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June 2015

Food allergy series: Take home points

Food allergy series: Food related allergic disorders

There are many types of allergic diseases caused by food.


Oral allergy syndrome:

  • IgE reaction.
  • Causes itching and swelling in the mouth and sometimes the throat.
  • Less than 2% of cases progress to anaphylaxis.
  • Your body mistakes certain raw fruits and vegetables for pollens and reacts.
  • Cooked foods are usually safe in patients with OAS to raw foods.

Asthma and rhinitis:

  • IgE mediated.
  • Caused by inhaling food protein.
  • Most common in infants and children.
  • Can affect adults in specific work environments, like bakeries.
  • Most commonly induced by the eight major food allergens: egg, milk, wheat, soy, peanut, tree nuts, fish and shellfish.

Urticaria and angioedema:

  • IgE mediated.
  • From ingestion or skin contact.
  • Food ingestion causes 20% of acute urticaria cases and 2% of chronic urticaria cases.
  • More common in children.
  • Usually due to eight major allergens.

GI hypersensitivity:

  • IgE mediated.
  • Immediate vomiting in response to major food allergens.

Food associated, exercise induced anaphylaxis:

  • IgE mediated.
  • Ingestion of food in close time proximity to exercising.
  • Exercise may affect the way the GI tract absorbs and digests allergens.
  • Wheat, shellfish and celery most common to provoke this reaction.

Delayed food-induced anaphylaxis to meat:

  • IgE mediated.
  • Occurs several hours after eating.
  • Body makes antibodies to carbohydrate a-gal.
  • A tick bite can cause the body to make these antibodies.
  • Beef, pork and lamb cause reactions.

Atopic dermatitis:

  • IgE and delated cell mediated reactions.
  • 35% reactions in children due to food.
  • May be due to food reactive T cells in the skin.
  • Egg and milk most common.
  • Usually resolves on its own.


Eosinophilic GI disease:

  • IgE and delated cell mediated reactions.
  • Due to eosinophil driven inflammation.
  • Can cause difficult or painful swallowing, weight loss, obstruction and edema.
  • Elimination diets are first line treatments.
  • Endoscopy is diagnostic.


  • Not due to IgE.
  • Usually found in infants.
  • Exposure to food proteins causes chronic vomiting, diarrhea, low energy and poor growth.
  • Cow’s milk, soy, rice and oat are most common offending foods.
  • Cells are more responsive to TNFa and less responsive to TGFb.
  • Usually resolves with age.

Food protein induced allergic proctocolitis:

  • Not due to IgE.
  • Causes mucousy, bloody stools.
  • In response to breast milk containing allergen.
  • Treated by removing food from mother’s diet.


Heiner Syndrome:

  • Not due to IgE.
  • Occurs in infants.
  • Triggered by milk, may be a milk specific IgG reaction.
  • Causes pulmonary infiltration, upper respiratory symptoms, iron deficiency anemia and failure to thrive.

Celiac disease:

  • Not due to IgE.
  • Autoimmune disease causes malabsorption and enteropathy.
  • Caused by reaction to gliadin, gluten protein.
  • Can cause bone abnormalities, IgA deficiency, and other issues.
  • Can present at any age.
  • Is lifelong.

Allergic contact dermatitis:

  • Not due to IgE.
  • Eczema in response to metals in foods.
  • Mostly adults.










December 2014: Post summaries and take home points

Food allergy series: Risk factors for developing food allergies

  • Genetics is a factor in development of food allergies.
  • Poor skin integrity makes food allergies more likely.
  • Children with peanut or tree nut allergies usually react on the first ingestion.
  • Household peanut exposure is a risk factor for peanut allergy in infants.
  • Not clear if maternal diet while gestating can affect food allergies.
  • Low vitamin A and low vitamin D are risk factors.
  • Sun exposure and vitamin D deficiency may be connected to food allergies.
  • Hygiene hypothesis posits that changes in hygiene and cleaning has caused immune changes that may lead to allergies.
  • Gut microbiota also important in food allergies.

Food allergy series: FPIES (Part 1)

  • FPIES is the most severe GI food hypersensitivity that is not IgE mediated.
  • Thought to be caused by a delayed allergic pathway.
  • Causes profuse, repetitive comiting, diarrhea, acute dehydration, lethargy and weight loss.
  • Vomiting usually occurs 1-3 hours after eating offending food.
  • Vomiting is seen in 100% of cases.
  • Diarrhea is seen in 24% of cases.
  • Can cause low blood pressure and hypothermia.
  • Chronic symptoms can develop if food is not avoided.
  • About 75% of patients look seriously ill.
  • 15% have blood pressure low enough to require hospitalization.
  • FPIES usually onsets between 1-3 months of age, but can be as late as 12 months.
  • Symptoms usually occur 1-4 weeks after introducing cow’s milk or soy.
  • About 30% later develop atopic conditions.
  • 20% have family history of food allergies.
  • 80% react to more than one food.
  • Usually improve after beginning casein hydrolysate based formula.

Food allergy series: FPIES (part 2)

  • FPIES is diagnosed clinically.
  • Endoscopy and biopsy is often performed to rule out other conditions.
  • GI tract of FPIES patients shows inflammatory changes, such as ulceration and bleeding.
  • Baseline intestinal absorption is usually normal.
  • Food specific IgE is not usually present.
  • FPIES is managed with diet.
  • Exclusive breastfeeding can be protective against FPIES.
  • Oral food challenges require significant precautions and medical supervision.
  • Challenges are recommended every 18-24 months in asymptomatic patients.
  • 60% of FPIES cases resolve by three years of age.
  • In the US, only 25% of cases resolve by three years of age.
  • Most FPIES patients have some form of atopic disease.
  • Some patients may change from an FPIES type reaction to an IgE allergy type reaction.
  • Prevalence is different in different populations.
  • Median age for resolution of FPIES depends on the food and ranges from 4-7 years of age.
  • FPIES overwhelmingly affects very young children.
  • In very rare cases, older children and adults develop FPIES to fish or shellfish.

