1. MAST CELLS
DR. MARIA ANN GEORGE

2. INTRODUCTION
 ‘Mastzellen’ (German “mast”, feeding, fattening) in 1878 by Paul Ehrlich
 He believed that the intracellular granules, which appeared purple in colour when stained
with aniline blue dyes, contained phagacytosed materials or nutrients
 Metachromasia- First coined by Acroyd in 1876- change in colour due to interaction of the
dyes with the highly acidic heparin contained within mast cell granules- used by Paul Erlich to
describe the mast cell granules in 1879.
 Long-lived cells that can survive in tissues for months to years and have retained the ability to
proliferate in response to appropriate signals.
 haematopoietic in origin

4. ORIGIN
 During the first 100 years after Paul Ehrlich discovered them, mast cells were
believed to be a component of connective tissue that was derived from
undifferentiated mesenchymal cells
 First line of defense against external pathogens and other environmental
insults
 Hematopoietic lineage (CD34+/CD117+ pluripotent progenitor cells) –
Kitamura et al
 Emrbyonic origin: Foetal liver or spleen

5. Pluripotent BM
precursors
Mast cell
progenitors
Migrate through
blood to target
tissue
Tissue
microenivironmet
and c-kit ligand
& SCF & IL-3
Differentiation Maturation Mature Mast cell

7. DISTRIBUTION
 Mucosal and epithelial tissues throughout the body.
 All vascularized tissues except for the central nervous system and the retina.
 Junction point of the host and external environment at places of entry of
antigen (gastrointestinal tract, skin, respiratory epithelium).
 In order for mast cells to migrate to their target locations, the coordinated
effects of integrins, adhesion molecules, chemokines, cytokines, and growth
factors are necessary.

9.  There are two phenotypes of human mast cells:
 MUCOSAL MAST CELLS(MCT
) that produce only tryptase – INNATE
IMMUNITY
 CONNECTIVE TISSUE MAST CELLS (MCTC
)that produce chymase, tryptase,
and carboxypeptidases – TISSUE REPAIR
 They all contain histamine.
 Almost all mast cells in the human skin belong to the MCTC
type, whereas MCT
cells predominate in the lung and bowel mucosa

10. STRUCTURE
 Diameter: 5-15 micron (Rook’s 9e)
 Shape: ovoid or spindle shaped; Fried egg appearance
 Nucleus: single unsegmented or occasionally binuclear
 Mast cell shows
 Large long villi at periphery
 Granules – round or oval membrane bound structures upto 0.8 mM in
diameter
 Surrounded by perigranular membrane

11. STAINING
 Mast cell granules (and some other tissue components such as cartilage
matrix) can naturally induce metachromatic staining.
 Mast cell granules don’t stain with H&E.
 Metachromatic stains include the Romanowsky combinations (Wright, Giemsa,
May-Grünwald Giemsa, and Leishman), toluidine blue, and others.
 Negative staining- PAS, Peroxidase
 Methylene blue and toluidine blue: granules stain PURPLE high HEPARIN
 Leder stain (Chloroacetate esterase): Brilliant RED colour

13. IMMUNOHISTOCHEMISTRY

14. ULTRASTRUCTURE
 large and long villi at their periphery
 granules appearing as round or oval
membranebound structures up to
0.8 μm in diameter surrounded by a
perigranular membrane.
 They contain two components:
lamellae and electrondense finely
granular material. The lamellae
appear in cross section as thick,
curved, and parallel filaments
forming whorls or scrolls that may
resemble fingerprints in their
configuration.

16. MAST GRANULES
 Histamine is probably the most well known, but other amines, such as
serotonin, are also found in mast cell granules.
 Mast cell granules include various cytokines such as TNF-α, vascular
endothelial growth factor (VEGF), various proteases, antimicrobial proteins
such as cathelicidins, and chemokines.
 Mast cells can also produce a large number of cytokine following activation,
including TNF-α, IL-3, IL-4, IL-5, and IL-6,43 as well as lipid mediators such as
leukotrienes, prostaglandins, and platelet-activating factor—these factors,
when released, contribute to increased vascular permeability and edema at
the site of infection or insult—the so-called wheal and flare response that
occurs within minutes.

