1. Diseases Related to Mast Cell Dysfunction
PHM Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
By: Aayushi Patel, Amy Botross, Ereny Botross & Mitali Kadakia

2. Outline: What are Mast Cells Function
Diseases Related to Mast Cell Dysfunction and Treatment:
Mastocytosis
Systemic vs. Cutaneous
Mast Cell Activation Syndrome (MCAS)
4) Summary
Mastocytosis (two types and how they differ from eachother)
Role vs function

3. What are Mast Cells?
An immune cell derived from the common myeloid lineage
A granulocyte
Leukotrienes
Prostaglandins
Histamine
Heparin
Proteases (chymase and tryptase)
Cytokines
Produced in bone marrow
Mature at tissue sites:
Host-environment interfaces
Found at the boundaries between the host and external environment such as in the stomach, intestine, skin, mucosal lining of the lungs and around blood vessels

4. Function Innate and adaptive immune system
Key player in inflammatory response: IgE mediated allergic reaction through FcϵRI → Degranulation → Amplify inflammatory response
Play a role in both the innate and the adaptive immune systems
Innate immune system: interaction between PAMPS (on the pathogen’s surface) and PRRs (pattern recognition receptors such as toll like receptors on the surface of mast cells) cause mast cell degranulation
Adaptive immune system: Upon invasion of the pathogen, B cells release IgE antibodies that go and bind to FcER1 receptors on the surface of the mast cells and upon re-exposure to that antigen, it cross links with the IgE and causes degranulation
The release of mediators bring about the hallmarks of inflammation, most common of which are vasodilaiton, and increase in vascular permeability that help recruit other immune cells (eosinophils, basophils, lymphocytes and neutrophils) from the blood stream to the target tissue. This is of course associated with the swelling, warmth and redness, the characteristics of inflammation

5. Diseases Related to Mast Cell Dysfunction
Mastocytosis
What is it?
How is it caused?
Symptoms
Two types
Systemic (SM)
Cutaneous (CM)
Mast Cell Activation Syndrome (MCAS)
Mastocytosis
What is it?
→ It is a rare disease that affects mostly the skin and other parts of the body such as the stomach, intestines and the bone marrow.
How is it caused?
→ it is caused by an abnormal accumulation of mast cells. These cells release histamine → a substance involved in allergic reactions as well as production of stomach acid resulting in mastocytosis
Symptoms include
→ red, itchy rash, rash that looks like freckles, diarrhea, and stomach pain
There are two types of mastocytosis which will be further discussed
And MCAS is the second disease that Ereny will talk about

6. Cutaneous Mastocytosis (CM)
Accumulation of mast cells limited to skin
Fixed dark red-brown macules
Subtypes of CM
Urticaria pigmentosa
Diffuse CM
Mastocytoma
Cutaneous mastocytosis primarily affects the skin. The rash appears to be dark red-brown colour. There are 3 subtypes of CM. The most common one is the presence of skin lesions of urticaria pigmentosa which is 0.5-1cm in size with a yellowish tan mainly affecting the extremities. Diffuse CM is a rare subtype mostly affecting children at birth or early infancy resulting in blisters and thick skin. Lastly, mastocytoma is a single nodular lesion appearing yellowish red. It manifests in childhood but heals spontaneously.

7. Systemic Mastocytosis (SM)
Abnormal accumulation of mast cells in various organs.
Somatic activation of kit point mutation on exon 17 – D816V. Autophosphorylation and activation of KIT receptor tyrosine kinase leading to mast cell proliferation.
Bone marrow biopsy can be used for diagnosis as bone marrow is often involved in the disease.
WHO uses B and C- clinical findings to establish the type of mastocytosis.
B-finding: organ involvement without organ failure
C-finding: organ involvement with organ dysfunction

8. Subtypes of Systemic Mastocytosis
Indolent Systemic Mastocytosis (ISM)
Most common form of SM involving skin and bone marrow occurring in adulthood
Urticaria pigmentosa seen in more than 90% of the cases.
2) Aggressive Systemic Mastocytosis (ASM)
Rare form of SM involving high infiltration of tissues of particular organs that leading to dysfunction of organs. Classified as C-finding.
IFN-α present in Prednisone is used as treatment.

9. 3) Mast Cell Leukemia (MCL)
Large number of atypical or immature mast cells present in the peripheral blood.
Rare with poor prognosis
Patients have approximately 6 months of survival time

10. Mast Cell Activation Syndrome (MCAS)
Hypersensitive mast cells
Excessive release of mediators
Asthma and Allergy
Two or more organs affected for diagnosis:
Skin, GI tract, cardiovascular, respiratory tract
Mastocytosis vs MCAS: unlike mastocytosis, MCAS does not involve elevation in the number of mast cells but rather normal levels of mast cells exhibit hypersensitivity > leads to release of too many mediators into the bloodstream > blood test show increase in serum/plasma levels of histamine, tryptase, and prostaglandins.
The main diagnostic criteria: presence of symptoms in at least 2 organs
Common symptoms include: wheezing, nasal congestion, itchiness…; patient usually suffers from a combination of symptoms

11. Treatment AntiHistamines H1 blockers (Ex: Loratadine)
b. Tyrosine kinase inhibitors: for SM
c. Topical steroids: for CM
d. Mast Cell Stabilizers: for MCAS
H1 blockers (Ex: Loratadine)
H2 blockers (Ex: Cimetidine, ranitidine)
Cromolyn sodium
Ex: Imatinib mesilate
Ex. Cromolyn, Ketotifen

12. Summary
Mast cells are granulocytes that derive from the common myeloid lineage. They are produced in the bone marrow but mature at vascularized tissue sites.
Mast cells play an important role in the IgE mediated inflammatory response.
Symptoms of Mastocytosis include: red, itchy rash, diarrhea, and stomach pain
The most common symptom of cutaneous mastocytosis (CM) is the presence of skin lesions of urticaria pigmentosa
Systemic Mastocytosis (SM) occurs in adulthood due to somatic missense mutation on kit gene - D816V. Autophosphorylation and activation of KIT receptor tyrosine kinase leading to mast cell proliferation.
Three subtypes of SM are: indolent SM, aggressive SM, and mast cell leukemia.
Mast Cell Activation Syndrome (MCAS) patients have normal levels of over-responsive mast cells > blood test shows elevated serum levels of histamines, tryptase and prostaglandins
Main MCAS diagnostic criterion: presence of symptoms in at least two organ systems (Skin, GI tract, respiratory tract, cardiovascular system)
Treatment include administration of antihistamines such as loratidine (for both), tyrosine kinase inhibitors (for SM), topical steroids (for CM), and mast cell stabilizers such as cromolyn (for MCAS)

13. References
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Kristensen, T., Vestergaard, H., & Møller, M. B. (2011). Improved Detection of the KIT D816V Mutation in Patients with Systemic Mastocytosis Using a Quantitative and Highly Sensitive Real-Time qPCR Assay. The Journal of Molecular Diagnostics : JMD, 13(2), 180–188.

14. References - Con’t
Kumar, V., & Sharma, A. (2010). Mast cells: emerging sentinel innate immune cells with diverse role in immunity. Molecular immunology, 48(1),
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