Food allergy series: Eosinophilic gastrointestinal disease (Part 1)

  • Eosinophilic gastrointestinal disease (EGID) is when eosinophils cause disease in the GI tract.
  • Eosinophils are white blood cells with similar functions to mast cells.
  • Eosinophils fight infections and participate in allergic response.
  • Eosinophils can degranulate.
  • Many GI conditions can elevate eosinophils in the GI tissue.
  • No consensus on what is a high eosinophil count/hpf.
  • Eosinophilic gastroenteritis can affect any part of the GI tract, but usually the stomach and small intestine.
  • Eosinophilic gastroenteritis causes swelling of the Gi tract, eosinophils in the tissue and ulcerations.
  • 50-70% of eosinophilic gastroenteritis is thought to be from allergic reactions.
  • The reason for eosinophilic gastroenteritis is not clear.
  • Eosinophilic esophagitis is 15 or more eosinophils/hpf in at least one field.
  • Eosinophilic esophagitis can be allergic or not.
  • Eosinophilic colitis is a rare condition with sudden onset colon inflammation with eosinophil infiltration that often spontaneously resolves.
  • Eosinophilic enteritis is limited to the small intestine.
  • Allergic proctocolitis affects rectum and/or colon of children under the age of 2.
  • Allergic proctocolitis can be the result of food allergy, most often soy or cow’s milk.

Food allergy series: Eosinophilic gastrointestinal disease (Part 2)

  • There are many conditions that can cause eosinophils to be increased in the GI tract.
  • Allergy associated colitis is when eosinophils aggregate in the small and large intestines as the result of an allergic reaction.
  • Hypereosinophilic syndrome is when people have too many eosinophils in the blood. Rarely, this causes eosinophils to become elevated in the colon.
  • Crohn’s disease causes inflammation of the digestive tract. Eosinophils in the GI tract can be elevated due to inflammation.
  • Ulcerative colitis causes inflammation of the colon. Eosinophils can be elevated in the colon due to inflammation.
  • Collagenous colitis causes inflammation of the colon and rectum. Eosinophils can be elevated. It may occur due to drug reactions.
  • Lymphocytic colitis causes inflammation of large portions of the colon. Eosinophils can be elevated in the mucosal layer.
  • Autoimmune colitis is when autoimmune patients experience colon inflammation. Eosinophils and mast cells are usually found together in affected tissue.
  • Graft versus host disease is a complication of a bone marrow transplant. Eosinophils can be elevated, including in the GI tract.
  • Peripheral/intestinal T cell lymphoma is a cancer that usually affects the small intestine. Eosinophils infiltrate the affected tissue.

Food allergy series: Eosinophilic gastrointestinal disease (Part 3)

  • 70% have family history of allergies
  • 10% have immediate family member with EGID
  • Can cause abdominal pain, GI dysmotility, vomiting, diarrhea, trouble swallowing, anemia, low blood protein and failure to thrive
  • Can cause malabsorption
  • EGID patients are very sensitive to foods. Eggs, milk and fish are most common problem foods.
  • Elimination diets are mainstays of treatment
  • Complete resolution often seen with elemental amino acid diet
  • Reintroduction of foods is not usually tolerated
  • Steroids effective but don’t produce lasting results
  • Mast cells often increased in EGID biopsies
  • Current treatment options not great

Food allergy series: Eosinophilic esophagitis (Part 1)

  • EoE patients are three times more likely to be male than female
  • Most patients have history of atopic disease
  • Usually presents in childhood or after third decade of life
  • Adults tend to have trouble swallowing, food impaction and upper abdominal pain
  • Children have less specific symptoms, including vomiting, abdominal and chest pain
  • 50-60% have at least one atopic condition
  • 15-43% have IgE mediated food allergies, are at greater risk for food induced anaphylaxis
  • No consensus on how many eosinophils/hpf is high

Food allergy series: Eosinophilic esophagitis (Part 2)

  • Endoscopy with biopsy is only reliable diagnostic method
  • May look normal by eye, so multiple biopsies should be taken
  • Mast cells are increased in EoE more than in GERD
  • Other tests rule like esophageal manometry, pH testing and barium swallows can help rule out other conditions
  • Important to exclude GERD
  • 40-50% EoE patients have increased in blood eosinophils
  • When EoE is effectively treated, blood eosinophil count decreases
  • Patients with EoE are found to have overexpression of several proteins
  • Other genetic links have been found

Food allergy series: Mast cell food reactions and the low histamine diet

  • Minimizes histamine in food consumed
  • Histamine from outside sources can induce mast cell degranulation
  • Common problem foods for mast cell patients, like alcohol, vinegar and aged cheeses, are high histamine and cause degranulation
  • There are many different versions of this diet. I use this one.
  • Avoid fermented foods, preservatives, dyes, leftovers, anything overly ripe, canned and pickled products
  • Recommends strict adherence for four weeks to determine if it works
  • Not all recipes labelled low histamine are low histamine

Food allergy series: Eosinophilic esophagitis (part 3)

  • Treatment first rules out GERD or PPI responsive esophageal eosinophilia by treatment with PPIs for 8-12 weeks
  • Some patients have primary EoE and secondary GERD
  • Dietary management is the cornerstone of EoE treatment
  • Dietary management is very effective in children, can achieve remission
  • Food tolerance is unlikely to be achieved even with long erm elimination
  • Steroids effective, but do not produce lasting benefits
  • Fluticasone and oral viscous budesonide effective in studies
  • Cromolyn has no clear benefit for EoE
  • Leukotriene receptor antagonists like Singulair might help, not clear
  • 11-55% of EoE patients suffer food impaction and require emergency intervention
  • Esophageal rings are common in EoE patients
  • Strictures larger than 1 cm in 11-31% of adults with EoE
  • Esophageal perforation can occur and may require surgery
  • Esophageal cancer and generalized EGID are not known to result from progression of EoE
  • Esophageal dilation is sometimes to treat difficulty swallowing and impaction

Food allergy series: Eosinophilic colitis

  • Can occur secondarily to many conditions, such as liver transplant and scleroderma
  • Less than 100 cases of primary eosinophilic colitis reported in literature
  • Experience lower GI symptoms, such as abdominal pain, constipation, diarrhea and rectal bleeding
  • More severe cases can cause malabsorption, obstructions, free fluid in the abdomen in weight loss
  • Symptoms often sudden onset, sudden resolve – relapsing/remitting
  • Dense eosinophilic infiltration in colon
  • Infiltration can occur in one large contiguous region or smaller isolated regions
  • No true consensus on what constitutes above average eosinophil count in GI tract
  • Sometimes have too many eosinophils in blood
  • Patients often have elevated total IgE
  • Treated with elimination diet, steroids, ketotifen and immunosuppressants



How to eat low histamine if you’re me

As requested, the details on how I eat low histamine.

