Skip to content

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.

Love and rainbows

A friend of mine died yesterday. We never met in person, and shortly after we began talking, she found out she was dying. We met through the mast cell community, but she was living with something far more insidious – a rapidly progressing, heritable form of ALS. She died a little over a year after being diagnosed. She is survived by her husband and young son, and many close friends and relatives.

I found out that she was dying yesterday through Facebook. She posted herself that it would be her last day, as she had chosen to invoke Oregon’s Right to Die. I scrolled through all the supportive posts on her page, all the pictures of her with her close friends, recipes she had left for her son.

I learned a lot from her about grace and how to die a good death. Her openness about her illness, and about the ways her body has failed her personally and those in her life in a larger sense, has been a constant source of solidarity for me. She truly embodied the fact that you can love your life and be truly alive even while your body is becoming incapable of sustaining life. She really taught me that life has very little to do with the things you can do and more to do with feeding the relationships you have. I am grateful to have known her.

Every day, I see articles and posts advocating for people to “turn off the screens” and “connect for real”. If it’s not in front of you, if you can’t touch it, it’s not as worthy of your attention, it seems these people think. If you have a conversation via text message, it doesn’t mean as much as one across a table. One of these posts was in my Newsfeed right below Sherrie’s post that was leaving this world today. I shook my head.

These people who write these things don’t know what it means to have a rare disease. They don’t know the loneliness you feel every day surrounded by people who don’t know what it’s like to live in a body that can go into shock without any provocation. They don’t know the overwhelming sense of belonging you feel when you find someone online like you. They don’t know that having someone say, “I understand, I’m the same way,” in a group online can sustain you and validate you just as much as any in person interaction ever will. It is connecting for real, and it’s not less because it happens online.

Sherrie believed that when she died, she would go back up the rainbow she slid down when she was born. She surrounded herself with rainbows, and it became a metaphor for her larger experience. Some weeks ago, after a few difficult days, she wrote the sentence, “The rainbow is calling me.” I shivered when I read it. I can’t believe that the courage and surrender embodied in these few words are less important because I didn’t hear them in person. That’s not how the world works.

What we are doing here, in this community, matters. Supporting each other and understanding each other matters.

When the harder days come, I will remember Sherrie and that life has very little to do with our bodies. It has to do with love and rainbows.

A comprehensive list of antihistamines: H1 receptor (part 2)

Chloropyramine is a first generation H1 antagonist. It is used for allergic eye and nasal symptoms, bronchial asthma, Quincke’s edema, and allergic reactions to food, medications and insect bites. It is available in several European countries as an oral or IV/IM preparation for emergent situations. It has the typical anticholinergic side effects seen in older H1 antihistamines. It is available under several names, including Allergosan, Suprastin, Supralgon and Avapena, in several countries, including Georgia, Hungary, Lithuania, Latvia, Russia, Croatia, Serbia, Bosnia and Herzegovina, Bulgaria and Mexico.

Chlorpheniramine is a first generation H1 alkylamine antihistamine. It is less sedating than other first generation antihistamines. It is sometimes used off label as an antidepressant and anti-anxiety medication as it has serotonin-norepinephrine reuptake inhibiting properties. It is available alone and in various combinations in the US, Canada, throughout Europe and Asia.

Chlorphenoxamine, more commonly known as Systral, is a medication with structural similarities to diphenhydramine. It is mostly used as an anti-Parkinsonian drug and is available in Latin American and Caribbean countries, as well as some European countries and Thailand.

Cinnarizine is an H1 antagonist that functions as both an antihistamine and also as a calcium channel blocker. It is a piperazine derivative. It improves blood flow to the brain and is used for cerebral apoplexy, cerebral symptoms following trauma and cerebral arteriosclerosis. It is also used for nausea and vomiting due to several causes. It is also antiserotinergic and antidopaminergic. Due to its action of dopamine receptors, it can cause parkinsonism if used frequently. It is not available in the US or Canada, but is available under a number of names in many countries, including Brazil, Peru, Philippines, Malaysia, China, Bangladesh, India, and Israel, among several others.

Clemastine is an H1 anthistamine. Though it can be sedating, it has fewer side effects than several other H1 medications. It is also a functional inhibitor of acid sphingomyelinase. It is available in many countries without prescription under brand names such as Tavist, Tavegil or Agasten. It is particularly effective for itching.

