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Mast cell inhibitory effects of some microorganisms

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

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

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

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

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

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

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

 

References:

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

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

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

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

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

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

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

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

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

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

We are Boston

It’s cold in Boston today, and damp and grey; the sort of unredeemable weather Boston is known for. I read the forecast from my iPhone as I drank my coffee this morning. I knew I should dress warmly, but it felt wrong to wear fleece tights and boots in April. I pulled on my blue tights with stars and crescent moons, slipped my feet into warm weather flats that don’t support my floppy ankles. Dressing for warm weather is a sort of hopefulness we Bostonians force upon ourselves – even if it doesn’t come to pass, at least we know we tried.

It was sleeting when I got off the train at Longwood, pebbles of ice bouncing off the pavement, cast aside by passing cars. My legs and feet were cold; I rubbed my fingers together to warm the tips. I put my head down and walked fast to the closest hospital entrance, running through a held-open door under the carved words, “The Peter Bent Brigham Hospital”.

People come from thousands of miles away to be seen here, at my local hospital, Brigham and Women’s. I was born in this hospital. Out of towners call it “Brigham’s”, but anyone from Boston knows that Brigham’s is an ice cream store. No, this is “The Brigham,” because it used to be two separate hospitals, the Peter Bent Brigham Hospital, and the Boston Lying In Hospital, where the discipline of obstetrics was first practiced as a medical science. The Lying In Hospital was a women’s hospital, and when the two merged, it became Brigham and Women’s.

I know lots of these arcane trivialities because I have lived in Boston all my life. I am a Bostonian; I am from Boston. This is my city, and it is part of me.

I rubbed my calves together while waiting for the E line train, my music in my headphones loud enough for a Deaf girl to hear. As I stood up to board the approaching train, I realized it was snowing. I climbed aboard and paid the fare. I folded myself into the smallest shape I could make and sat in the first empty seat, the one closest to the driver. I pulled out my phone and opened the browser. I navigated to CNN, read the banner in bright red.

“They found him guilty,” I said to an E line train car full of strangers. Everything stopped talking and looked at me; they knew who I meant. It is April 8th and snowing in Boston, and Dzhokhar Tsarnaev was found guilty of all thirty charges in relation to the Boston Marathon Bombing.

The day of the 2013 Boston Marathon was warm and sunny. I was babysitting my friend’s daughter that day and I had walked her over to my mother’s house to run around in the yard. I carried the baby into my mother’s living room, where the tv showed live coverage of the finish line. As I sat the baby on the sofa, the bombs exploded.

In the beginning, there was some speculation that this had been a gas explosion. I walked the baby home to make her dinner, watching the muted news from another room as I fed her chicken nuggets. There were early reports of explosions at the JFK Library, which later turned out to be an unrelated electrical fire. I texted, emailed and called everyone I thought might be near Boylston St.

Within a couple of hours, it was obvious that this was a terrorist attack. I packed a bag full of the baby’s things and my father drove over to get us. It didn’t seem like the time to be alone with a toddler.

The news coverage was harrowing. It was uncensored and so graphic and so bloody. The insides of ruined legs, shorn blood vessels, shrapnel. And people who ran to help, regular people picking up the injured and running with them to safety, regular people pinching the ends of veins and holding wounds closed with their bare hands. Not just regular people. Bostonians.

I didn’t think it would be worse the following day, but that was before I knew my mother would call me in the afternoon. “They are showing the names of the people who were killed, and the girl… who died… it’s Krystle Campbell,” she said. I was holding the baby, same baby, on my hip. I packed her things up again and we went back to my parents’ house to think about Krystle Campbell and how she had been murdered by a bomb in our city.

One of my father’s best friends when he was growing up was Billy Campbell. They both grew up and had families; my father had two daughters; Billy had a son, also named Billy, and a daughter, named Krystle. Krystle was my friend when I was a little girl, when we were both little girls together. We spent most warm weekends together for several years when we were kids, swimming in the lake, riding bikes on dirt roads in the woods, sitting by campfires on summer nights. We went to each other’s birthday parties and watched fireworks together on the Fourth of July.

We got older and started doing different things and lost touch. Suddenly it was April 16, 2013, more than half a lifetime later, and Krystle’s face was on the news and on the internet and all I could think about was that she used to be really proud of the streamers she had on the handlebars of her bike. And that that same little girl with the streamers lived for another twenty years until one day when she stood at the finish line of the Boston Marathon and someone killed her and two other people.

Two nights later, the entire city watched the press conference in which they released the pictures of the Tsarnaev brothers. Hours later, an MIT police officer was shot and killed. I knew right away it was connected. I don’t know why I assumed that, but I went to sleep that Thursday night feeling like I might wake up to a very tense situation. I was not wrong.

By Friday morning, residents were being asked to shelter in place and to stay off Boston streets to assist the police in apprehending Dzhokhar Tsarnaev. News crews broadcast images of Faneuil Hall, the Boston Common, Kenmore Square, the Esplanade – all still, completely vacant.

That night, Dzhokhar Tsarnaev was apprehended, found hiding in a boat in a backyard in Watertown, a mile from my grandmother’s house. And I was happy. I was really happy because two days later I went to Krystle’s wake and hugged her parents and her brother and thought about her bike streamers and I was really happy that they had caught him before her family had to say their final goodbye. I was happy that he wouldn’t be able to blow up anything else in my city and that those four people were the only ones he would be able to kill.

If I could point to any one quality that defines Boston and its people more than anything else, it would be the ability to keep going when bad things happen. We are not people who give up. We are not people who let things get to us. We are ordinary people who run towards the sound of explosions in case people need help. We are police officers who chase terrorists through city streets while they throw homemade bombs at us. We are citizens who shovel off the Boston Marathon finish line in the middle of a recordbreaking snowfall in memory of those who died there. We are runners who minutes after finishing the marathon run to Mass General and the Brigham to donate blood to explosion victims. We are first responders who ensure that every person who made it into an ambulance survived their grievous injuries. We are medical professionals in world class hospitals who saved the lives of 264 people in a matter of hours. We are Boston.

The day of the Boston Marathon the year after the bombing, the spectator turnout was great. I never doubted it for a second. Because this is Boston and that’s what we do. Because fuck terrorism. Because fuck Dzhokhar Tsarnaev.

Today is April 8th, and it’s snowing in Boston.  Dzhokhar Tsarnaev was convicted of murdering Krystle Campbell, Martin Richard, Lu Lingzi, and Officer Sean Collier, and injuring 264 other people.

 

 

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.