The low histamine diet is confusing. There are several lists of which foods are high and which are not. Various sources cite different instructions for food preparation, storage, etc. There isn’t a lot of agreement on what is considered best practice for following a low histamine diet. I figured out what works for me by trial and error and that is what most people need to do. This is what my life looks like on a low histamine diet.

I started the low histamine diet January 1, 2014. I found a bunch of recipes online and spent three hours in Whole Foods trying to find everything. That first month was phenomenally expensive as I needed to get organic and/or low histamine versions of typical pantry products like oils, flours, spices, sugars and so on. The good news is that after that first month, my food bill has been much more manageable (though still more expensive than competing supermarkets like Stop and Shop).

I chose to follow the low histamine/low tyramine diet you can find on the Canadian Mastocytosis Society page. Foods that are canned or preserved are generally considered not to be low histamine as preservatives can be triggered and something bad is supposedly generating by the canning process (I’m unclear on what that is, but it seems possible to me). Vinegar is not allowed and I used many types of vinegar regularly, so that was a bummer. No wine or liquor for cooking because no fermented products and no alcohol. Several of the prepared sauces I used to cook Thai and Vietnamese food also contained verboten ingredients. When you start this diet, I strongly urge you to look at the labels of everything in your kitchen and discard anything that doesn’t qualify. Most sources recommend doing the diet for thirty days to determine efficacy and using one unapproved ingredient in that time period can really make it hard to tell if it’s helping.

Another big no-no is leftovers, but again there isn’t a real consensus. Not being able to cook meals for an entire week really threw a wrench into my schedule. I used to cook two meals on Sunday and eat the leftovers all week. As a microbiologist, I can verify that bacterial degradation of meat begins quite soon after it’s done cooking and this generates histamine as a side product. So no meat leftovers seemed like a good idea to me. I had to trial other types of leftovers to see what I tolerated.

I eventually got to a decent place with this diet where I was spending more time preparing than before but not a ridiculous amount. This is what that looks like.

I juice a lot. I started juicing this past winter. I am not particularly sensitive to taste so I just chop up a bunch of stuff ahead of time and throw it in. I juice one large mason jar of chopped veggies and one small mason jar of chopped fruit in the morning on weekdays. This gives me about a full 8 oz glass. I chop all the veggies at once and set up the mason jars in the fridge for the whole week. It takes about 45 minutes. Vegetables include carrots, parsnips, celery, celeriac, fennel, parsley, kale, arugula, cucumbers and beets. Beets give me energy, and this is apparently a well known phenomenon. I use ¼ beet per juice because more than that gives me cramps. Fruits include apples, pears, mango, star fruit, passion fruit, pomegranate, longan fruit, lychee, rambutan, and kiwis. I sometimes add ginger. I’m not very sensitive to taste, but if it tastes really bad, I just add a little pomegranate juice and it covers it. So that’s usually what I do for breakfast.

Other breakfasts include apples or pears with honey and peanut butter, scrambled eggs, hash browns or home fries (potato or sweet potato) with onion and black pepper, and Applegate chicken and apple or chicken and maple breakfast sausages.

If I forget to pack a lunch and have to go to work, I eat one of the following: apples and peanut butter, mozzarella with yeast free crackers, or multiple pieces of fruit. I can get these items at a nearby supermarket and they are safe fall backs for me.

If I have some time to prepare food, I usually bring with me one of the following: mashed potatoes with salt and butter, sweet potato casserole, saffron rice, mixed cooked vegetables, various versions of daal (lentil dishes, I usually also add chickpeas) and sometimes yeast free flat bread. I can prepare any of these meals and eat them for the following two days without a problem (so if I cook on Sunday, I can eat it Sunday, Monday and Tuesday). This is really helpful. I store them in mason jars and stick them in the fridge. Some people find it is better for them to freeze anything they don’t eat immediately and then thaw and eat it when they choose. I don’t do well with that.

For dinner, I generally have mashed potatoes and an Applegate chicken and apple sausage. I peel and dice two medium, yellow organic potatoes and add to small pot of boiling water. I then put the sausage in its own small pot of boiling water and both are done in about ten minutes. Quick and easy. Sometimes I use a little turnip instead of the second potato and whip it with butter and sage.

If I’m feeling more adventurous or have more time, I have some other dinner dishes. Saffron chicken and rice is really good. I buy organic meat and eat it the day I bought it. Any meat not eaten is either given to someone who can eat it or thrown away. This also includes anything cooked directly with meat, like the rice in the saffron chicken and rice.

Squash risotto is good. Squash lasagna is good. I eat a lot of squash. I make decent squash soups. There are many different types of squash so if you can eat squash, you can often get a lot of variety in taste and texture with squash. Sometimes I candy squash and beets and walnuts with brown sugar, salt and maple syrup. I can eat the risotto and lasagna for two days after cooking and I can successfully freeze and thaw the squash soup.

I strongly recommend making your own stock, both because it is much cheaper and also because it is much safer for mast cell patients who react to lots of foods. I boil down entire bones. I get bones from an organic food store or keep the bones from something I have cooked (like turkey or chicken). I soak the bones in cold water with the juice of one lemon for a few hours. While I’m doing that, I cook celery, carrots, onions and garlic in butter in a large pot. I add the bones and cold water to that pot. I add quartered onions, turnips and potatoes and whatever miscellaneous veggie odds and ends I have. I season it and add water until it’s about an inch from the top, then turn the heat down really low. Every couple of hours, I remove the debris that has floated to the top and stir the pot. I add more water as needed. I cook it for about twenty four hours, then pour it (with funnel) into mason jars and freeze immediately. This stock is really soothing on my GI tract when it has that burny type of pain.

For snacks, I usually eat peanut butter or potato chips. Plain potato chips are generally safe for me. I will sometimes indulge in chocolate or ice cream if I’m not pushing my luck already that day. I can eat most versions of Rice Krispies treats safely. I can eat cake if I make it (and the frosting) myself. I have some low histamine cookie recipes. I make my own low histamine hummus (I tolerate tahini okay, so sometimes I include it and sometimes I don’t) and will eat that with carrot and cucumber spears.

I really enjoy salads but my GI tract has a hard time with them so I am only recently eating them again. I make salads with lettuce or a green that’s not spinach, cucumbers, lots of chickpeas, black olives (safe for me) and a hummus based salad dressing. It’s pretty good. I pack the salads up in mason jars and the lettuce stays crunchy for a few days.

