, it can take a few days to get back to baseline.

Sometimes it’s worth it. Sometimes you can sort of game your body into getting more than $100 out of a day. This is the purpose of premedication for procedures and surgery. This is the purpose of good sleep hygiene, eating safe foods, not getting stressed, taking medications appropriately and on a schedule. You can bank a little. Not as much as you can overdraft, but you can get ahead a little bit.

Today, I went to the supermarket to grab some things for lunch at work. They didn’t have organic apples that looked in decent shape. They had non-organic apples and my safe peanut butter/honey and my safe pretzel chips. I had to run through my entire day to determine how much physical activity and stress was likely to be in the rest of my day to figure out what I could (probably) safely eat for lunch.

It’s like this all day, every day. This math wouldn’t be hard except that it’s constant and unavoidable and controls my life.

Mast cells in the GI tract: How many is too many? (Part eight)

One study assessed whether mast cell count would be influenced depending on which part of the organ biopsies were taken from. While the difference in count was not large, it is worth considering that these counts all straddle the cut off of 20 mast cells/hpf.  This means that patients with the same GI symptoms could have biopsies with over or under 20/hpf depending on the site of the biopsy.  See Table 24 for details.

Table 24: Effect of sampling site on mast cell count/hpf in colon of chronic diarrhea patients
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: Tryptase (IHC), toluidine blue
Rectum Sigmoid Descending colon Transverse colon Ascending colon Cecum
20.5±5 18.3±3.5 22.6±3.9 20.7±4.9 25.5±6.7 22.1±4.9

 

The same paper also looked at effect of season on mast cell count.  There was no significant difference, but again, the range of biopsies in each season straddles the 20/hpf line. See Table 25 for details.

Table 25: Effect of season on mast cell count in colon of diarrhea patients
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: Tryptase (IHC), toluidine blue
Spring Summer Fall Winter
20.6±4.7 24.2±4.9 19.5±3.9 20.3±4.9

 

The most telling portion of this study compared mast cell counts when using a simple stain (toluidine blue) and when using IHC (antibody for tryptase) to find mast cells in biopsies.  Mast cells are not easy to see on biopsy.  They require special stains, and even then, they are hard to see.  Immunohistochemistry (IHC) uses antibodies to identify markers on cells that are easier to see with a microscope.  It is not uncommon for unfamiliar doctors to refuse the use of IHC testing (which usually includes CD117, CD25, CD2 or tryptase) in lieu of commonly available stains in the lab.  However, even stains that visualize mast cells are inferior to IHC methods.  In biopsies taken from all parts of the colon, toluidine blue staining showed less than half of the mast cells visualized using IHC for tryptase.  This means that when IHC testing isn’t ordered, counts reported by simple staining are much lower than the true count. See Table 26 for details.

Table 26: Comparison of mast cell count in biopsies stained with toluidine blue and with tryptase antibody (IHC)
Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gastroenterol 2012; 18 (5): 322-326.
Microscopy method: 400x magnification, mast cells counted in 5 hpf and averaged
Visualization: Tryptase (IHC) and toluidine blue
Staining method Rectum Sigmoid Descending colon Transverse colon Ascending colon Cecum
IHC 20.5±5 18.3±3.5 22.6±3.9 20.7±4.9 25.5±6.7 22.1±4.9
Toluidine blue 8.5±0.7 6.8±1.2 10.3±4.2 10.3±3.5 12.5±5 8.1±2.9
% of cells identified by IHC seen by toluidine blue staining 41% 37% 46% 50% 49% 37%

 

There are other factors that contribute to lack of consensus in mast cell counts in GI tissue. One of the biggest causes is that not all labs use standard size high powered fields.  HPF is usually 0.25mm2, but it is not uniform throughout the research world.  Many papers don’t even provide the size of their high powered fields.  More than that, many papers report mast counts per mm2 without providing conversion factors so it’s not always possible to compare results from one paper to another.  There were some papers I wanted to use for this series that I couldn’t because I couldn’t be sure that I could convert their mast cells/mm2 confidently to mast cells/hpf.

Together with the fact that number of hpf counted, methods of biopsy slide preparation, stains and IHC antibodies are variable, it is hard to get a real understanding of whether the cut off of 20 mast cells/hpf is meaningful.  It is my finding that there are a number of conditions that cause mast cells/hpf to be higher than controls in an experiment.  It is also my finding that in some experiments, control subjects have baseline mast cell counts over 20 mast cells/hpf. It is reasonable to assume that inflammatory GI conditions can cause mast cell hyperplasia.  But the fact that chronic urticaria patients often have mast cell counts higher than control subjects is also telling.  It speaks to the fact that an allergic process can elevate mast cell counts in a space where there is no appreciable symptomology. If patients have reactions to “pseudoallergens” as described in that paper, then it is possible that these reactions could drive the increase in mast cell count in the GI tract.  If this is true, then the many mast cell patients who have “pseudoallergen” responses could see an increase in GI mast cell burden as a result of their mast cell disease.

