There are 5 parts to the question.

Patient Medical History

Georgia is a 32 year old woman who has been suffering fromrecurrent (sometimes severe) headaches, and periods of fatiguesince late childhood (~10-11 years of age). In her early twenties(21 years of age) she was diagnosed with gastroesophageal refluxdisease (GERD) and began to experience periods of unexplainedabdominal pain.

Georgia’s symptoms have waxed and waned over times, sometimesshe feels fine but other times (since ~10-11 years of age) theheadaches, fatigue and abdominal pain (since ~21 years of age) seemoverwhelming. Lately the fatigue and abdominal pains have beenparticularly bad.

Georgia is afraid to eat because she does not know when theabdominal pain will strike or what is causing it. She has begun tolose weight but her food restriction has not addressed the pain.Regardless of whether she has eaten a large or small meal, andregardless of ingredients the pain can occur.

Georgia’s doctor performed several tests and noticed symptoms ofinflammation in some areas of the intestine, after ruling out otherconditions her doctor has suggested Georgia may have InflammatoryBowel Disease (IBD). However, IBD would not explain why Georgiasometimes experiences upper abdominal pain or why the location ofthe pain seems to move around different areas of the abdomen.

Georgia feels tired all of the time; the amount of sleep shegets does not seem to lessen the fatigue. She finds morningsespecially difficult but fatigue is present throughout the day. Shefinds it difficult to concentrate and her performance at work hasbegun to suffer. She sometimes feels too tired to climb the stairsto her second floor apartment.Her doctor sent her to a sleep clinicbut an overnight sleep observation study did not find anythingabnormal.

While Georgia is most concerned with the abdominal pain andfatigue she has other symptoms as well.

Georgia's Symptoms

• Mild cognitive dysfunction (“brain fog”)
• Dermatographism
• Inflammation and pain in several joints (hips, knees, elbows,hands/fingers) and lower back pain
• Occasional flushing (noticeably red face and sometimes otherareas of the skin with no cause; different from blushing which isusually milder and caused by emotions such as embarrassment)
• Occasional diaphoresis (excessive sweating for no apparentreason usually across the whole body or multiple areas of thebody)
• Occasional mild dyspnea (shortness of breath; feeling like youcan’t get enough air)

Georgia’s doctor has consulted some colleagues who recommended afull blood work up and tests to measure the levels of some keyimmune response molecules.

Georgia's Test Results

• Mild and transient leukocytosis (transient = in blood drawn atsome times but not others)
• Mild and transient elevated serum total tryptase level(transient = in blood drawn at some times but not others)
• Elevated urinary histamine metabolites and urinary levels ofPGD2 (prostaglandin D2)

1. How might an immune response contribute to abdominalpain?

1. What common immune response involves all of the markerselevated in Georgia’s tests: tryptase, histamine and prostaglandinD2 (1 mark)?

After reviewing her tests Georgia’s doctor concludes she hasMast Cell Activation Syndrome (MCAS), a disease characterized bychronic multi-system inflammation. Her doctor rules outmastocytocis (accumulation of mast cells).

Basically Georgia’s mast cell responses are too strong whichcould be because she has too many mast cells, her mast cells arehyperactive or both. Since her doctor has ruled out mastocytosisthere are not an abnormal number of mast cells.

We initially looked at white blood cells commonly found incirculation and therefore when it came to granulocytes focused onbasophils, eosinophils and neutrophils. Mast cells are alsogranulocytes but are found in tissues.

We initially looked at white blood cells commonly found incirculation and therefore when it came to granulocytes focused onbasophils, eosinophils and neutrophils. Mast cells are alsogranulocytes but are found in tissues.

1. What do granulocytes all have in common both instructure and in immune response roles ?

1. Describe the link between aberrant (too strong) mastcell responses and chronic multi-system inflammation .

In other words, how does it “make sense” – if you tell animmunologist that a chronic multi-system inflammatory disorder iscaused by overactive mast cells that explanation “makes sense”,why? (Don’t forget there are three words – chronic, multi-system,inflammation)

Dermatographism

Let’s revisit the dermatographism now that you know more aboutGeorgia’s condition.

Dermatographism is sometimes referred to as “skin writingdisease”. In people with dermatographia/dermatographismnon-pathogenic stimuli like mild scratching can cause localizedhives to quickly and transiently (temporarily) form at the site ofthe stimulation.

The immune responses that cause the “writing” are not triggeredby pathogens but by simple pressure/scratching (sometimes heat orother non-pathogenic stimuli too). However, the underlyingreactions are similar to the immune responses you’d see if aforeign particle was introduced under the skin.

This is also true for conditions like MCAS. For exampleGeorgia’s mast cells are over-reacting to a scratch on her skin butthey are still releasing all the same signalling molecules andcausing a similar reaction to ‘normal’ mast cell responses (i.e.,they might be reacting more strongly, and responding to things thataren’t dangerous but they aren’t acting radically different).

One of Georgia's symptoms was dermatographism.

1. Using what you know of the immune response and knowingGeorgia's diagnosis (MCAS) describe how her skin “writing” isoccurring. Assume that while the trigger for the response ispressure on the skin (a scratch) the response itself is “normal”(i.e., similar to what you’d see if a foreign organism was underthe skin; 5 marks). Make sure to relate the symptoms (what we'reseeing in dermatographism) to the immune response underlyingthem.

Some symptoms of MCAS occur after an easily identifiabletrigger/triggering event and some seem to appear randomly. Whethertriggers can be identified (and therefore modified/avoided) dependson the symptom and/or patient. Even those symptoms that appear“random” can still be due to a triggering event but triggers can bevariable and not always easy to identify.

For example, Georgia only notices the symptoms ofdermatographism when pressure is applied to her skin (like ascratch or wearing clothing that is too tight). She has begun towear looser clothing and is less likely to scratch at minor skinirritations. However her stomach pains seem to be random andnothing she eats or doesn’t eat impacts the presence or level ofpain.

Depending on the type and severity of symptoms, and how theyimpact a patient’s quality of life there are different treatmentoptions. Usually trying to identify and avoid triggers of mast cellresponses, when possible, is the first step. Why might avoidance oftriggers be the first step instead of trying to modify the mastcell responses (i.e., “fix” the mast cells; stop them fromoveracting)? (Hint: this is a general question, no particularpathways necessary; tie your answer into what you know of theimmune responses in general)

Like many patients, Georgia could identify triggers for some ofher symptoms and not others. Georgia’s doctor prescribed an H1 andH2 antihistamine, as well as cromoglicic acid to help lower theoveractivity of her mast cells. Georgia was also given aproton-pump inhibitor to help with the stomach pain and GERD, andtold to take acetaminophen for more general pain. She was put on abrief course of prednisone to decrease gastrointestinalinflammation but is now off the prednisone.

Georgia is feeling better and while her symptoms are not goneshe now has less acute episodes.