Eating low histamine can really be a royal pain in the ass because of how much work goes into food prep. However, if you can identify some quick items for when you’re really not feeling well or out of your house, it will seem a lot less stressful. Knowing that I can get a Rice Krispies treat at Starbucks to hold me over until I get home helps a lot. Finding out I can eat some Applegate products which can be prepared in a few minutes has made my life much less stressful. It is really difficult in the beginning because you have to check everything and cook everything from scratch, but once you get in a routine it’s not that bad.



April 2015: Post summaries and take home points

Chronic urticaria and angioedema: Part 1

  • Urticaria is the medical term for hives.
  • Hives are usually called by allergic processes, but can occur for other reasons.
  • Angioedema is swelling in the dermis, subcutaneous tissue, mucosa and submucosa. It is sort of “inside hives”.
  • Angioedema can be dangerous, especially if it affects the airway.
  • Urticaria and angioedema are closely related.
  • If acute, they last for less than six weeks. If chronic, they last for more than six weeks.
  • Acute urticaria is usually due to activation of mast cells and basophils.
  • Antihistamines and brief courses of steroids usually manage acute urticaria.
  • Chronic urticaria usually does not have an identifiable cause.
  • CU patients can have urticaria and angioedema, either alone or together.
  • Cutaneous mast cells drive CU and histamine is the most important mediator.
  • CU is rarely IgE mediated.
  • CU is associated with several chronic conditions, including autoimmune diseases, neoplastic diseases and thyroid disease.
  • 30-50% CU patients make IgG antibodies to the IgE receptor.
  • 5-10% CU patients make IgG antibodies to the IgE molecule.


Chronic urticaria and angioedema: Part 2

  • CU lesions are swollen pink or red wheals of variable size, sometimes with surrounding redness.
  • CU lesions are itchy rather than painful or burning.
  • Angioedema is not itchy, is non-pitting and without redness.
  • Physical urticarias are triggered by environmental sources. There are many types.


Prostaglandin E2, mast cells and asthma

  • Prostaglandin E2 has inflammatory and anti-inflammatory effects in the body.
  • PGE2 induces fevers and has many other functions.
  • PGE2 can cause mediator release from mast cells.
  • PGE2 can enhance IgE production by B cells.
  • PGE2 relaxes the smooth muscle and opens the airway.
  • When asthmatics take NSAIDs, their asthma often worsens due to interfering with production of PGE2.


Mast cell mediators: PGD2

  • Prostaglandin D2 is the dominant prostaglandin made by mast cells.
  • It has many functions, including regulation of sleep and perception of pain.
  • 9a,11b-PGF2a is a breakdown product of PGD2. Both can be tested for in urine as markers of mast cell disease.
  • PGD2 is a strong bronchoconstrictor and is important in asthma.
  • PGD2 is involved in nerve pain via the COX-1 pathway.
  • Aspirin is commonly used in mast cell patients to inhibit production of PGD2. This protects against PGD2 from both COX-1 and COX-2 pathways.
  • PGD2 causes characteristic mast cell flushing.


Prostaglandins and leukotrienes

  • Prostaglandins, thromboxanes and leukotrienes are all types of eicosanoids.
  • Eicosanoids are made from arachidonic acid.
  • COX-1 and COX-2 are enzymes that make prostaglandins.
  • 5-LO (lipoxygenase) makes leukotrienes.
  • Non steroidal anti-inflammatories interfere with COX-1 and/or COX-2, depending on the medication. This interferes with production of prostaglandins.
  • Zileuton is a lipoxygenase inhibitor and interferes with production of leukotrienes.


Mast cell medications: Everything but antihistamines

  • Mast cell stabilizers interfere with structures on the cell membrane that prevent with release of mediators.
  • Beta-2 adrenergic agonists relax smooth muscles and open airways.
  • Leukotriene receptor antiagonists interfere with function of leukotrienes.
  • 5-lipoxygenase inhibitors prevent production of leukotrienes.
  • Corticosteroids interfere with activity of mast cells and production of mediators.
  • Proton pump inhibitors reduce gastric acid.


Mast cell medications: Antihistamines by receptor activity

  • H1 antihistamines turn off the H1 receptor. This helps with many symptoms.
  • H2 antihistamines interfere with action of the H2 receptor. This helps mostly with GI symptoms, but also skin symptoms.
  • H3 antihistamines modulate nerve pain and may normalize levels of neurotransmitters like serotonin.
  • While three medications are known to have H3 activity, they are not designed for this purpose and have serious risks.
  • Thioperamide is promising as an H3 and H4 blocker, but is not yet available for patient use.


Mast cells in nerve pain

  • Mast cells are heavily involved in the generation and sensation of pain.
  • Chronic pain has been associated with mast cell degranulation.
  • Hyperalgesia, exaggerated pain response, is associated with mast cells.
  • Histamine may be important in hyperalgesia.
  • Mast cells can transmit nerve pain signals.
  • Overly sensitive and painful skin can also be caused by mast cells.


What do all these words mean? (Part 1)

  • A neoplasm is an abnormal group of cells.
  • SM is a neoplasm.
  • Receptors are proteins on the outside of cells that bind specific molecules. This causes a specific action to occur.


What do all these words mean? (Part 2)

  • CD117 (CKIT) is a normal marker found on the outside of mast cells.
  • CD117 is sometimes not seen on the outside of mast cells in biopsies because the test is not very sensitive.
  • Being CD117 positive in a biopsy is not the same as being CKIT positive.
  • Being CKIT positive affects options for chemotherapy and disease classification.
  • CD25 and CD2 are abnormal markers on the outside of mast cells linked to SM.
  • CD30 is sometimes positive on mast cells in SM.
  • CD34 is a marker of cells that become mast cells, and on new mast cells.



Mast cells in vascular disease: Part 1

  • Mast cells cause formation, progression and destabilization of atherosclerotic lesions.
  • Mast cell released histamine can cause coronary spasms.
  • Histamine can cause acute coronary vasoplasm that results in heart attack. This is called Kounis Syndrome.


Mast cells in vascular disease: Part 2

  • Chymase is a mast cell mediator that participates in blood pressure regulation.
  • Chymase release can make atherosclerotic plaques unstable.
  • Mast cell activation increases size of atherosclerotic plaques.
  • Atherosclerosis is not known to be elevated in mastocytosis.
  • Cardiovascular symptoms are common in mastocytosis.
  • Some mastocytosis patients have vascular instability.