References:

Jakate S, et al. Mastocytic enterocolitis: Increased mucosal mast cells in chronic intractable diarrhea.  Arch Pathol Lab Med 2006; 130 (3): 362-367.

Akhavein AM, et al. Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility. Gastroenterology Research and Practice (2012): Article ID 950582.

Martinez C, et al. Diarrhoea-predominant irritable bowel syndrome: an organic disorder with structural abnormalities in the jejunal epithelial barrier. Gut 2013; 62: 1160-1168,

Sethi A, et al. Performing colonic mast cell counts in patients with chronic diarrhea of unknown etiology has limited diagnostic use. Arch Pathol Lab Med 2015; 139 (2): 225-232.

Doyle LA, et al. A clinicopathologic study of 24 cases of systemic mastocytosis involving the gastrointestinal tract and assessment of mucosal mast cell density in irritable bowel syndrome and asymptomatic patients. Am J Surg Pathol 2014; 38 (6): 832-843.

Ramsay DB, et al. Mast cells in gastrointestinal disease. Gastroenterology & Hepatology 2010; 6 (12): 772-777.

Zare-Mirzaie A, et al. Analysis of colonic mucosa mast cell count in patients with chronic diarrhea. Saudi J Gatroenterol 2012; 18 (5): 322-326.

Walker MM, et al. Duodenal mastocytosis, eosinophilia and intraepithelial lymphocytosis as possible disease markers in the irritable bowel syndrome and functional dyspepsia. Aliment Pharmacol Ther 2009; 29 (7): 765-773.

Hahn HP, Hornick JL. Immunoreactivity for CD25 in Gastrointestinal Mucosal Mast Cells is Specific for Systemic Mastocytosis. American Journal of Surgical Pathology 2007; 31(11): 1669-1676.

Vivinus-Nebot M, et al. Functional bowel symptoms in quiescent inflammatory bowel diseases : role of epithelial barrier disruption and low-grade inflammation. Gut 2014; 63: 744-752.

Minnei F, et al. Chronic urticaria is associated with mast cell infiltration in the gastroduodenal mucosa. Virchows Arch 2006; 448(3): 262-8.

Hamilton MJ, et al. Mast cell activation syndrome: A newly recognized disorder with systemic clinical manifestations. J Allergy Clin Immunol 2011; 128: 147-152.

Barbara G, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004; 126(3): 693-702.

Guilarte M, et al. Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut 2007; 56: 203-209.

Dunlop SP, et al.  Age related decline in rectal mucosal lymphocytes and mast cells. European Journal of Gastroenterology and Hepatology 2004; 16(10): 1011-1015.

Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3 (1): 1-17.

Molderings GJ, et al. Mast cell activation disease: a concise, practical guide to diagnostic workup and therapeutic options. J Hematol Oncol 2011; 4 (10).

Akin C, et al. Mast cell activation syndrome: proposed diagnostic criteria. J Allergy Clin Immunol 2010; 126 (6): 1099-1104.

Valent P, et al. Definitions, criteria and global classification of mast cell disorders with special reference to mast cell activation syndromes: a consensus proposal. Int Arch Allergy Immunol 2012: 157 (3): 215-225.