19. RECEPTORS AND MEDIATORS

21. MECHANISM OF ACTION
 Mast cells are known for their main mechanism of action: IgE-mediated
allergic reactions through the FcϵRI receptor.
 IgE antibodies are produced by mature B cells in response to CD4+ Th2 cells.
Naïve mature B cells produce IgM and IgD antibodies.
 After activation, B cells will proliferate.
 These B cells interact with cytokines, such as IL-4 (which is modulated by
CD4+ Th2 cells) and produces IgE.

23.  IgE is produced from IgM via class switching in response to the activation of
B cells in the presence of IL-4. Mast cells express the receptor for IgE (FCεRI)
constitutively on their surface, and the best known cause of mast cell
activation is when antigens crosslink immunoglobulin E bound to these
receptors.
 A relatively low level of allergen is sufficient to trigger degranulation of mast
cells.
 In addition to FcϵRI, mast cells also express Fc receptors for IgA and IgG,
receptors for adenosine, C3a, chemokines, cytokines, and pathogen-
associated molecular patterns (PAMPs), as well as toll-like receptors (TLRs),
all of which are involved in mast cell activation and immune response.

25.  Mast cells can also bind immunoglobulin G antibodies through FcγRII
receptors.
 Mast cells can also act as sentinels of infection and are equipped with pattern
recognition receptors, including various TLRs, which are activated in response
to conserved pathogen-associated molecular patterns.
 The responses elicited to pathogens depend on the stimulus.
 TLR4 activated by lipopolysaccharide on mast cells leads to cytokine
production in the absence of degranulation.
 In contrast TLR2 activation by peptidoglycans induces both degranulation and
cytokine production.

26. MAST CELLS IN SKIN HOMEOSTASIS
 very important as regulators of epidermal barrier function and skin
homeostasis and play important roles in wound healing and skin aging
 MC- FB:
 MCs induce fibroblast proliferation via IL-4, IL-13, VEGF and basic fibroblast
growth factor.
 FB secretes stem cell factor (SCF), the MC growth factor, - promotes MC
differentiation and controls MC activation

27.  ,MC- KC
 MCs are reported to have both inhibitory and activating effects on KCs.
 keratinocyte growth factor (KGF) [58] and platelet-activating factor (PAF)-
KC activated.
 histamine, heparin and other MC mediators inhibits KC proliferation
 C tryptase and chymase are reported to promote FB proliferation while
inhibiting KC proliferation

28.  MC-EC
 Angiogenesis is an important process for normal skin development, homeostasis, and
remodeling
 TRYPTASE- degrades BM and promotes angiogenesis
 Blood EC: histamine, TNF, leukotrienes, prostaglandin D2 (PGD2), PAF, VEGF-A and VEGF-B,
IL-13 and IL-1β
 Lymphatic EC: histamine, VEGF-C and VEGF-D
 VEGF-A that is expressed by ECs can regulate MC proliferation and maturation within the
skin
 Collectively, the homeostatic environment of the skin is regulated very precisely, and
MCs play a crucial role in maintaining skin barrier homeostasis and integrity by
interacting with neighboring non-immune cells, like FBs, KCs and ECs

29. MAST CELLS IN IMMUNITY
 MCs contribute to the first line of host defense against invading pathogens
 MCs express a broad spectrum of pattern recognition receptors, including
Toll-like receptors (TLRs), Fc receptors and complement receptors
 Additionally, MCs have the ability to sense cell stress and tissue
damage, through alarmin and purinergic receptors and to be activated
or modulated by binding cytokines, growth factors, chemokines and
neuropeptides
 In addition to their innate functions that foster adaptive immune responses,
MCs can indirectly affect adaptive immunity by modulating dendritic cell (DC)
functions

30.  Soluble MC mediators, such as histamine and TNF, or uptake of intact MC
granules by DCs promotes DC migration, DC maturation and T cell priming
capacity
 MC-DC synapse formation culminates in MHCII transfer from DCs to MCs,
thereby equipping MCs with antigen-presentation capacities that may
contribute to effector T cell activation
 MCs critically contribute to innate host defense but also link the innate and
adaptive immune response. - Katsoulis-Dimitriou et al