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

  • PAF is released by many cells.
  • PAF receptors are on many cells.
  • PAF causes airway constriction and is heavily linked to asthma.
  • PAF induces leukotriene production.
  • PAF is correlated to severity of anaphylaxis.
  • PAF causes mast cell degranulation and increased release of PGD2.


Anti-inflammatory properties of H1 antihistamines

  • Some H1 antihistamines have anti-inflammatory properties.
  • They reduce eosinophil accumulation near allergic sites.
  • Some H1 antihistamines inhibit bradykinin induced formation of hives.
  • H1 antihistamines have also inhibited allergy processes of methacholine and platelet activating factor.


Pharmacology of H1 antihistamines

  • When histamine binds to the H1 receptor, it keeps the receptor “turned on”, causing symptoms.
  • H1 antihistamines prevent histamine from “turning on” the H1 receptor.
  • First generation H1 antihistamines cross the blood-brain barrier, which can interfere with sleep-wake cycle, memory, cardiovascular regulation and cause other effects.
  • First generation H1 antihistamines also bind to other types of receptors.
  • Second generation H1 antihistamines only bind to the H1 receptor.
  • Second generation H1 antihistamines do not cause sedation or the neurologic issues seen in first generation H1 antihistamines.


Circadian rhythm of mast cells

  • The circadian clock is the “body’s clock”. It tells the body what to do on a 24 hour cycle.
  • Mast cells and eosinophils have internal clocks.
  • Allergic symptoms, including pulmonary ones, are worse between midnight and morning, with onset around 10pm.
  • This causes sleep disruption, morning attacks”, poor rest and decreased quality of life.
  • Circadian rhythm affects mast cell mediator release.
  • Tryptase and histamine are lower in the afternoon and higher at night.
  • A signal from adrenal glands “starts the clock”.


Mast cell inhibitory effects of some microorganisms

  • Some organisms decrease mast cell mediator release.
  • Some of these organisms can cause disease and some are harmless.
  • Lactobacillus and Bifidobacteria are healthy bacteria that inhibit mast cell degranulation and activation.




March 2015: Post summaries and take home points

Allergic effector unit: The interactions between mast cells and eosinophils

  • Eosinophils are white blood cells that have granules like mast cells.
  • Mast cells and eosinophils are often found together in late and chronic stages of allergic inflammation.
  • Mast cells, eosinophils and their effects on the body are collectively called “the allergic effector unit”.
  • Mast cells release signals that affect eosinophil behavior and receive signals from eosinophils. The reverse is also true.
  • Mast cells and eosinophils can activate each other and cause mediator release.
  • Eosinophils make mast cells more responsive to IgE.
  • When mast cells and eosinophils are in contact, eosinophils live longer than usual.


Mast cell mediators: Sphingosine-1-phosphate

  • S1P is involved in development of vessels, vascular permeability and immune function.
  • Receptors for S1P are found on many cell types, including mast cells.
  • When the IgE receptor on mast cells is stimulated, S1P is produced and secreted.
  • Histamine can stimulate S1P production.
  • S1P regulates blood pressure and heart rate.
  • S1P is involved in anaphylaxis recovery and probably helps to counteract low blood pressure.


Allergic to infections: Other behaviors of toll like receptors

  • Toll like receptors (TLRs) are receptors that bind products from bacteria, fungi and viruses to fight infection.
  • TLRs are found on mast cells.
  • When TLRs are bound, mast cells secrete inflammatory molecules like TNF, IL-6, IL-13 and IL-1b.
  • TLRs function independently of IgE.


Leptin: the obesity hormone released by mast cells

  • Leptin is a hormone mostly released by adipose tissue, but also by mast cells.
  • Leptin is a “starvation” signal sent to the brain.
  • Patients with obesity have higher circulatory leptin than those without obesity.
  • Patients with obesity are more resistant to the effects of leptin, so they often feel hungry even if they have eaten.
  • Leptin actives inflammatory cells and induces production of TNF, IL-2 and IL-6.
  • Leptin suppresses signals from the IgE receptor to make mediators.
  • High levels of leptin may suppress ghrelin, the “hunger” hormone.


Allergic to infections: How bacteria, viruses and fungi activate mast cells

  • TLRs are found on several cell types, including mast cells.
  • Unlike many receptors that only have one “matching” molecule, TLRs bind lots of molecules.
  • These molecules are usually from infecting organisms.
  • Some molecules induce production of cytokines.
  • Some molecules, like peptidoglycan from bacterial cell walls, may induce degranulation.
  • Viral, fungal and bacterial infections can all cause mast cell activation.


Diabetes, steroids and hypoglycemia

  • High levels of glucocorticoids deplete mast cell populations.
  • Glucocorticoids interfere with production and release of stem cell factor, a mast cell growth factor.
  • Glucocorticoids decrease mast cell growth and activity.
  • The mechanism by which this occurs is thought to involve insulin.
  • Insulin activates mast cell signaling pathways.
  • Activity in the HPA axis, which regulates steroid levels, is increased in type I and II diabetes, causing elevated cortisol.
  • Hypoglycemia can cause mast cell degranulation.
  • Anaphylaxis can cause hypoglycemia.


Diabetes, mast cells and allergic disease

  • Type I and II diabetes can protect against anaphylaxis and allergic reactions.
  • Mast cells are involved in development of glucose intolerance and insulin resistance.
  • In mice with type II diabetes, mast cell stabilizers protects against glucose intolerance and insulin resistance.
  • In a patient with type II diabetes, treatment with cromolyn normalized plasma glucose and A1C.
  • Type I diabetes has a more complicated relationship with mast cells.
  • Diabetes reduces mast cell degranulation.


Questions on bone involvement

  • Osteosclerosis is hardening of the bones.
  • Osteoblast is the cell type that makes new bone.
  • In osteosclerosis, osteoblasts may lay down new bone faster than osteoclasts can eat up old bone.
  • Osteolysis occurs when abnormal cells grow rapidly and inhibit osteoblasts, and osteoclasts do not work fast enough.
  • It is not clear if having osteosclerosis makes progression of SM more likely.
  • People with all forms of SM have been found ot have osteosclerosis.
  • Osteosclerosis with swelling of liver and spleen, presence of CKIT mutation in multiple cell types and high increase of baseline serum tryptase warrants careful monitoring.
  • For mast cell disease, large osteolytic lesions are the “worst” bone involvement because it immediately classifies you as ASM.
  • Multiple bone breaks due to severe osteoporosis also classifies you as ASM.


