Mast Cells and Immunological Skin Diseases

Clinical Reviews in Allergy - Tập 33 - Trang 144-155 - 2007
Daniel Navi1, Jun Saegusa1, Fu-Tong Liu1
1Department of Dermatology, School of Medicine, University of California, Davis Sacramento, USA

Tóm tắt

Mast cells play an important role in both adaptive and innate immunity, and a large body of literature demonstrates their functions in skin immunity. This article reviews the literature on the role of this cell type in the pathogenesis of a number of immunological skin diseases, including contact dermatitis, atopic dermatitis, immunobullous disease, scleroderma, and chronic graft-vs.-host disease. In all these diseases, mast cells are noted to increase in number and undergo degranulation in the affected skin, and in some cases, their specific mediators are detected. Elucidation of the contribution of mast cells to the pathogenesis of these diseases has been aided significantly by the use of animal models, especially mouse models. The studies of mast cell-deficient mice in conjunction with normal congenic mice have been particularly fruitful, although in some cases, such as contact dermatitis, a definitive conclusion has not been achieved despite extensive efforts. The role of mast cells in atopic dermatitis has also been suggested by studies of gene polymorphism, which have linked some of the mast cell-related genes to the disease. In the case of scleroderma and chronic graft-vs.-host disease, the function of mast cells in fibrosis is further supported by the ability of these cells and their mediators to induce activation and proliferation of fibroblasts. Therapies targeting mast cells may prove beneficial for treatment of these inflammatory and autoimmune diseases.