Cyclizine is an H1 antihistamine mostly used for nausea, vomiting and dizziness from motion sickness or medications, such as anesthesia. It is also used to potentiate the effects of opiates and opioids. It is a piperazine derivative and is available in the US and UK as IM/IV and oral formulations.

Cyproheptadine is a first generation H1 antihistamine. It is also antiserotonergic and for this reason is used to manage serotonin syndrome. It has a variety of unusual uses, including as a local anesthetic, to treat nightmares in children and due to PTSD, for hyperhidrosis, and to prevent migraine.

Dexbrompheniramine is a widely available medication with structural similarities to chlorpheniramine. It is used to manage general allergic symptoms. It is available in the US and Canada as Drixoral.

Dexchlorpheniramine is the one form of the drug chlorpheniramine. It is available in the US and Canada as Polaramine.

 

Initial diagnosis and treatment of mast cell activation disease: General notes for guidance

Mast cell disease is becoming more well known among both the public and medical providers, but there is still a lot of confusion regarding exactly what it is, how to diagnose and how to treat.

There are several tests that should be used when working up a patient for mast cell disease. Tryptase is the most well known of these tests, due to over 85% of patients with systemic mastocytosis (SM), a form of mast cell disease, having elevated tryptase. However, tryptase can be normal in mast cell patients, or may only be elevated during times of severe symptoms or anaphylaxis. While an elevated baseline tryptase can be used as confirmation for a mast cell disease (in the absence of frank hematologic disease), a normal tryptase test should not be used to discard the possibility of mast cell disease.

24-hour urine tests for mast cell mediators are most likely to capture evidence of mast cell activation when executed correctly. These tests measure n-methylhistamine, a metabolite of histamine, and prostaglandins D2 and F2a, which are all released by mast cells. Urine collected for this test should be kept refrigerated or on ice during collection and transport to the lab. I STRONGLY recommend communicating with the lab prior to beginning to this test to be sure that they understand the temperature requirements. The molecules being tested are not stable at room temperature and inappropriate storage can result in a negative test result in a positive patient. (For details on this topic and specific recommendations for testing, please refer to Afrin 2013).

Some providers also find utility in the measurement of other less specific mediators. Please refer to my previous post on this topic: https://www.mastattack.org/2014/10/mast-cell-mediators-recommended-testing-for-mcas-diagnosis/

Due to the well established time sensitive nature of these tests (Afrin 2013), a patient who presents a “mast cell clinical picture” and responds to typical mast cell medications may in fact have mast cell disease in the presence of negative tests.

Depending on the clinical picture, a provider may feel it necessary to order a bone marrow biopsy, skin biopsy or biopsy of another organ to determine if mast cell infiltrates are present. This is not always immediately done in the presence of positive tryptase, n-methylhistamine, D2 prostaglandin or F2a prostaglandin test and will not always affect treatment. It is common knowledge among mast cell fluent providers that a negative biopsy does not exclude mast cell disease, but it is instead used to rule in the presence of specific proliferative entities like systemic mastocytosis (Picard 2013, Molderings 2011). Furthermore, a single biopsy may fail to capture a positive specimen in a known-positive patient (Butterfield 2004).

For more specific details regarding differentiation among the diagnostic categories of mast cell disease, please refer to my previous post on this topic: https://www.mastattack.org/2014/07/diagnosis-of-mast-cell-diseases/

There are a number of well known, well tolerated medications that can be used to manage mast cell disease. First line medications include antihistamines, leukotriene inhibitors, and mast cell stabilizers (Cardet 2013, Picard 2013, Molderings 2011, Afrin 2013).

Histamine is released by activated mast cells in large quantities. Histamine acts on the body by interacting with four different types of receptors, called H1, H2, H3 and H4. Medications that block the H1 and H2 receptors are available in plentiful supply in many countries. Once diagnosed, mast cell patients generally begin daily treatment with both H1 and H2 antihistamines. Longer acting, non-sedating H1 blockers like cetirizine are typically used to provide a baseline H1 coverage. H2 coverage is achieved with medications like Zantac or Pepcid. Dosage can be increased as needed to provide effective symptom relief, and these medications are often taken in moderate to high doses by mast cell patients. It is not uncommon to take multiple drugs together to block one type of histamine receptor, but this should be managed by a provider.