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.
  • Carter MC, Escribano L, Hartmann K, Lieberman P, Nedoszytko B, Orfao A, Schwartz LB, Sotlar K, Valent P, Akin C, Arock M, Brockow K, Butterfield JH, Sperr WR, Triggiani M, Valenta R, Horny HP, Metcalfe DD. Definitions, Criteria and Global Classification of Mast Cell Disorders with Special Reference to Mast Cell Activation Syndromes: A Consensus Proposal. Int Arch Allergy Immunol 2012;157:215–225.
  • Frieri, Marianne, et al. Pediatric mastocytosis: A review of the literature. Pediatr Allergy Immunol Pulmonol. Dec 1, 2013; 26(4): 175-180.
  • Georgin-Lavialle, Sophie, et al.  Mast cell leukemia.  Blood 2013;10 (11).
  • Gülen, H. Hägglund, B. Dahlén and G. Nilsson. High prevalence of anaphylaxis in patients with systemic mastocytosis – a single-centre experience. Clinical & Experimental Allergy, Volume 44, Issue 1, pages 121–129, January 2014.
  • Haenisch B, Nothen M, Molderings GJ. Systemic mast cell activation disease: the role of molecular genetic alterations in pathogenesis, heritability and diagnostics. Immunology 2012, 137, 197–205.
  • 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.
  • 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.
  • Lange M., Nedoszytko B., Górska A., Żawrocki A., Sobjanek M., Kozłowski D. Mastocytosis in children and adults: clinical disease heterogeneity. Arch Med Sci 2012; 8:533–541.
  • 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.
  • Matito, Almudena, et al. Serum tryptase monitoring in indolent systemic mastocytosis: association with disease features and patient outcome. 2013; PLOS One.
  • Mital A, Piskorz A, Lewandowski K, Wasag B, Limon J, Hellmann AA 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.
  • Molderings GJ, Haenisch B, Bogdanow M, Fimmers R, Nöthen MM. Familial occurrence of systemic mast cell activation disease. PLoS One, 8 (2013), p. e76241
  • Molderings GJ. The genetic basis of mast cell activation disease – looking through a glass darkly. Critical Reviews in Oncology/Hematology 2014.
  • Noack F, Sotlar K, Notter M, Thiel E, Valent P, Horny HPAleukemic 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).
  • Pardanini A. Prognostically relevant breakdown of 123 patients with systemic mastocytosis associated with other myeloid malignancies. Blood 2009, 114 (18).
  • Pardanini, Animesh. Systemic mastocytosis in adults: 2013 update on diagnosis, risk stratification, and management. 2013; American Journal of Hematology: 88 (7).
  • Picard M, Giavina-Bianchi P, Mezzano V, Castells M. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics 2013: 35 (5), 548–562.
  • 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.
  •  Valent et al. Chronic mast cell leukemia: A novel leukemia-variant with distinct morphological and clinical features. Leukemia Research 39 (2015) 1-5.
  • Valent, Peter, et al. How I treat patients with advanced systemic mastocytosis. 2010; Blood: 116 (26).
  • Wimazal F., Geissler P., Shnawa P., Sperr W.R., Valent P. Severe Life-Threatening or Disabling Anaphylaxis in Patients with Systemic Mastocytosis: A Single-Center Experience. Int Arch Allergy Immunol 2012; 157: 399–405.

Testing and diagnosis of mast cell disease

  • Freeman JG, Ryan JJ, Shelburne CP, Bailey DP, Bouton LA, Narasimhachari N, Domen J, Siméon N, Couderc F, Stewart JK. Catecholamines in murine bone marrowderived mast cells. J. Neuroimmunol. 2001 Oct;119(2):231-238.
  • 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.
  • Laroche D, Vergnaud MC, Sillard B, Soufarapis H, Bricard H. Biochemical markers of anaphylactoid reactions to drugs: comparison of plasma histamine and tryptase. Anesthesiol. 1991 Dec; 75(6):945-949.
  • 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.
  • Pregun I, Herszényi L, Juhász M, Miheller P, Hritz I, Patócs A, Rácz K, Tulassay Z. Effect of proton-pump inhibitor therapy on serum chromogranin A level. Digestion 2011; 84:22-28.
  • 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.
  • Sur R, Cavender D, Malaviya R. Different approaches to study mast cell functions.  Int. Immunopharmacol. 2007 May;7(5):555-567.
  • Takeda J, Ueda E, Takahashi J, Fukushima K. Plasma N-methylhistamine concentration as an indicator of histamine release by intravenous d-tubocurarine in humans: preliminary study in five patients by radioimmunoassay kits. Anesth. Analg. 1995; 80:1015-1017.

Neurologic aspects of mast cell activation

  • Ikuko Mohri, Masako Taniike, Hidetoshi Taniguchi, Takahisa Kanekiyo, Kosuke Aritake, Takashi Inui, Noriko Fukumoto, Naomi Eguchi, Atsuko Kushi, Hitoshi. Prostaglandin D2-Mediated Microglia/Astrocyte Interaction Enhances Astrogliosis and Demyelination in The Journal of Neuroscience 2006; 26(16):4383– 4393.
  • 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

  • Bedeir A, et al.  Systemic mastocytosis mimicking inflammatory bowel disease: A case report and discussion of gastrointestinal pathology in systemic mastocytosis.  Am J Surg Pathol. 2006 Nov;30(11): 1478-82.
  • 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.
  • Jensen RT. Gastrointestinal abnormalities and involvement in systemic mastocytosis. Hematol Oncol Clin North Am. 2000;14:579–623.
  • Kirsten Alfter, Ivar von Ku gelgen, Britta Haenisch, Thomas Frieling, Alexandra Hu lsdonk, Ulrike Haars, Arndt Rolfs, Gerhard Noe, Ulrich W. Kolck, Jurgen Homann and Gerhard J. Molderings. New aspects of liver abnormalities as part of the systemic mast cell activation syndrome. 2009 Liver International 29(2): 181-186.
  • Lee, Jason K, et al.  Gastrointestinal manifestations of systemic mastocytosis.  World J Gastroenterol. 14(45): 7005-7008.