32. ROLE OF MAST CELLS IN VENOM DETOXIFICATION
 1991- Margie Profet - allergic responses beneficial in defense against
venoms.
 Marichal et al - that IgE antibody binding to FcεRI
 IgE-dependent MC activation, the mode of allergic reactions [77], has a
protective role against noxious substances
 Although MCs in general respond to and degrade venoms, they can
also have a detrimental role.
 A massive MC reaction to a small amount of poison, such as a single bee
sting, may overshoot and lead to anaphylaxis, a complication that may be
exacerbated in patients suffering from mast cell activation syndromes (MCAS)

33. INFECTIONS

35. ROLE OF MAST CELLS IN FUNGI INFECTIONS
 Lopes et al. reported that, in vitro, human MCs are able to mount specific early, mid and late
responses against C. albicans.
 More specifically, MCs were able to phagocytose the fungi and reduce its viability, followed
by recruitment of Nph.
 In addition, infected MCs formed extracellular DNA traps suggesting, overall, a protective role
of MCs against Candida infection
 human MCs can detect and respond to Malassezia sp. by engagement of the CLRs Dectin 1
and Mincle- Ribbing et al
 MCs do not always have a protective role in fungi infections. In lung infections with
Aspergillus fumigatus, resulting in IgE mediated allergic bronchopulmonary aspergillosis
(ABPA), MC proteases are responsible for the release of growth factors from ECs, promoting
lesions and fibrosis

36. ACUTE ALLERGIC CUTANEOUS RESPONSE

37. ACUTE ALLERGIC CUTANEOUS RESPONSE

38. ATOPIC DERMATITIS

40. ROLE IN PSORIASIS AND URTICARIA

42. MASTOCYTOSIS
 Mastocytosis is the term for a diverse group of conditions where a single (or clonal)
population of mast cells accumulate in one or more tissues, for example, skin, bone
marrow, liver, spleen, gastrointestinal tract and lymph nodes.
 The severity of symptoms depends on the number of mast cells in the tissues. A high
load of mast cells leads to more severe symptoms.
 Cutaneous mastocytosis causes itching, swelling and blistering of the affected skin,
particularly when it is rubbed or scratched.

43.  Abnormalities in SCF/Kit signaling
have been implicated in
mastocytosis: activating mutations
in Kit gene on 4q12 chromosome
have been reported in a variety of
patients with mastocytosis.
 Cutaneous mastocytosis is usually
diagnosed by its clinical appearance
and positive Darier sign. However, a
skin biopsy may be helpful for
confirmation

44. CLASSIFICATION
 Mastocytosis can be broadly
characterised into two groups:
• Localised mastocytosis
(localised to a single tissue)
• Systemic mastocytosis
(involving one or more
tissues)
 The World Health Organisation (WHO) classifies
mastocytosis (2016) as:
• Cutaneous mastocytosis
• Indolent systemic mastocytosis
• Systemic mastocytosis with
associated haematological disease
• Aggressive systemic mastocytosis
• Smouldering systemic mastocytosis
• Mast cell leukaemia
• Mast cell sarcoma
• Extracutaneous mastocytoma.

45. CUTANEOUS MASTOCYTOSIS
 CHARACTERISTIC FINDING: POSITIVE DARIER’S
SIGN
 Two-thirds of cases of cutaneous mastocytosis occur in
children.
 Solitary mastocytoma and maculopapular mastocytoma
are the most common forms of mastocytosis in children.
 Cutaneous mastocytosis is classified as follows:
• Solitary mastocytoma
• Maculopapular cutaneous mastocytosis
• Diffuse cutaneous mastocytosis
• Telangiectatic cutaneous mastocytosis
(telangiectasia macularis eruptiva perstans)
• Plaque-type mastocytoma
• Solitary and multiple nodular mastocytomas

46.  SOLITARY MASTOCYTOMA is present
in infancy as an itchy reddish or
yellowish brown thickened patch of
skin
 Self limiting: resolves by itself in
time

47. DARIER’S SIGN: MASTOCYTOMA AFTER RUBBING

48. MACULOPAPULAR MASTOCYTOSIS
 Aka urticaria pigmentosa
 most common form of mastocytosis in adults
and children.
 Maculopapular mastocytosis in adults is unlikely
to resolve with time.
 It is associated with systemic involvement, where
the mastocytosis spreads to more than one
tissue.