Leukotrienes are also released by activated mast cells. Singulair is an example of a leukotriene inhibitor that is a common add-on for mast cell patients. This medication is not a replacement for antihistamines.

Mast cell stabilizers achieve effects by making mast cells less likely to release chemicals. Cromolyn is typically the first line mast cell stabilizer in the US. This medication can take several weeks to demonstrate its full effect, so patients and providers should be aware of this fact. Another mast cell stabilizer, ketotifen, is also available in the US through compounding pharmacies. Ketotifen is also an H1 antihistamine.

Medications should ideally be added one at a time to allow easy identification of a bad actor in the event of a med reaction. As a result, tweaking a patient’s medication regimen takes time and patience. If a patient reacts to a medication, care should be taken to determine if the medication is truly the issue or if it is an inactive ingredient in the preparation (lactose, etc).

Mast cell disease can result in a highly variable clinical picture and mast cell patients are often only diagnosed following years of investigation for other possible causes of their symptoms. For this reason, many mast cell patients have acquired a long list of diagnoses prior to a mast cell diagnosis. In some cases, these diagnoses may be accurate and co-existing. All existing prior diagnoses should be considered for their accuracy in light of a mast cell diagnosis.

Additionally, there are a number of conditions which are frequently comorbid with mast cell disease, including Ehlers Danlos syndrome, postural orthostatic tachycardia syndrome (POTS), a variety of autoimmune diseases and several digestive conditions.  Patients should be evaluated according to their clinical picture and laboratory findings.

 

References:

Afrin, Lawrence B. Presentation, Diagnosis and Management of Mast Cell Activation Syndrome. 2013. Mast Cells.

Juan-Carlos Cardet, Maria C. Castells, and Matthew J. Hamilton. Immunology and Clinical Manifestations of Non-Clonal Mast Cell Activation Syndrome. Curr Allergy Asthma Rep. Feb 2013; 13(1): 10–18.

Matthieu Picard, Pedro Giavina-Bianchi, Veronica Mezzano, Mariana Castells. Expanding Spectrum of Mast Cell Activation Disorders: Monoclonal and Idiopathic Mast Cell Activation Syndromes. Clinical Therapeutics, Volume 35, Issue 5, May 2013, Pages 548–562.

Gerhard J Molderings, Stefan Brettner, Jürgen Homann, Lawrence B Afrin. Mast cell activation disease: a concise practical guide for diagnostic workup and therapeutic options. Journal of Hematology & Oncology 2011, 4:10.

I still live here

I flew home from Florida today. I am feeling pretty beat up. I had an amazing time and regret nothing, but I need to recover in a serious way. I need rest and IV fluids and soft, safe foods. Probably for several days.

My immediate reaction to this thought to be repulsed. I don’t like the idea of spending days in bed, even if I need it. I make so many judgments about my body and what I think it should do. I sleep too much. I don’t sleep enough. I need to exercise more. I need to do yoga every day. Every day, all day, I judge my body and its abilities, a ceaseless undercurrent to my more complicated feelings about being sick.

Why do I do that? Why do I compare every day to the day before? Why does every aspect of my life have to be measured against its previous self?

I judge my body so harshly sometimes. It is too weak. It is too fat. It is incapable of adapting to change. But sometimes I am struck by how utterly amazing my body is in the larger context of my life. It may react while flying through the air at hundreds of miles an hour but it let me ride roller coasters a few days ago. And really, that is amazing.

It is astounding to think how much I could achieve if I just stopped comparing my body to what I think it should be. Because the fact is that every time my body overcomes a reaction or a trigger, it is the result of the convergence of thousands of complex reactions executed in the name of self preservation. It is a miracle it can still recover after all this time.

I am alive. I live in this body. It might fight me, but I still live here. For the first time in a long time, it doesn’t feel like my body is filled up with nausea and bleeding and pain. It feels like it’s filled up with me.

Not a sad story

About a month ago, I had finally had enough of the oppressive snow wasteland known as Boston and I booked a trip to Florida. I told my masto friend I was coming down and we chirped excitedly about plans and what to do and all of those vacation things. It is no secret that my life has been generally frustrating recently so it seemed like this would provide an appropriate escape.