Mastocytic enterocolitis

  • Akhavein, A, et al.  Allergic mastocytic gastroenteritis and colitis: An unexplained etiology in chronic abdominal pain and gastrointestinal dysmotility.  2012, Gastroenterology Research and Practice.
  • 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.

Great wall

I have always wanted to travel. From a young age, I was fascinated by language and traveling seemed an extension of that, places to hear foreign words and see strange alphabets. When I was 19, while sitting at my desk one night, it occurred to me that there was no reason I couldn’t just save up and go wherever I wanted to. I planned my first trip abroad and spent 26 days in Europe the following summer.

Traveling made me happy in a way that I have never been able to replicate in any other way. Over the next several years, I spent all my money on travel. I didn’t care if I ate the same thing every day or drove a junkbox. Nothing mattered to me like the joy of being in strange, faraway places. I started planning my magnum opus: a nine month trip around the world that took me through six continents. It was slated for January 2011.

In 2009, I lost a lot of my hearing. I spent all of the money I had saved for the trip on medical expenses, much in an effort to stop my rapid march towards deafness. I lost my hearing anyway. I haven’t travelled out of the US since 2010.

For a while, I went through the motions, even when I was clearly in no shape, financially or physically, to go anywhere. I bought guidebooks, priced flights and drew maps of places I hoped to visit. I printed out pictures of every country in the world and glued them to cardstock. I hung them in my apartment, passive encouragement that I would once again be strong enough to see some of them.

Then my health declined rapidly and I was in massive pain and puking constantly and unable to go to the bathroom. I stopped everything. I couldn’t fly anywhere anyway, so there was really no point. I couldn’t even think about it. I was so tired and the pain was so bad and I was scared. My illness was this huge wall around my life and I couldn’t even try to climb out. I could only hope not to be buried by it.

Last year, I decided that it was time to try again. I flew to Seattle with my best friend, emboldened by my ready IV access and growing restlessness. I took a few other domestic trips, Colorado, Florida, California. My health was mostly fine and when it wasn’t, I knew how to manage it with medication to stay safe. Every new trip gave me confidence that I could be independent in travel, provided I had a predetermined, safe place to stay and eat, and someone to help me if I got sick. The majority of my luggage was medication and medical supplies and I didn’t care.

In less than a month, I will be flying to Asia and fulfilling a lifelong dream of seeing the Great Wall of China. It has been logistically complicated, with medical notes and forms and notaries and translations and all the doctors. I will be taking a sixteen hour direct flight from Boston to Hong Kong, where I will spend some time with a dear friend before we travel to Beijing and then the Great Wall.

I feel it again. And even though I’m scared, I am happy.

Happiness is a kind of fighting. It is a way of saying that maybe today was miserable and so were a lot of yesterdays but maybe tomorrow will be different. It is the refusal to be subjugated by pain and fear and uncertainty. It is the memory of joy and the knowledge that even if you don’t believe it, you could again. It is the way memories catch light in your mind, a technicolor feeling that goes on forever. It is the only fight that matters.

Some things are best viewed not as they are, but in the light of a prior incarnation and the hope that it could reascend to this splendor once again. It took years, but I climbed out of the high walled prison of this disease and next month, on the other side of the world, I will put my hands on another Great Wall.

Chronic mast cell leukemia: A new variant of systemic mastocytosis

Mast cell leukemia (MCL) is a variant of systemic mastocytosis (SM) marked by a significantly shortened lifespan.  In MCL, patients experience massive and devastating proliferation of immature mast cells.  The bone marrow is always affected and the huge amount of mast cells means there is no room for other types of blood cells. Usually, the bone marrow smear reveals over 20% of nucleated cells in bone marrow are atypical mast cells, as well as large quantities present in the blood.  In the aleukemic variant, less than 10% of all white cells in the blood are mast cells.