Bone involvement in ISM, SSM, SM-AHNMD and ASM: More literature review (part 3)

  • Osteoporosis is the most common form of bone involvement in SM.
  • Osteoporosis is more common in mast cell patients than in the general population.
  • Patients with rapidly increasing serum tryptase and those without have similar incidence of osteoporosis.
  • Patients with rapidly increasing serum tryptase were more likely to develop osteosclerosis during the period of the study.


Bone involvement in ISM, SSM, SM-AHNMD and ASM: Literature review (part 2)

  • Overall, about half of SM patients have bone involvement.
  • Markers associated with both bone resorption and bone formation were higher in mastocytosis patients.
  • Osteoprotegerin is higher in mastocytosis patients. This protein regulates the activity of osteoclasts.
  • Levels of c-telopeptide were significantly higher in patients with SM-AHNMD and ASM than in ISM or CM.
  • Presence of skin lesions does not change risk for osteoporosis.
  • Bone mineral density and serum tryptase do not correlate with serum markers of bone turnover.


Bone involvement in SM (ISM, SSM, SM-AHNMD, ASM): Clarifications (part 1)

  • In osteosclerosis, your body makes new bone faster than it resorbs it.
  • In osteoporosis, your body resorbs bone faster than new bone is made.
  • In osteolysis, your body resorbs bone faster than new bone is made, but much worse than in osteoporosis.
  • Both osteoporosis and osteolysis can cause pathological fractures.
  • Osteoporosis does not classify you as having ASM.
  • Osteoporosis that caused multiple fractures classifies you as having ASM.




February 2015: Post summaries and take home points

How to activate mast cells: Complement protein C3a

  • The complement system is part of the immune system. It allows infecting organisms to be more readily found and destroyed by the immune system.
  • Mast cells express a receptor for C3a, a fragment produced during activation of the immune system.
  • C3a is an anaphylatoxin. It participates in exaggerating the anaphylactic response.
  • C3a increases vascular permeability, causes smooth muscle contraction, and draws white blood cells to inflamed spaces.
  • In mucosal mast cells (GI mucosa), C3a inhibits histamine and TNF release.
  • In serosal mast cells (skin, peritoneum, respiratory tract), C3a induces degranulation when stimulated by IgE or IgG.
  • Inhaled allergens activate complement system in mucosa of respiratory tract, resulting in formation of C3a.
  • Tryptase can change C3 to C3a.


Corticotropin releasing hormone, cortisol and mast cells

  • The term HPA axis refers to the mechanisms by which the hypothalamus, pituitary gland and adrenal glands control each other.
  • The HPA axis regulates many things, including the stress response, immune modulation, emotions, sexuality and digestion.
  • The hypothalamus is in the brain. It turns signals from the nervous system into endocrine signals that allow changes by using hormones.
  • The hypothalamus makes corticotropin releasing hormone (CRH).
  • The pituitary gland makes and releases many hormones, including adrenocorticotropic hormone (ACTH), thyroid stimulating hormone, growth hormone and others.
  • When the pituitary gland receives signals from the hypothalamus, it releases these hormones.
  • CRH from the hypothalamus stimulates the pituitary to produce ACTH.
  • The adrenal glands make and release cortisol, epinephrine, norepinephrine and other molecules in response to hormones from the pituitary.
  • ACTH from the pituitary stimulates the adrenals to produce cortisol.
  • Cortisol tells the hypothalamus to stop releasing CRH and the pituitary to stop making ACTH.
  • Taking steroids regularly suppresses ACTH so your body stops making its own steroids. This is weaning steroids is important.
  • CRH is released in response to stress, such as anaphylaxis.
  • CRH can bind to mast cells and cause release of VEGF.
  • CRH is also released by mast cells.



January 2015: Post summaries and take home points

Mast cell mutations: JAK2 and myeloproliferative neoplasms

  • JAK2 is a helper protein that helps other molecules send signals to make more cells and to increase inflammation.
  • JAK2 mutation V617F makes some cells more responsive to growth factors, so they grow too much. These cells include red blood cells, platelets and mast cells.
  • Marker associated with other myeloproliferative diseases essential thrombocythemia (too many platelets), polycythemia vera (too many red blood cells), myelofibrosis (fibrosis of bone marrow).
  • About 5% of SM patients have JAK2 V617F mutation. Indicates higher probability of developing another myeloproliferative disease.
  • Doesn’t necessary mean lifespan is shorter.

Heritable mutations in mastocytosis

  • About 75% of MCAD patients have at least one first degree relative with MCAD.
  • The CKIT D816V mutation is not known to be heritable, but other CKIT mutations have been found in multiple family members.

Progression of mast cell diseases (Part 1)

  • Life expectancy with indolent systemic mastocytosis (ISM) is normal.
  • Average age at diagnosis of ISM is 49.
  • Type and severity of symptoms vary and do not correlate with disease type, presence of CKIT D816V mutation or tryptase level.
  • Mediator related symptoms are not indicative of aggressive or progressing disease.
  • Organ swelling is not always indicative of ASM. Organs can be swollen for many years without functional damage or C findings.

Progression of mast cell diseases (Part 2)

  • 5-10 years from diagnosis with ISM, 1.7% of patients progressed to SSM/ASM.
  • 20-25 years from diagnosis with ISM, 8.5% of patients progressed to SSM/ASM.
  • Risk of transformation of ISM to acute leukemia or ASM was less than 1% and 3% respectively.
  • ASM and MCL are associated with accumulation of neoplastic mast cells in organs, impairment of organ function, drug resistance, poor prognosis and organ failure.
  • In most SSM patients, disease stays stable over years or decades.
  • SSM patients have higher incidence of anemia, constitutional symptoms and mast cell mediator levels than ISM patients.
  • SSM is diagnosed later than ISM, around 64 years.
  • ASM can be slow progressing and stable for many years or rapidly progressing.
  • During progression of ASM and MCL, some patients lose the CKIT D816V mutation.
  • Slow progression ASM can be kept under control for several months or even years with interferon and cladribine.
  • In a group of 342 patients, 0.6% ISM patients developed MCL or AML, 6.5% ASM, and 13% SM-AHNMD.
  • It is possible for disease to convert to less severe category.