We made tentative plans for everything in the way only two people with mast cell disease can and generally derped out with excitement. We went back and forth about meds and supplies and safe foods. We decided to go to Disney.

Disney is one of my favorite places and a place I haven’t really had time to explore in several years. It also has an excellent reputation for accommodating health issues (including the very complex ones) and food allergies. We figured we would spend a couple days there, but I didn’t have high expectations for how much I would be able to do. Warm weather is a welcome change given the winter Boston just survived, but I don’t do well in heat, humidity or sunlight, especially when there is a lot of physical stress (like walking or standing for long periods of time). So I pretty much just hoped for the best in the same way I always do. A bad day at Disney is better than a bad day anywhere else.

I flew out of Boston on Thursday. It went pretty smoothly, with the exception of one woman who saw me get out of the wheelchair to walk into the bathroom. When I walked to the sink to wash my hands, she said, “You should be ashamed of yourself, there are people who really need those.” My reply was blistering and ended with, “People like you are the reason people like me kill themselves.” She was stunned to say the least.

Aside from this 90 seconds of unpleasantness, everything else was great. I touched down in Orlando around 6:15 on Thursday night. My friend Nikki picked me up and we checked into our room at the Port Orleans – French Quarter at Disney. It was so pretty. I know all Disney properties are pretty, but I liked this one a lot. We went out to a really nice, allergy safe dinner at a nearby hotel.

The next morning, we medded up and headed for Epcot. I LOVE Epcot. The only thing I wanted to do there was go to all the countries in the World Showcase. We got some (allergy safe) food and made it to all the countries before it started pouring. We covered our (accessed) ports and ran for the bus back to hotel.

It was a little hairy with gummy dressings and symptoms from the sudden temperature change, but we took meds and handled it. We took a nap back at the hotel and headed over to Magic Kingdom around 8. We went on the Haunted Mansion, It’s a Small World, Space Mountain and the new Seven Dwarfs Mine Ride, saw the fireworks and caught the end of the Electric Light Parade. We got back to the room around midnight and crashed hard, but in that exhausted way where you can’t sleep.

We had originally only booked two nights at Disney because we are crazy people who overestimated our physical capabilities. I figured that if we wanted to extend, it would be possible, even if we needed to switch hotels. I didn’t realize it was the start of Florida school vacation. We had called the Disney reservation line several times on Friday and they kept telling us nothing was available. Around 3am, I figured I would search online for available rooms since I wasn’t sleeping anyway and there was a room available at French Quarter! So I booked it and then we could not have to worry about waking up early to pack and also lack of sleep is one of my worst triggers so I had been worried about that. We got really lucky and slept in before heading to Animal Kingdom in the afternoon.

I have never seen a lot of the things at Animal Kingdom before so I was really excited. We went on the safari and saw lots of savannah animals, like giraffes, lions, zebras and hippos. We had booked fast passes for some rides so we did a lot of running around. (I should probably mention here that running is not something I do or tolerate well.) We went on this Mt. Everest roller coaster which was SO MUCH FUN (side note: at this point I learned that if you have a port and are on a roller coaster going backwards, it will feel like your port is pushing through your chest wall. It was really funny, when we started going backwards, both Nikki and I put our hands on our ports at the same time). We went back to the hotel and napped for a while and then took the ferry to Downtown Disney to get some food and watch Insurgent.

I was thoroughly fried by this point, and in that super uncomfortable, muscles hurt, about to react/actually reacting, nausea/vomiting space that I really hate. I was nauseous pretty much the whole time, but it was getting worse. I slept really late the next day and met Nikki at the MGM park, which I had also never seen in its entirety. We saw the Indiana Jones show, the Great Movie ride, a really cool stunt driving show and the Star Wars ride. At this point I was feeling the liquid courage effect of Benadryl so we waited in line (in the shade) for an hour for the Aerosmith Rockin’ Roller Coaster (which is one of my all time favorite roller coasters). It did not disappoint. Then there was only a short line for the Tower of Terror so we did that, too.