In most patients with MCL, C-findings (markers of organ infiltration and damage progressing to organ failure) are present.  These include such features as hypersplenism, liver damage, very low blood cell counts, and others.  However, in the last several years, a number of MCL patients described who do not have C findings.  These patients have over 20% mast cells in the nucleated cells of the bone marrow, but the mast cells are mostly mature, and most do not circulate in the blood stream.  This population often demonstrates stability rather than rapid progression toward death, as was previously seen in most MCL patients.  The term “chronic MCL” has been suggested to describe this group.

The more classic MCL presentation (now called acute MCL) has a number of differences from chronic MCL.  In acute MCL, most of the mast cells are not mature, with metachromatic blast cells.  In acute MCL, CD25 receptor is always present on the cells, while this only sometimes occurs in the chronic course.  Chronic MCL never expresses Ki-67 on the outside of the cells, while this is sometimes seen in acute MCL.  Both acute and chronic sometimes have CD2 and D816V mutation, but not always.  Spindle shaped mast cells are almost never present in acute MCL.  Swelling of the spleen is always seen in acute MCL, but only sometimes in the chronic form.  Chronic MCL patients have no C findings.  If they develop a C finding, they are reclassified as acute MCL.

Acute MCL has long been associated with very short survival times following diagnosis, most often less than a year.  This can be extended in some patients with the use of newer medications.  Remarkably, patients with chronic MCL demonstrate a largely stable clinical course comparable to smouldering SM.  In both of these conditions, tryptase levels are high but stable; the spleen is most often swollen; and mast cell burden is high.  Patients with chronic MCL usually have no mast cell skin lesions.

Chronic MCL patients can be stable for years, but can progress to acute MCL or MCL-AHNMD at any time.  Mediator release symptoms more often seen in indolent mast cell diseases are also common in chronic MCL, while less so in acute MCL.

Reference:

P. Valent et al. Chronic mast cell leukemia: A novel leukemia-variant with distinct morphological and clinical features. 23eukemia Research 39 (2015) 1-5.

Glossary of mast cell related terms: F-L

FceRI: the high affinity IgE receptor; where IgE molecules bind to the outside of cells, like mast cells; binding the FceRI receptor triggers mast cell activation

Food associated, exercise induced anaphylaxis: An IgE mediated reaction that is triggered by ingesting certain foods in close time proximity to exercise

Food protein induced enterocolitis syndrome (FPIES): An allergic reaction to food proteins that is not mediated by IgE, usually found in infants; the most severe non-IgE mediated food hypersensitivity

Gastroparesis: a condition in which stomach contents are not emptied into the small intestine within an appropriate time period without an obvious anatomical explanation

Granule: a pocket inside a cell that holds molecules to be released outside of the cell

Granulocyte: white blood cells that have granules inside the cells that hold molecules to be released outside of the cell; mast cells, eosinophils, basophils and neutrophils are granulocytes

H1: histamine 1 receptor

H1 inverse agonist: a class of drugs that interferes with the effect of histamine at the H1 receptor

H2: histamine 2 receptor

H2 blocker: a class of drugs that interferes with the effect of histamine at the H2 receptor

Heparin: a mast cell mediator; a blood thinner

Hepatomegaly: swelling of the liver

Hepatosplenomegaly: swelling of the liver and spleen

Hereditary angioedema (HAE): a heritable blood disorder that causes episodes of protracted swelling that can be life threatening.

Histamine: a neurotransmitter; responsible for a large portion of symptoms seen in mast cell disease and anaphylaxis

HPA axis: the signals and feedback loops that regulate the activities of the hypothalamus, pituitary gland and adrenal glands to coordinate the body’s stress response; also helps regulate digestion, immune activation, sexuality and energy metabolism

Hypersensitivity: allergic reaction

Hypersplenism: overactivity of the spleen

IgE: an antibody that triggers allergic responses

Kounis Syndrome: an event in which a patient experiences severe chest pain or heart attack as the result of an allergic reaction; also called allergic angina or allergic myocardial infarction

Late onset anaphylaxis: Anaphylaxis that begins several hours after exposure to trigger

Leukotrienes: Structural class related to prostaglandins produced by the enzyme 5-lipoxygenase (5-LO); mediators released by mast cells.

Leukotriene receptor antagonist: A class of drugs that interferes with the function of leukotrienes; examples include montelukast and zafirlukast.

Ligand: a molecule that binds to another molecule, triggering a specific effect; with regards to mast cell disease, ligands bind to receptors, such as IgE (ligand) binding to FceRI (receptor)

LO: lipoxygenase; the enzyme that produces leukotrienes

Low histamine diet: a diet which minimizes dietary sources of histamine, which can help reduce symptoms for some mast cell patients; there is no authoritative list of low histamine foods and some trial and error is required