49. DIFFUSE CUTANEOUS MASTOCYTOSIS
 Erythroderma
 Sometimes with widespread blistering of the
skin.
 Adults and adolescents with diffuse cutaneous
mastocytosis often have a generalised
thickening leathery appearance and texture to
most or all of their skin
 positive Darier sign.

50. TELANGIECTATIC CUTANEOUS MASTOCYTOSIS
 Aka telangiectasia macularis eruptiva perstans
(TMEP).
 very persistent and may sometimes lead to
systemic involvement. The name relates to
extensive telangiectases.

51. OTHER FORMS OF MAST CELL PROLIFERATION
 Mast cell leukaemia
 Mast cell leukaemia is a rare disease of circulating malignant mast cells with a very poor prognosis.
 Mast cell sarcoma
 Mast cell sarcoma is a solid tumour of malignant mast cells.
 Extracutaneous mastocytoma
 Extracutaneous mastocytoma is a benign mast cell tumour where a localised area of mast cell proliferation is not
in the skin.

52. INVESTIGATIONS
 SOLITARY MASTOCYTOMA generally require no work up. However, a full history should be taken, and skin,
lymph nodes, liver and spleen should be examined to check for diffuse or systemic mastocytosis.
 Skin biopsy
 Full blood count
 Serum biochemistry
 Liver function tests
 Serum tryptase level: tryptase is a mast cell enzyme. Systemic mastocytosis is unlikely with a tryptase level <
20 ug/L.
 Abdominal ultrasound
 Bone density scan
 Bone marrow trephine
 Blood and marrow smears
 Flow cytometry (to measure CD2 and CD25)
 Genetic examination (looking for c-KIT mutation D816V in bone marrow mast cells)

53. TREATMENT
 Avoid all possible histamine triggers
 Physical agents
• Heat and cold
• Sunlight
• Sudden changes in temperature
• Rubbing of/pressure on skin lesions
 Emotional factors
• Stress/anxiety
• Sleep deprivation

54.  Drugs
• Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs)
• Morphine, codeine and derivatives (narcotics)
• Cough medications
• Alcohol
• Local anaesthetics
• Beta-blockers
• Anticholinergic medications (eg scopolamine)
• Vancomycin
• Amphotericin B
• Thiamine (Vitamin B1)

55.  Venoms
 Hymenoptera
 Snakes
 Infectious diseases with fever
 Viral and bacterial
 Others
 Dental and endoscopic procedures
 Vaccines
 Surgery
 Contrast media (particularly those containing iodine)

56. SPECIFIC TREATMENT
 Antihistamines
 Leukotriene antagonists
 H2 blockers (cimetidine, ranitidine)
 Sodium cromoglycate
 Omalizumab
 Phototherapy ( narrow band UVB or PUVA)
 Subcutaneous adrenaline/epinephrine (eg, EpiPen®)
 Oral steroids may be used in some cases of systemic mastocytosis. They act as mast cell
stabilisers.
 Osteoporosis should be treated in patients with this complication of mastocytosis.
GI SYMPTOMS

57. SYSTEMIC OR AGGRESSIVE MASTOCYTOSIS
 MILTEFOSINE
 KIT inhibhitors: midostaurin, dasatinib
 Interferon alpha
 Chemotherapy: cladribine, cytarabine, fludarabine, and hydroxyurea

58. REFERENCES
 Okayama Y, Kawakami T. Development, migration, and survival of mast cells. Immunol Res. 2006;34(2):97-115.
doi:10.1385/IR:34:2:97
 Harvima, Ilkka & Nilsson, Gunnar. (2011). Mast Cells as Regulators of Skin Inflammation and Immunity. Acta dermato-
venereologica. 91. 644-50. 10.2340/00015555-1197.
 Voss, Martin, Johanna Kotrba, Evelyn Gaffal, Konstantinos Katsoulis-Dimitriou, and Anne Dudeck. 2021. "Mast Cells in the
Skin: Defenders of Integrity or Offenders in Inflammation?" International Journal of Molecular Sciences 22, no. 9: 4589.
https://doi.org/10.3390/ijms22094589
 Fitzpatrick’s Dermatology, 9e
 Rook’s textbook of dermatology, 9e
 IADVL TEXTBOOK OF DERMATOLOGY, 5e
 https://dermnetnz.org/topics/mastocytosis