So, to summarize: two mast cell patients (who have had multiple surgeries, require regular IV meds and semi-regular epi, and have complicated food restrictions) went to Disney for three days, saw all four parks and Downtown Disney, ate food they didn’t prepare themselves and through the use of naps and liberal application of medication/IV fluids, were able to see/do literally all of the things they wanted to. LIKE FUCKING BOSSES.

Now we are at Nikki’s farm outside of Ocala which is very farmy and very beautiful. It is so calm here (except when the dogs and the pigs fight because the baby pig wants them to play with her, but still). I am recovering from the visceral adventures of Disney and feeling very glad that I came.

I try very hard to depict my life as realistically as possible, the good and the bad. I am in a place in my life right now where my life is hard a lot of the time and so that is what I write about. It’s not always my reality, it’s just my reality right now.

Everyone has hard things in their lives. I don’t think that being sick is any harder than losing a parent or a difficult divorce. It’s just different, and because my particular illness is unusual and uncommon, it seems worse to people. People say things to me sometimes, about how sad it makes them that I’m so young and so sick, or that I need a colostomy, or that I have a port, or whatever. They think my life is sad or tragic. My life is neither of those things.

I think sometimes that it’s easy to get stuck on how hard things are and how upsetting it is that you will never have your old life again. But we have these bright spots, and you can choose to elevate them in your mind so that they wash out the hard things, at least for a little while.

Don’t pity me, or people like me. This is my life, and it’s not a sad story.

 

Disney

Allergic effector unit: The interactions between mast cells and eosinophils

Eosinophils are granulocytes that can localize to the tissues under certain conditions, including allergic response. Eosinophilic granules contain the positively charged proteins major basic protein, eosinophil peroxidase, eosinophil cationic protein, and eosinophil-derived neurotoxin. Like mast cells, eosinophils release these granules in response to many things, including inflammatory signals, parasitic infection, tissue damage and allergic inflammation. They express many receptors, including receptors for platelet activating factor (PAF) and histamine receptors. PAF and histamine are both released by mast cells.

Mast cells and eosinophils are overwhelmingly found together in late and chronic stages of allergic inflammation. They function in such close concert that mast cells, eosinophils and their effects have been termed the allergic effector unit (AEU). Mast cells release signals that affect eosinophil behavior and receive signals from eosinophils. These cells often also function while in physical contact with one another. When eosinophils are in physical contact with mast cells, they live longer than normal. CD48, 2B4, DNAM-1 and Nectin-2 are all involved in the mast cell – eosinophil contact mechanism.

Major basic protein can activate mast cells and eosinophil peroxidase is taken up by mast cells as a signaling molecule. Tryptase draws eosinophils to mast cells and causes release of eosinophil peroxidase, IL-6 and IL-18 from eosinophils. Histamine and prostaglandin D2 also signal eosinophils to migrate towards mast cells. Mast cell secreted eotaxin activates eosinophils by the histamine 4 (H4) receptor. Both cell types secrete leukotrienes and both express leukotriene receptors.

When grown together, researchers are able to investigate the behavior of mast cells and eosinophils together. This is called co-culture. In 29% of cases, eosinophils will migrate towards resting (non-activated) mast cells. In 45% of cases, eosinophils will migrate towards IgE activated mast cells. In 47% of cases, eosinophils will migrate towards mast cells activated through a non-IgE pathway. The specific attractant signal has not been identified.

When co-cultured with eosinophils, basal mast cell mediator release was 5% higher. When the mast cells were activated by IgE, degranulation was 15% higher. In order to activate mast cells, eosinophils must be in contact with them. However, mast cells can activate eosinophils without contact. In co-cultures with mast cells, eosinophil peroxidase constituted 47% of eosinophil released proteins, compared with 18% normally.

In low term co-cultures, both mast cells and eosinophils stayed activated. TNF was high in the co-culture, but not IL-6, IL-8 and IL-10. Importantly, low relative numbers of mast cells could activate eosinophils, but mast cell activation was most effective when eosinophils were more numerous. Eosinophils are thought to reduce the threshold of mast cell responsiveness to IgE.

 

References:

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.

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.

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.