Progression of mast cell diseases (Part 3)

  • Mast cell accumulation is mostly due to decrease in apoptosis (cell death) rather than excessive proliferation.
  • 20-30% of SM patients have tryptase below 20 ng/ml.
  • If you test negative for CKIT D816V in blood, you may still be positive.
  • Bone marrow test for CKIT D816V is most accurate.
  • Histamine intolerance has been proposed as deficiency of enzymes to metabolize histamine. There is no evidence that this occurs in mast cell disease.
  • 33% of MCAS patients are positive for elevated tryptase, 56% n-methylhistamine, 44% PGD2.
  • 66% of patients with MCAS have major or complete regression in symptoms after one year of treatment.

Progression of mast cell diseases (Part 4)

  • ISM is not life threatening in and of itself. Anaphylaxis, a symptom of ISM, is life threatening.
  • 49% of SM patients experience anaphylaxis in their lifetime. 48% of anaphylaxis episodes in ISM patients were severe.
  • There is no consensus on what is a normal count of mast cells in GI tract. Some healthy patients have more than 20 mast cells/hpf.
  • Most patients with adult onset cutaneous mastocytosis also have systemic mastocytosis.
  • Early studies indicated CM and MCAD were different, but frequency of CKIT mutations the same in patients with CM, SM and MCAS (about 86% in each group in one study). NOTE: The CKIT mutations were not always the D816V mutation.
  • Patients with MMAS (monoclonal mast cell activation syndrome) and MCAS (mast cell activation syndrome) never have CM.
  • ASM and MCL patients frequently lack CM.

Progression of mast cell diseases (Part 5)

  • 55% of pediatric mastocytosis cases occur in the first two years of life.
  • 35% occur between ages of 15 and 18.
  • Cutaneous mastocytosis can result in mediator release symptoms without having systemic mastocytosis.
  • 2/3 of childhood mastocytosis patients had complete resolution of cutaneous disease and symptoms before adulthood. They were not treated with steroids, PUVA or chemo drugs.
  • Bone marrow biopsies of children with CM often show more mast cells than normal. High bone marrow mast cells in these children does not affect resolution.
  • In a study of 50 pediatric CM patients, 86% had a CKIT mutation and36% had the D816V mutation.

Mast cell mutations: TET2 and mutation profiles of aggressive subtypes

  • TET2 is mutated in 20.8-29% of SM patients.
  • Several mutations are seen.
  • TET2 is involved in DNA methylation which affects gene expression.
  • 96% of SM patients with major blood abnormalities had mutations in at least two genes regardless of SM subtype.

Mast cell mutations: SRSF2 in SM-AHNMD

  • SRSF2 is a protein that affects gene expression.
  • An SRSF2 mutation was found in 24-37% of SM patients.
  • Most common mutation in SM after CKIT D816V.
  • Strongly associated with SM-AHNMD.
  • Also found in other cell types besides mast cells. In SM-AHNMD, may cause both mast cell disease and associated blood disorder.

Anticholinergic use and dementia

  • People who took higher amounts of anticholinergics had an increased risk of dementia.
  • Some medications used to treat mast cell disease are strong anticholinergics, like diphenhydramine and doxepin.
  • It is not clear if the medications caused dementia or if the conditions that required those medications caused dementia.

Mast cells in wound healing

One of the most well described non-allergic functions of the mast cell is wound healing. Mast cells are involved in many functions integral to remodeling and closing wounds.

Immediately following formation of a wound, signals are sent to constrict vessels near the injury to decrease the risk of bleeding and infection. After bleeding has been minimized, the blood vessels become a little more permeable to let cells and molecules from the bloodstream into the injured area in order to promote healing and prevent infection. These actions activate the complement clotting system, which produces molecules C3a and C5a. These molecules bind to mast cells and induce degranulation.

Following degranulation, vessels become more permeable through the action of histamine and other mediators. Fibrinogen, important in clot formation, leaves the blood stream and accumulates in the tissue. This triggers thrombin to change fibrinogen to fibrin, forming a clot. Mast cells are active in preventing excessive clotting. Tryptase and heparin are released from granules bound together, and this complex degrades fibrogen and inactivates thrombin.

The extracellular matrix is the structures which give substance to groups of cells and vessels. Following wound formation, fibronectin and type III collagen molecules gather near the injury. Mast cell proteases chymase and tryptase break down the extracellular matrix molecules to make room for newly made cells to close the wound. It is also possible that mast cell mediator CMA1 breaks down fibronectin.

Granulation tissue forms when wounds are healing. Granulation involves several activities, such as cell proliferation, develop of blood vessels, and building of new skin. Fibroblasts, which make collagen and extracellular matrix molecules, are drawn to the injury by mast cell signaling. Once there, they are induced to proliferate by action of the presence of histamine, tryptase, heparin and fibroblast growth factor. Mast cell degranulation also drives generation of new blood vessels through action of histamine, heparin, chymase, fibroblast growth factor, VEGF and tumor necrosis factor. Formation and proliferation of new epithelial tissue is also encouraged by TGF-b1, histamine, IL-1a, IL-1b, IL-6, tryptase, and heparin.

Once enough new cells have been made, the fibroblasts become myofibroblasts to make new muscle. Histamine and tryptase mediate this step. The fibroblasts directly interact with mast cells. Mast cell proteases tryptase and chymase trigger the activation of several molecules that mediate remodeling of the extracellular matrix. The wound is closed following this remodeling and laying down of new skin.


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.

Christine Möller Westerberg, Erik Ullerås, Gunnar Nilsson. Differentiation of mast cell subpopulations from mouse embryonic stem cells. Journal of Immunological Methods 382 (2012) 160–166.




The high water mark

I spent most of the latter half of May in bed. People woke me up take medication on schedule and I fed myself small meals periodically. I watched movies and TV and drifted in and out of sleep, pain killers and Benadryl making the world soft around the edges.

Every day, even as I felt myself healing, my strength and stamina waned. My legs felt weak when I stood up. I got winded walking around the block. Holding my head up felt difficult. All of the stamina I had built up before surgery was gone. All of my progress was undone.

I spend so much energy trying to get somewhere I’m never going to get – to this place of physical health where I can exercise and sleep at night and wake in the morning without bleary eyes and a pounding headache. I have been trying to reach this milestone since well before I knew I was sick.

