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Home , Pyogenic granuloma

320 ROLE OF MAST CELL IN ORAL PATHOLOGY Supriya Kheur Deepali Patekar Neeta Bagul Meena Kulkarni Samapika Routray 1 Varsha Dhas Department of Oral Pathology,Dr. D.Y.Patil Dental College and Hospital, Pimpri, Pune-18, India 1Department of Oral Pathology, GITAM Dental College, Vishakhapattanam, India Corresponding Author: Supriya Kheur, Department of Oral Pathology,Dr. D.Y.Patil Dental College and Hospital, Pimpri, Pune-18, India. Ph -09970150760, Email : [email protected]

Abstract Mast cells in oral tissues releases various pro-inflammatory cytokine tumor necrosis factor alpha (TNF-Ü) which promotes leukocyte infiltration in various inflammatory condition of oral cavity such as oral (OLP), periapical lesions, & periodontitis. T lymphocyte derived cytokines influences mast cell migration & mediator release. Mast cell secreted proteases, activates matrix-metalloprotinases-9 (MMP-9) which may contribute to alteration in basement membrane in inflammatory condition such as Lichen Planus. Hence by understanding the role of mast cells in the pathogenesis of various diseases; therapies should be targeted to enhance the prognosis of the diseases. Key Words: Mast cells, Degranulation, Cytokines, Tryptase, Chymase.

Introduction chemotactins, cell activating & cell growth Mast cells (MC) are large spherical or factor. Tissue mast cells are not homogenous elliptical mononuclear cells found in a variety for eg. enzymes within granules of mucosal & of tissues including skin, submucosa or connective tissue mast cells are different from connective tissue of various organs & each other. The ranges of mast cell activity is (1) specialized for their anatomic location, as the mucosal epithelial tissues & also in dental granules are different for mucosal and . They are mobile, bone marrow derived, (3) (2) connective tissue mast cells. Under light and typically containing 80-300 granules. microscope mast cells gives a characteristic These metachromatic granules are easily metachromatic staining pattern with toluidine detected by stains such as toluidine blue. They blue. are typically distributed in perivascular & perineural regions. The granules are rich in Ultrastructure of Mast Cell:- heparin, chondroitin sulphate, proteoglycan In & skin the granules in & numerous enzymes including collagenase. mast cell have complex form with the These cells believed to play role in remodelling amorphous region located next to crystalline of extracellular matrix (ECM) during wound region. The crystalline region ranges in healing, progresion of rheumatoid arthritis & configuration & three types of mast cell the progression of a fibrotic diseases such as population is identified.(4) interstitial pulmonary fibrosis, progressive systemic sclerosis, retroperitoneal fibrosis.(3) 1. Cells deeper in connective tissue Mast cells also produces a variety of lipid & (except that in close vicinity to blood vessels) protein alpha mediators with pro- are round /oval in shape & dark purple in inf lammator y activities including colour. The cell borders are well defined & Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol. 4 No. 1 Jan - June 2013 ISSN 0976 - 1225 Role of Mast Cell in Oral Pathology 321 nucleus is not visible due to granules making keratinocytes & mast cell. RANTES secreted by the nucleus & is called as intact cells. (4) activated T-cells attract mast cell & stimulates (8) 2. In the superficial connective tissue. degranulation. Immediately below infiltrate in OLP & near Mediators of Mast Cells:- the blood vessels the mast cells appear The degranulation mediators can be flattened / irregular & cytoplasm appears (2) grouped into 2 categories granular. The cell borders are not defined & a) Mediators that are preformed in their the nucleus is only partially appreciable; these (5) granules are:- serine proteases:- Tryptase, cells are called spreading cells. chymase & cathepsin G, histamine, heparin, 3. The third type called degranulated cells serotonin, acid hydrolases &cytokine, TNF-á, found within the infiltrate & appeared paler as IL -16. the staining has changed from metachromatic b) Mediators following activation of mast cell violet to light pink, the nucleus blue in color & (2,3,5,9) (2) are :- IL-1, IL-3 ,IL-4,IL-5,IL-6,IL-8,IL- well defined. 10IL-13 &IL-16, platelet activating factor Masts cells are classified according to protease (PAF) RANTES, macrophage inflammatory content in:- protein (MIF -1alpha ) & arachidonic acid metabolites, prostaglandin & leukotriene C4 a) MC phenotype contain tryptase only T (LTC4). (2,5). b) MC contain both tryptase & chymase TC Role of mast cell released cytokines: - (5) IL-3 – induce basophil recruitment & activation Mast Cell Degranulation:- IL-5-eosinophil recruitment & activation Degranulation of mast cell releases IL-13 – induction of IgE synthesis pro-inflammatory mediators such as: - TNF- Mast cell bears receptors for IgE & alpha (TNF-Ü), chymase, tryptase, MMPs, degranulates when this cytophilic antibody is bFGF, heparin, histamine, various interleukins cross-linked by antigen. But other factors such (IL3, IL4, IL5, IL6, IL8, IL10, IL13, IL16 and (6,7) as mechanical trauma, complement C5a, cytokine RANTES. Tryptase is the most eosinophil –derived cationic protein, and abundant serine proteinase stored in MC bacterial products can cause mast cell RANTES granules. It promotes , ECM degranulation. Thus mast cell can promote degranulation and tissue remodeling & is inflammation in the absence of IgE mediated considerd an important angiogenic factor. Mast activation & likely infiltrate inflammatory cell degranulation is induced by various (9) events under many circumstances. stimulus such as IgE receptors, neuropeptides (substance P), chemokines & other physical T h u s , m a s t c e l l s r e l e a s e stimulus.(2) RANTES (regulated on activation, proinflammatory mediators, promotes normal T cells expressed & secreted), TNF-Ü inflammation and angiogenesis, extracellular may up regulates endothelial cells adhesion matrix degeneration and tissue remodeling. The molecule (CD62E, CD54 & CD106) main role of mast cells are in the following oral expression in OLP that is required for diseases:- lymphocyte adhesion to the luminal surface of Role of MC in Oral Pathologies: blood vessels & subsequent extravasation. RANTES are a member of chemokine family 1) Role of MC in OLP produced by various cells; such as activated T- MC play major role in non-specific mechanism lymphocyte, bronchial epithelial cell, oral of the OLP. (6,10)

Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol. 4 No. 1 Jan - June 2013 ISSN 0976 - 1225 Role of Mast Cell in Oral Pathology 322

RANTES activation MC

Mast Cells chemotaxis and degranulation Histamine

TNF- Ü Increase vascular permeability of small Endothelium cell adhesion molecule expression (Cd62 E, CD54, CD106) MCs are present in both inflammatory infiltrate and fibrous area of periapical lesions. MC contributes to fibrous tissue formation by Chymase activation production of hyaluronic acid.

MMP- 9 activation 3) Role of MC in Pyogenic MC on stimulation undergoes Disruption of basement membrane degranulation and causes inflammatory and vascular changes leading to formation of (12) Keratinocyte apoptosis pyogenic granuloma as follows- MC + neuropeptides neural Intra epithelial CD 8+ immune network with LC in mucosa tissue T-cell migration through BM Degranulation of MC Survival of inflammatory cell Cytokine, vasoactive amine and enzyme Non-specific T-cell recruitment Inflammatory and vascular changes 2) Role of MC in Periapical lesions Mast cell express KIT (CD117) Pyogenic granuloma which is a Trans membrane tyrosine kinase receptor protein encoded by the MC related pyogenic granuloma protooncogene c-kit that maps to (9,11) represents a reactive lesion resulting from chromosome 4 (4q11-12). According to local etiological factors like gingival Drazic et al 2012, MC can be analyzed inflammation, or trauma which qualitatively and semi quantitatively in activates MC resulting in release of mediators p e r i a p i c a l l e s i o n s b a s e d o n which leads subsequent changes in tissue immunohistochemistry expression of leading to formation of pyogenic granuloma. CD117. There is strong membrane reactivity of CD117 for MC and can be helpful in 4) Role of MC in wound healing diagnosis of MC disorder. MC can also be Wound healing is a dynamic process demonstrated in periapical granuloma and consisting of four continuous overlapping (13) .(11) Its pathogenesis is phases. connected with hypersensitivity reactions. (9) 1. Homeostasis 2. Inflammation

Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol. 4 No. 1 Jan - June 2013 ISSN 0976 - 1225 Role of Mast Cell in Oral Pathology 323 3. Proliferation inflammatory condition which occurs mainly 4. Tissue remodeling and resolution in the lower in adulthood, which is caused by chronic in excessive exposure of the MC can activate fibroblast via tryptase (7) synthesize collagens. As well as due to hyaluronic to solar U.V radiation. This lesion is acid MC contributes to fibrous tissue potentially malignant and may transform to formation.MC along with fibroblast adheres to . Product of MC fibronectin integrin receptor and helps in wound degranulation like histamine and TNF- Ü are healing. (13) MC derived MMP-9 also facilitate key mediators of U.V induced immune wound healing.(13) Wound healing involves separation, which can increase the degradation, cell migration, synthesis of susceptibility for skin and actinic matrix consisting of fibronectin, fibrin and .(2,7) high amount of collagen type II and matrix remodeling to return the tissue to normality. Also it is found that enzymes which MMP-9 is linked with remodeling of are linked to elastosis formation such as (14) cathepsin G, carboxypeptidase and granulation tissue matrix. gelatinases A & B are found in MCTC. 5) Role of MC in angiogenesis in oral squamous cell carcinoma 7) Role of MC in Angiogenesis/Neovascularization helps in progression and metastasis of Orofacial granulomatosis is a malignant tumor. Mast cells cause descriptive term used for a group of chronic neovascularization by producing angiogenic granulomatous disorders which share similar factors, such as VEGF, or substances with clinical and histological characteristics. It is angiogenic properties, such as tryptase, FGF, characterized clinically by labial and facial TNF, interleukin (IL)-8, histamine and swelling and histologically by the presence of lymphoedema and non-caseating epithelial heparin. The accumulation of mast cells is a (16) harbinger of the growth and invasion of granulomatous lesions. The term orofacial several kinds of malignancy. The heparin granulomatosis is restricted to otherwise from the mast cells cause vasoproliferation healthy patients in whom systemic and increases the half-life of basic granulomatous diseases have been excluded. fibroblastic growth factor (FGF), which is a Degradation of MC mediators is potent angiogenic substance, thereby deposited in extra cellular compartment and promoting tumour angiogenesis and affects endothelial cells. Histamine binds to facilitating local tumour invasion. Interleukin- specific cell surface receptors H1 and H2, seen (15) 1 leads to epithelial proliferation. on endothelial cell surface. When bound Tryptase is thought to be potent contraction of endothelial cell occurs, leading angiogenic factor for tumor angiogenesis in to the widening of the gaps between these cells oral squamous cell carcinoma as it directly which promotes inflammation by aiding the extravasations of fluid, proteins and induce cell proliferation of human dermal (16) microvasculature and endothelial cell. circulating inflammatory cells into the tissue. Tryptase and chymase act as a powerful TNF- Ü also contributes to the inflammatory MMP activator. Among MMP's, gelatinase B process by - (MMP-9), plays vital role in angiogenesis, 1. Endothelial expression of E selective tumor invasion and metastasis because of its CD62E (ELAM-1) which is a adhesion ability to cleave type IV collagen in basement molecule. membrane.(7) 2. Chemotaxis of macrophages and neutrophils. 3. Activation of langerhans cells (LC) 6) Role of MC in 4. Autocrine stimulation of MC to Actinic cheilitis is a chronic release histamine and tryptase. Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol. 4 No. 1 Jan - June 2013 ISSN 0976 - 1225 Role of Mast Cell in Oral Pathology 324 It is found that there is direct relationship diseases. It makes it easier for us to direct between MC degranulating and development therapeutic modalities against mast cell and its of inflammatory leading to orofacial granules to alter the course of the disease. granulomatosis. Reference 8) Role of MC in Oral submucous 1) Jyothi Mahadesh. Mast Cells-The Master fibrosis (OSMF) Blaster:An Overview.Annals and Essences of Dentistry(2011); Vol.-111 Issue 1;130-133 (OSMF) is associated with chronic inflammation in 2) Lawrence J. Walsh. Mast Cells and Oral adjacent connective tissue. Mast cells are the Inflammation.Crit Rev Oral Biol Med(2003); local residents of the connective tissue, and 14(3);188-98. are said to be pro-inflammator y, 3) Ivan Damjanov, James Linder. Textbook of immunoamplifying in action and producing Anderson's Pathology. Vol 1; pg.397-398, mitogenic cytokines. These functions of mast 433, 570. cells may play a significant role in the 4) Mahija Janardhanan,V.Ramesh. Mast Cells in pathogenesis of OSMF.(17) Histamine could Oral Lichen Planus. OMPJ(2010); Vol 1 No 2 probably attribute to submucosal edema seen 5) I.G.Rojas, A.Martinez, A.Pineda, et in early stages of oral submucous fibrosis. al.Increased mast cell density and protease Due to increased vasopermeability, content in actinic cheilitis.J Oral Pathol eosinophilic chemotactic factor (ECF) is Med(2004);33:567-73 released from the mast cells. This could probably attribute to the eosinophils that are 6) P.B.Sugerman, N.W.Savage, L.J.Walsh et al. sometimes a part of inflammatory cell The Pathogenesis of Oral Lichen Planus. J Oral infiltrate seen in the early stages of oral Pathol Med (2002); 13:350 submucous fibrosis. Interleukin-5 causes 7) S.F.Valeria, A.S. Pedro Paulo, A.F.Roseana increased proliferation and differentiation of et al. Mast cells and matrix metalloproteinase 9 eosinophils. Interleukin-1 from the mast cells expression in actinic cheilitis and lip squamous could cause increased fibroblastic response cell carcinoma. Oral Surg Oral Med Oral and mast cell derived tryptase causes increased Pathol Oral Radiol Endod (2011); 112:342- production of type-I collagen and fibronectin 348. thereby attributing to the increased fibrosis.(17) 8) Z.Z.Zhao, P.B.Sugerman, L.J.Walsh et al. Conclusion Expression of RANTES and CCR1 in oral Mast cells are multifunctional cells lichen planus and associated with mast cell migration. that play an important role in inflammation in J Oral Pathol Med (2002);31:158-62. oral mucosa and the dental pulp. They are 9) Radojica Drazic, Jelena Sopta, Arsa J et al. associated with both resistance and greater Minic. Mast cells in periapical lesions: potential susceptibility to tumor development. Because role in their pathogenesis. J Oral Pathol Med of the unique properties of the mast cells, (2010) 39:257-262. these cells are ideally poised to serve as 'gatekeepers' of the microvasculature in the 10) M.R.Roopashree, Rajesh V Gondhalekar, oral cavity. An appreciation of the multiple M.C.Shashikanth, et al. Pathogenesis of oral interactions among mast cells, endothelial lichen planus- a review. J Oral Pathol Med cells, nerves, and other immune system (2010) 39: 729-734. provides a basis for therapies for targeting mast cell responses. Hence, this overview aims to understanding of role of mast cells in 11) Hornick J, Fletcher C. Immunohistochemical the pathogenesis of various diseases; could staining for KIT (CD117) in soft tissue target to enhance the prognosis of the is very limited in distribution. Am J

Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol. 4 No. 1 Jan - June 2013 ISSN 0976 - 1225 Role of Mast Cell in Oral Pathology 325 Clin Pathol (2002); 117:188-193. carcinoma. J Oral Pathol Med (2003);32:195-5. 12) Reet Kamal, Paveen Dahiya, Sangeeta 16) N. N. Nwizu and D. G. Macdonald. Mast Palaskar, et al. Comparative analysis of mast Cell Quantification in Or ofacial cell count in normal oral mucosa and oral Granulomatosis. Nig. Ot J.Hosp. Med. pyogenic granuloma. J Clin Exp Dent, (2011); (2003);Vol. 13(3-4) July-Dec. 3(1):e1-4. 17) Madhuri R Ankle, Alka D Kale, Ramakant 13) S. Guo and L.A.DiPietro. Factors affecting Nayak. Mast cells are increased in , wound healing. JDent Res (2010);89(3):219- oral submucous fibrosis, oral lichen planus and 229. oral squamous cellcarcinoma. JOMFP(2007); Vol 11, Issue : 1 , Pg. : 18-22 14) Sahitya S, Babitha Nugala, Santosh Kumar B.B. Matrix metalloproteinases. J Orofac Sci(2010); 2(1) 75-81. 15) Anak Iamaroon, Surawut Pongsiriwet, Komkhan Pattanaporn, et al. Increase of mast Source of Support - Nil cells and tumor angiogenesis in oral squamous cell Conflict of Interest - None declared

How to cite this article: Kher Supriya, Patekar Deepali, Bagul Neeta, Kulkarni Meena, Routray Samapika, Dhas Varsha: Role of mast cell in oral pathology: Oral Max Path J, 4(1), Jan-Jun 2013: 320-325

Oral & Maxillofacial Pathology Journal [ OMPJ ] Vol. 4 No. 1 Jan - June 2013 ISSN 0976 - 1225