Mast cell mediators: Sphingosine-1-phosphate

Sphingosine-1-phosphate (S1P) is a lipid mediator involved in many processes, including development of vessels, vascular permeability, and immune function. It is found in the blood, often bound with proteins such as high density lipoprotein (HDL, “good cholesterol”). Receptors for S1P are found on many cell types.

Activation of the high affinity receptor for IgE causes production of S1P by mast cells. This may also affect the expression and activation of S1P receptors. Mast cells then secrete S1P into the surrounding space.  Mast cells also have receptors to bind S1P.

The S1P1 receptor helps to direct mast cells to sites of inflammation, but does not influence degranulation. The S1P2 receptor deters from localizing to sites of inflammation but enhances degranulation once they have migrated. S1P is known to increase during acute tissue inflammation, in airways following asthmatic challenge and in joints of rheumatic patients. S1P may be responsible for the accumulation of immune cells in such places, but the exact nature of this role is unclear.

S1P receptors regulate the vascular system, including heart rate and permeability.  S1P2 receptor makes vessels more permeable and regulates blood flow to various organs. S1P2 receptor is involved in counteracting the vasodilation effect of histamine (and thus low blood pressure). Histamine can stimulate S1P production.

S1P can also cause bradycardia and high blood pressure via the S1P3 receptor.  I am curious to know if S1P is involved in the high blood pressure type of anaphylaxis some people have.

In models where the genes for making S1P have been deleted, recovery from anaphylaxis is delayed, with severe hypotension. However, in mice with S1P2 receptors, injecting S1P could rescue mice from anaphylaxis. For this reason, molecules that can act on the S1P receptors are being investigated as possible drug targets to produce an alternative to epinephrine.

 

References:
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.

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 “in press”.

Allergic to infections: Other behaviors of toll like receptors

I posted earlier this week about Toll-like receptors (TLRs). These are receptors on the outside of mast cells (and other cells) that tell them there is an infection. Instead of only being able to bind very specific molecules like receptors often do, these TLRs are able to bind lots of molecules that look alike. Once these are bound, it tells mast cells to activate, make mediators and release them.

After TLR2, TLR4 is the most well understood Toll-like receptor. Molecules that bind TLR4 are from infectious gram negative bacteria, several viruses (including RSV), Cryptococcus neoformans, and Candida albicans. It also binds fibrinogen, which is involved in the clotting cascade, and nickel. When infected with a gram negative bacteria, like E. coli or Ps. aeruginosa, mast cells secrete inflammatory molecules TNF, IL-6, IL-13, and IL-1b.

TLR4 also has a very intriguing behavior with opioid receptors on mast cells. These opioid receptors are the binding sites for opiate medications, like morphine, which are common triggers for mast cell patients. One study found that treatment with morphine actually interferes with TLR4 making inflammatory molecules. Other studies have found that opiates can bind TLR-4 directly. When bound, TLR-4 signals for release of TNFa, CCL1 and IL-5.

Other TLRs on mast cells can be bound by various molecules and produce and release mediators in return. TLR3 is bound by viral proteins and induces release of interferon a and b; TLR5 binds proteins from some flagellated bacteria and releases TNF and IL-1b; TLR9 binds unmethylated DNA of the type released by bacteria and DNA viruses, and releases interferon a, TNF, IL-1b and leukotrienes.

All TLR receptors can function independently of IgE. This is one example of an IgE independent pathway, or a way mast cells can degranulate or secrete mediators without IgE.

 

References:

Hilary Sandig and Silvia Bulfone-Paus. TLR signaling in mast cells: common and unique features. Front Immunol. 2012; 3: 185.

Abraham S. N, St John A. L. (2010). Mast cell-orchestrated immunity to pathogens. Nat. 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. Proc. Natl. Acad. Sci. U.S.A.1078748–8753

Gilfillan A. M., Tkaczyk C. (2006). Integrated signalling pathways for mast-cell activation. Nat. Rev. Immunol.6218–230.

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. Mol. Immunol. 442087–2094.

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. J. 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. Inflamm. 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.

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. J. Allergy Clin. Immunol. 120, 452–461.

Varadaradjalou, S., Feger, F., Thieblemont, N., Hamouda, N.B., Pleau, J. M., Dy,M., and Arock, M. (2003). Toll-likereceptor2 (TLR2)and TLR4 differentially activate human mast cells. Eur. J. Immunol. 33, 899–906.

