Disease linked to Mast cell Dysfunction

Nahid Wazed, Maninder Chahal, Raijivi Ranjithan, Marc-Anthony Pinizzotto

PHM142 Fall 2015Coordinator: Dr. Jeffrey HendersonInstructor: Dr. David Hampson

Outline

Background

Biochemistry

Role in diseases

Mast cell activation disorders

Mastocytosis

Mast cell activation syndrome

What are mast cells?1

Large ameboid cells

Derived from myeloid stem cells

Distributed throughout connective tissue

Many granules containing histamine, heparin

Function of mast cells2,3,4

Pathogen defense

- Innate immunity

- Adaptive immunity

Tissue repair

Angiogenesis

Immune tolerance

Function of mast cells5

Important pathways6

Activation via FcεRI receptor (and others as well)

ɑ-chain binds IgE (or other signalling molecules)

β and ɣ are responsible for signalling

Important pathway - eicosanoid production7,8,9

Molecules synthesized from arachidonic acid

Has key role in inflammatory immune response

Mast cell becomes more sensitive to degranulation from antigen presentation

Important pathway - cytokine production10,11

Releases cytokines aiding innate and adaptive immune systems

Many cytokines are released via degranulation

Sometimes associated with disease (e.g. TNF-ɑ and rheumatoid arthritis)

Important pathway - degranulation12

A mechanism to release already made cytokines (and other molecules) in response to an infection

Histamine is released in this fashion in response to an allergen

Role in diseases13

Mast cell activation diseases

Mastocytosis

Mast cell activation syndrome

Mast cell activation disease - causes and classification14

Mastocytosis occurs in two forms:

Cutaneous (most cases)

Systemic (possibly involving the bone marrow & internal organs)

c-KIT normal pathway for proliferation15

c-KIT receptor

Mast cell division

Stem cell growth factor

c-KIT gene

KIT protein

c-KIT mutation and association with Mastocytosis15,16

c-KIT gene

KIT protein

c-KIT receptor

Mast cell division

Stem cell growth factor

Mutation D816V

Mast cell disease - signs and symptoms17

Skin (80-90% reactions)Hives (urticaria)ItchFlushingMucosaItch, swelling –lips, tongue, mouth)

Airways (70% of reactions)Throat tightening, swellingLungs - chest tightness, wheeze, cannot take deep breath

Genito-Urinary tract(>10% reactions)Uterine CrampingSwelling -labia

Gastrointestinal tract (30-45% reactions)NauseaCrampingAbdominal PainVomitingDiarrhea

Heart, Blood Pressure(10-45 % reactions)Chest PainFast Heart Rate,Palpitations (pounding)Weak pulseDizzinessFainting

Brain (> 20% reactions)Sense of uneasinessHeadacheDizzinessConfusionTunnel Vision

Treatment

There is currently no cure for mastocytosis.

Treatments available for the symptoms:

Antihistamines - H1 and H2 blockers (hydroxyzine, cetirizine)

Leukotriene antagonists (singulair) Proton pump inhibitors ([H+] increased in patients with

mastocytosis) Epinephrine (for increased ventilation)Corticosteroids (reduces inflammation)

Mast cell activation disease - Allergic diseases18

What happens during an allergic response19

Role in diseases

Summary

Mast cells are granulated cells containing histamine, heparin, and various other compounds

Mast cells are involved in pathogen defense, wound healing, angiogenesis, immune tolerance, and more

A key receptor for mast cells is the FcεRI - this receptor binds to IgE

Eicosanoids are important inflammatory molecules that are created from arachidonic acid

When cytokines and eicosanoids are formed, they are stored in vesicles until the mast cell is stimulated; when stimulated, mast cells undergo degranulation where all the necessary chemicals are released via exocytosis

Mastocytosis is the proliferation of abnormal mast cells

Mutation in tyrosine kinase receptor results in signal cascade that causes abnormal mast cell proliferation

Works Cited

1. Askenase ,PhilipW. Immunopathology of parasitic diseases: Involvement of basophils and mast cells. .

2. Hardy MA. The biology of scar formation. Phys Ther. 1989;69(12):1014-1024.

3. Norrby K. Mast cells and angiogenesis. APMIS. 2002;110(5):355-371.

4. Lu LF, Lind EF, Gondek DC, et al. Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature. 2006;442(7106):997-1002.

5. Metz M, Siebenhaar F, Maurer M. Mast cell functions in the innate skin immune system. Immunobiology. 2008;213(3-4):251-260.

6. Gilfillan AM, Tkaczyk C. Integrated signalling pathways for mast-cell activation. Nat Rev Immunol. 2006;6(3):218-230.

7. Rocha PN, Plumb TJ, Coffman TM. Eicosanoids: Lipid mediators of inflammation in transplantation. Springer Semin Immunopathol. 2003;25(2):215-227.

8. Harizi H, Gualde N. The impact of eicosanoids on the crosstalk between innate and adaptive immunity: The key roles of dendritic cells. Tissue Antigens. 2005;65(6):507-514.

9. Woolley DE, Tetlow LC. Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion. Arthritis Res. 2000;2(1):65-74.

10. Bax HJ, Keeble AH, Gould HJ. Cytokinergic IgE action in mast cell activation. Front Immunol. 2012;3:229.

11. Chakravarty N. Mechanism of histamine release from isolated mast cell granules by calcium with phosphatidyl serine. Agents Actions. 1983;13(2-3):126-129.

12. Starkl P, Marichal T, Galli SJ. PLA2G3 promotes mast cell maturation and function. Nat Immunol. 2013;14(6):527-529.

13. Theoharides TC, Alysandratos KD, Angelidou A, et al. Mast cells and inflammation. Biochim Biophys Acta. 2012;1822(1):21-33.

14. Horny HP, Sotlar K, Valent P. Mastocytosis: State of the art. Pathobiology. 2007;74(2):121-132.

15. Molderings GJ, Brettner S, Homann J, Afrin LB. Mast cell activation disease: A concise practical guide for diagnostic workup and therapeutic options. J Hematol Oncol. 2011;4:10-8722-4-10.

16. Bibi S, Arslanhan MD, Langenfeld F, et al. Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: Possible new targets of therapy. Haematologica. 2014;99(3):417-429.

17. Lee JK, Whittaker SJ, Enns RA, Zetler P. Gastrointestinal manifestations of systemic mastocytosis. World J Gastroenterol. 2008;14(45):7005-7008.

18. Sicherer SH. Food allergy. Lancet. 2002;360(9334):701-710.

19. Kumar S, Verma AK, Das M, Dwivedi PD. Molecular mechanisms of IgE mediated food allergy. Int Immunopharmacol. 2012;13(4):432-439.

20. Poulsen LK, Hummelshoj L. Triggers of IgE class switching and allergy development. Ann Med. 2007;39(6):440-456.

Mediator Release20

HistamineVasodilationIncreased vascular permeabilityEnzymesAct directly on tissuesProstaglandinsLeukotrienes