I’m not even sure I know the closest I ever came. What is the highwater mark of this particular struggle? Was it the few weeks before my last birthday when I was sleeping at night and waking without an alarm? Or that really good day last September? The few weeks after my colostomy healed? I don’t know. I’m not sure there is a high water mark. Everything is relative.

Living with a sickness that causes regular setbacks – and requires treatments that sometimes do the same – is difficult. This halting start has become a sort of rhythm, the timing an inherent part of this experience. I’m never getting anywhere. I’m always getting it wrong. It feels like if I could do the right things in the right order that it would make a difference. `

But what if every time I started again, it didn’t mean that every time before was a failure? All those times before, all the moves in the wrong order, kept me alive and participating in the world. How wrong could they be? What if the high water mark of this struggle is just being alive?

Reversing the ostomy was the right move. I am noticeably less inflamed and my body is responding. I am having fewer reactions. I am eating without vomiting. The squishiness, the swelling weight is melting away so I can see the features beneath. I am still in pain, but I think I always will be.

I’m getting stronger. It’s slow, but it’s happening. I can walk for twenty minutes now, Astoria happily padding along beside me. I’m short of breath and sweaty when I’m done, but I can do it.

Maybe it’s time to stop blaming myself for all the times I had to start over. Maybe it’s time to see these setbacks as opportunities to understand my body and learn from it.

Maybe this is enough.


Angioedema: Part 4

Deficiencies of an early component of the classical complement pathway (C1q, C1r, C1s, C2, C4) have been associated with lupus like autoimmune conditions. The reason for this is that these proteins help to clean up large groups of molecules called immune complexes before they can cause inflammation. Dead cells are also removed by these complement molecules. Without these proteins, immune complexes and dead cells are not removed and cause local irritation.

In HAE types I and II, complement proteins C2 and C4 are low. However, HAE patients have been shown to have a normal level of immune complexes. For this reason, it is still unclear whether or not low C2 and C4 may contribute to overall inflammation and pain profile for these patients. Despite this fact, it is still possible that deficiency in C2 and C4 may predispose HAE patients to autoimmune diseases.

A number of studies have assessed the prevalence of autoimmune conditions in HAE patients. One study looked specifically for two thyroid antibodies and found that 13.2% HAE patients had autoantibodies to the thyroid.

When expanding the autoimmune profile to include “lupus-like” conditions such as those often associated with complement deficiencies, a much higher prevalence of autoantibodies was found in HAE patients. Three other studies measured the frequency of ANA (anti-nuclear antibody, a generic marker found in many autoimmune conditions); RF (Rheumatoid Factor, associated with rheumatoid arthritis); anti-thyroglobulin(autoimmune thyroiditis); TPO (thyroid peroxidase, autoimmune thyroiditis); and thyroid antibodies along with some or all of the following antibodies: anti-dsDNA (anti double stranded DNA, systemic lupus erythematosus); ENA (extractable nuclear antigens, a panel of six tests that can identify mixed connective tissue disease, systemic lupus erythematosus, Sjogren’s, Scleroderma and dermatomyositis); TMA (microsomal antibodies, autoimmune thyroiditis); AMA (antimitochondrial antibodies, drug-induced or systemic lupus erythematosus, Sjogren’s, autoimmune hemolytic anemia, autoimmune liver disease); ANCA (antineutrophil cytoplasmic antibodies); anti-cardiolipin (systemic lupus erythematosus, Behcet’s, antiphospholipid syndrome); anti-b2GPI (b2-glycoprotein I, systemic lupus erythematosus, Behcet’s, antiphospholipid syndrome); anti-C1q (urticarial vasculitis); anti-P ribosomal (systemic lupus erythmatosis); EMA (anti-endomysial antibodies, Celiac disease); tTG (anti-tissue transglutaminase antibodies, dermatitis herpetiformis); and ASCA (anti-saccharomyces cerevisiae antibodies, Behcet’s, Celiac disease, Crohn’s disease, ulcerative colitis). The three studies found that 47.5-48% HAE patients had at least one of these autoantibodies. In comparison, the average for healthy controls was 10%.

Other studies looked at prevalence of autoimmune disease rather than autoantibodies. One study found that 12% of HAE patients had at one of the following autoimmune conditions: glomerulonephritis, Sjogren’s syndrome, irritable bowel disease, thyroiditis, systemic lupus erythematosus, rheumatoid arthritis, drug induced lupus, pernicious anemia, juvenile RA with IgA deficiency, or sicca syndrome.

Other studies found that 3.4% HAE patients had lupus rash or glomerulonephritis; that 0.9% had RA or Sjogren’s; that 11.5% had Crohn’s, Celiac, Hashimoto’s thyroiditis, discoid lupus erythematosus, chronic lymphocytic leukemia, MGUS, or IgA deficiency; that 11.4% had systemic lupus erythematosus, Celiac, multiple sclerosis-like syndrome, systemic sclerosis, or mixed connective tissue disease; that 4.2% had lupus like syndrome, psoriatic arthritis, mixed connective tissue disease or antiphospholipid syndrome; that 0.4-0.9% had lupus-like or unspecific cutaneous lupus or subacute lupus.

An interesting feature of HAE is the frequent complaint of decreased sense of smell. Facial edema and chronic rhinosinusitis were not found to be the cause. However, systemic lupus erythematosus and Sjogren’s syndrome can also cause impairment of smell. Despite the frequency of lupus in HAE patients, it usually affected the mucocutaneous regions of the body and was generally mild.

In addition to the frequent prevalence of autoantibodies and autoimmune disease, HAE patients have increased B cell activation and autoreactive B cells. This can also contribute to an inflammatory and autoimmune profile.



Kaplan AP, et al. Pathogenic mechanisms of bradykinin mediated diseases: dysregulation of an innate inflammation pathway. Adv Immunol 2014; 121:41-89.

Kaplan AP, et al. The plasma bradykinin-forming pathways and its interrelationships with complement. Mol Immunol 2010 Aug; 47(13):2161-9.

Firinu, Davide, et al. Characterization of patients with angioedema without wheals: the importance of F12 gene screening. Clinical Immunology (2015) 157, 239-248.

Csuka, Dorottya, et al. Activation of the ficolin-lectin pathway during attacks of hereditary angioedema. J Allergy Clin Immunol 134 (6) 1388-1393.e3.

Triggianese, Paola, et al. The autoimmune side of hereditary angioedema: insights on the pathogenesis. Autoimmunity Reviews 2015 (ahead of press).