My surgery with mast cell disease pro-tips

Surgery with mast cell disease is a bit of a logistical circus. I am fortunate to be able to have my surgeries at a major teaching hospital where my mast cell specialists are also located and mast cell disease is understood to some degree by most people. Even still, there are a lot of things that must be organized in order to ensure the safest procedure possible.

Surgery is an inherently triggering process. It’s stressful. Even if you know it’s coming and feel fine about it, it’s still stressful. It is mechanically triggering to the body due to manipulation of the skin and tissue damage and remodeling. Operating rooms (and hospitals generally) can be hard for mast cell patients, with chemicals everywhere, poor control over temperature and the use of things like blood pressure cuffs and masks. Please assume that surgery will trigger you and plan ahead. Do not expect to be able to undergo surgery without mast cell precautions.

The first thing to do is make sure all of your (relevant) doctors are on the same page. Schedule appointments with all of them. Do it face to face.

Schedule any testing with enough time to have conversations with all of these doctors. This is frustrating but necessary. You do not want to find out later that another option would have been better, or that there was a precaution that wasn’t taken.

Meet with the anesthesia team in person. If you are in the hospital/seen by hospital providers frequently, they will sometimes say that you don’t need a face to face pre-op because you have recent blood work/they already have your anesthesia protocol/whatever. Do not listen to them. When you meet with the anesthesia team, open with the fact that you have a rare, life threatening blood disorder that causes severe non-IgE mediated reactions. Say it like you mean it. Then ask them to go through their entire procedure with medications they will use. Tell them what medications cannot be used for you. Do not be shy. I bring a list of meds contraindicated in mast cell disease, as well as a list of meds that I personally react to. Give them this list.

If you have reason to believe that these doctors are not familiar with mast cell disease, bring them a review article.

After pre-op, I also prefer to meet with the surgeon again face to face to go over in excruciating detail what they will do and what materials will be used to do it. Give appropriate substitutions (betadine for chlorhexidine, or whatever). If you are unclear on this, please consult your mast cell specialist ahead of time. Ask them if the hospital stocks all of your meds and if they don’t, find out what alternative they use. Try these alternatives ahead of time whenever possible.

Discuss your dietary needs with your surgeon ahead of time.  Bring a list of foods and meals you can eat.  If they cannot make you food safely, you may have to have someone bring you food, but you do not want this to be a surprise.

If you need an interpreter, make sure this is very clear to everyone involved as early as possible.

Make sure your pain management plan is rock solid. If you need to trial pain meds in order to find a safe one before surgery, do it. Do NOT have surgery without a pain management plan. It delays healing and is very triggering for mast cell patients. Also, that just sucks.

Same for anti-nausea meds. You will get nauseous.

If your surgery requires prep of some kind, I strongly advise you to trial it before you need to use it. As an example, the typical bowel preps they use for colonoscopies and GI surgeries just do not work for me. You do not want to find that out two days before surgery.

If you are having bowel surgery, expect to react to the prep. It is physically stressful. Discussion adding medication during this period with your mast cell specialist. I take extra Benadryl and oral steroids during this period. If you are adrenally insufficient, please consult with your endocrinologist regarding the need for additional steroids.

Pick a date when your doctors do not have imminent out of town time coming up. (For me, I want my mast cell GI specialist, immunologist and surgeon to be available.) And make sure that whoever is covering their service during out of office hours understands mast cell disease! This is so important. Sometimes you have one doctor in a group who treats mast cell disease, you do not want to be talking to someone who specializes in food allergy when you are having trouble.

I often see that people have not followed the premedication protocol recommended for mast cell patients. Let me be very clear. You are going to react to surgery in some way. Premedication is not a suggestion. It is a requirement. This protocol is designed to suppress anaphylaxis and to allow your body to behave during the procedure and the 24 hours or so following. If you have a hard contraindication to one or part of the premedication protocol, ask your mast cell specialist what you should take instead. STEROIDS AND ANTIHISTAMINES SHOULD BE TAKEN AS PREMEDS FOR SURGERY 12 HOURS BEFORE THE PROCEDURE AND ONE HOUR BEFORE THE PROCEDURE. THIS IS NOT NEGOTIABLE.

The day of the surgery, bring your medications with you to the hospital in case they don’t have your brand/med/whatever. BRING YOUR EPIPENS.  If you use special dressings/have a central line/ostomy/G-tube/something, bring all your stuff for that.  They will probably not need it, but you never know.  Also bring a copy of your health care proxy/ advanced directive and your “greatest hits” (current meds, health conditions, allergies, etc). Try to get scheduled for the first surgery of the day, but remember that you will need to be there about two hours before they operate in order to get settled and get IV meds an hour before the procedure. Even if you schedule this ahead of time and no matter how many notes are written, someone is still going to give you a hard time about one or all of your premeds. Do not be dissuaded. These are compulsory.

If you have a bad feeling about what is happening, feel your necessary precautions are not being respected, or generally feel like you are being pushed into something you do not want to do, reschedule your surgery. I do not care if you are in your fancy hospital gown with your IV started. If you feel that you are not in the hands of providers who will take care of you, leave. Your safety is more important than convenience for these people. Your health is not a democracy.

If you are a mast cell patient, you are likely going to need some babysitting after surgery. I was not allowed to be alone for three weeks after my 2013 surgery. Schedule this ahead of time. Do not worry about entertaining people. Type up a list of your meds, what they do, how to take them, etc, for your babysitters.   Also type up a list of signs to watch for. MAKE SURE THAT ANYONE WHO IS TAKING CARE OF YOU KNOWS HOW TO USE AN EPIPEN.

Relax. Surgery is a bummer but with precautions, it is still very safe for mast cell patients.

 

Leptin: the obesity hormone released by mast cells

Leptin is a hormone that is primarily secreted by adipose tissue, but is also produced and released by mast cells. In turn, mast cells also have leptin receptors. Leptin is primarily known for its action of part of the hypothalamus to inhibit the hunger response. Importantly, the body responds forcefully to leptin levels by engaging both biological and behavioral mechanisms to conserve energy. It is seen by researchers as less of a “hunger satiety” signal and more of a “starvation” signal.

Patients with obesity often have higher circulating levels of leptin than those without obesity. This occurs because leptin is secreted by adipose tissue, which obese patients have in higher amounts due to their higher percentage of body fat. These people seem to be resistant to the chemical action of leptin, possibly through a change in activity of leptin receptors in the hypothalamus. Some studies suggest that in obese patients, less leptin leaves the blood stream and crosses into the brain.

Leptin is now known to have a variety of other effects on the body, including modulating the immune system. It activates inflammatory cells, promotes T cell responses and mediates production of TNF, IL-2 and IL-6. In many inflammation models, cells express more leptin receptors than usual. In diet induced obese mice, mast cells have been observed to store and secrete TNF. In immune mediated diseases like autoimmune diseases, circulating levels of leptin are increased, and this in turn translates to higher levels of inflammatory cytokines.

Interestingly, leptin suppresses signals from the IgE receptor to make mediators. In leptin receptor deficiency models, magnified IgE anaphylaxis was observed. Leptin also seems to control the number of mast cells through some unclear mechanism. In leptin deficient mice, mast cell density is significantly higher in abdominal lymph nodes and fat deposits.

Leptin influences the release of many other molecules, including ghrelin. Ghrelin is the “hunger hormone,” released in the stomach and possibly elsewhere. It stimulates the hunger response in the body and also acts on the hypothalamus. The relationship between leptin and ghrelin is very complex and still being elucidated. However, it is thought that high levels of circulating leptin suppress secretion of ghrelin. This is especially of interest in inflammatory conditions as ghrelin suppresses production of a number of inflammatory markers, including TNF, IL-8, MCP-1, IL-1b, IL-6, CRP and others. This effect is so pronounced that it is being investigated as a treatment option for many conditions. Ghrelin has also been observed in one study in induce mast cell activation through a receptor independent pathway.

 

References:

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.

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.

Patricia Fernández-Riejos, Souad Najib, Jose Santos-Alvarez, Consuelo Martín-Romero, Antonio Pérez-Pérez, Carmen González-Yanes, and Víctor Sánchez-Margalet. Role of Leptin in the Activation of Immune Cells. Mediators of Inflammation, Volume 2010 (2010), Article ID 568343, 8 pages.

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