Tài liệu tham khảo

Sharma BB, Apgar JR, Liu FT (2002) Mast cells. Receptors, secretagogues, and signaling. Clin Rev Allergy Immunol 22:119–148 Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M (2005) Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 23:749–786 Galli SJ, Nakae S, Tsai M (2005) Mast cells in the development of adaptive immune responses. Nat Immunol 6:135–142 Vliagoftis H, Befus AD (2005) Mast cells at mucosal frontiers. Curr Mol Med 5:573–589 Lu LF, Lind EF, Gondek DC, Bennett KA, Gleeson MW, Pino-Lagos K, Scott ZA, Coyle AJ, Reed JL, Van Snick J, Strom TB, Zheng XX, Noelle RJ (2006) Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature 442:997–1002 Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF (1991) Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci USA 88:4220–4224 Schleimer RP, Sterbinsky SA, Kaiser J, Bickel CA, Klunk DA, Tomioka K, Newman W, Luscinskas FW, Gimbrone MA Jr, McIntyre BW et al (1992) IL-4 induces adherence of human eosinophils and basophils but not neutrophils to endothelium. Association with expression of VCAM-1. J Immunol 148:1086–1092 Sironi M, Sciacca FL, Matteucci C, Conni M, Vecchi A, Bernasconi S, Minty A, Caput D, Ferrara P, Colotta F et al (1994) Regulation of endothelial and mesothelial cell function by interleukin-13: selective induction of vascular cell adhesion molecule-1 and amplification of interleukin-6 production. Blood 84:1913–1921 Nakae S, Suto H, Iikura M, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (2006) Mast cells enhance T cell activation: importance of mast cell costimulatory molecules and secreted TNF. J Immunol 176:2238–2248 Nakae S, Suto H, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (2005) Mast cells enhance T cell activation: importance of mast cell-derived TNF. Proc Natl Acad Sci USA 102:6467–6472 Mekori YA, Metcalfe DD (1999) Mast cell-T cell interactions. J Allergy Clin Immunol 104:517–523 Tkaczyk C, Frandji P, Botros H-G, Poncet P, Lapeyre J, Peronet R, David B, Mecheri S (1996) Mouse bone marrow-derived mast cells and mast cell lines constitutively produce B cell growth and differentiation activities. J Immunol 157:1720–1728 Pawankar R, Okuda M, Yssel H, Okumura K, Ra CS (1997) Nasal mast cells in perennial allergic rhinitics exhibit increased expression of the FcŒRI, CD40L, IL-4, and IL-13, and can induce IgE synthesis in B cells. J Clin Invest 99:1492–1499 Gauchat J-F, Henchoz S, Mazzel G, Aubry J-P, Brunner T, Blasey H, Life P, Talabot D, Flores-Romo L, Thompson J, Kishi K, Butterfield J, Dahinden C, Bonnefoy J-Y (1993) Induction of human IgE synthesis in B cells by mast cells and basophils. Nature 365:340–343 Kohda F, Koga T, Uchi H, Urabe K, Furue M (2002) Histamine-induced IL-6 and IL-8 production are differentially modulated by IFN-gamma and IL-4 in human keratinocytes. J Dermatol Sci 28:34–41 Kanda N, Watanabe S (2004) Histamine enhances the production of granulocyte-macrophage colony-stimulating factor via protein kinase Calpha and extracellular signal-regulated kinase in human keratinocytes. J Invest Dermatol 122:863–872 Ioffreda MD, Whitaker D, Murphy GF (1993) Mast cell degranulation upregulates alpha 6 integrins on epidermal Langerhans cells. J Invest Dermatol 101:150–154 Jawdat DM, Albert EJ, Rowden G, Haidl ID, Marshall JS (2004) IgE-mediated mast cell activation induces Langerhans cell migration in vivo. J Immunol 173:5275–5282 Suto H, Nakae S, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (2006) Mast cell-associated TNF promotes dendritic cell migration. J Immunol 176:4102–4112 Mazzoni A, Siraganian RP, Leifer CA, Segal DM (2006) Dendritic cell modulation by mast cells controls the TH1/TH2 balance in responding T cells. J Immunol 177:3577–3581 Theiner G, Gessner A, Lutz MB (2006) The mast cell mediator PGD(2) suppresses IL-12 release by dendritic cells leading to Th2 polarized immune responses in vivo. Immunobiology 211:463–472 Frandji P, Oskéritzian C, Cacaraci F, Lapeyre J, Peronet R, David B, Guillet J-G, Mécheri S (1993) Antigen-dependent stimulation by bone marrow-derived mast cells of MHC class II-restricted T cell hybridoma. J Immunol 151:6318–6328 Fox CC, Jewell SD, Whitacre CC (1994) Rat peritoneal mast cells present antigen to a PPD-specific T cell line. Cell Immunol 158:253–264 Frandji P, Tkaczyk C, Oskéritzian C, Lapeyre J, Peronet R, David B, Guillet J-G, Mécheri S (1995) Presentation of soluble antigens by mast cells: upregulation by interleukin-4 and granulocyte/macrophage colony-stimulating factor and downregulation by interferon-gamma. Cell Immunol 163:37–46 Frandji P, Tkaczyk C, Oskeritizian C, David B, Desaymard C, Mecheri S (1996) Exogenous and endogenous antigens are differentially presented by mast cells to CD4+ T lymphocytes. Eur J Immunol 26:2517–2528 Malaviya R, Twesten NJ, Ross EA, Abraham SN, Pfeifer JS (1996) Mast cells process bacterial ags through a phagocytic route for class I MHC presentation to T cells. J Immunol 156:1490–1496 Dvorak AM, Mihm MC Jr, Dvorak HF (1976) Morphology of delayed-type hypersensitivity reactions in man. II. Ultrastructural alterations affecting the microvasculature and the tissue mast cells. Lab Invest 34:179–191 Jung JY, Yasoshima A, Saegusa J, Nakayama H, Doi K (2003) Ultrastructural features of mast cells in picryl chloride (PCL)-induced contact dermatitis in IQI/Jic mice. Exp Toxicol Pathol 54:265–271 Kumamoto T, Shalhevet D, Matsue H, Mummert ME, Ward BR, Jester JV, Takashima A (2003) Hair follicles serve as local reservoirs of skin mast cell precursors. Blood 102:1654–1660 Subramaniam M, Saffaripour S, Watson SR, Mayadas TN, Hynes RO, Wagner DD (1995) Reduced recruitment of inflammatory cells in a contact hypersensitivity response in P-selectin-deficient mice. J Exp Med 181:2277–2282 Kerdel FA, Belsito DV, Scotto-Chinnici R, Soter NA (1987) Mast cell participation during the elicitation of murine allergic contact hypersensitivity. J Invest Dermatol 88:686–690 Jung JY, Saegusa J, Nakayama H, Doi K (2004) Comparative study on picryl chloride (PCL)-induced contact dermatitis in female IQI/Jic and BALB/c mice. Exp Anim 53:89–96 Shimada Y, Hasegawa M, Kaburagi Y, Hamaguchi Y, Komura K, Saito E, Takehara K, Steeber DA, Tedder TF, Sato S (2003) L-selectin or ICAM-1 deficiency reduces an immediate-type hypersensitivity response by preventing mast cell recruitment in repeated elicitation of contact hypersensitivity. J Immunol 170:4325–4334 Thomas WR, Vardinon N, Watkins MC, Asherson GL (1980) Antigen-specific mast cell degranulation in contact sensitivity to picryl chloride. An early event. Immunology 39:331–336 Natsuaki M, Yano N, Yamaya K, Kitano Y (2000) Immediate contact hypersensitivity induced by repeated hapten challenge in mice. Contact Dermatitis 43:267–272 Kitagaki H, Fujisawa S, Watanabe K, Hayakawa K, Shiohara T (1995) Immediate-type hypersensitivity response followed by a late reaction is induced by repeated epicutaneous application of contact sensitizing agents in mice. J Invest Dermatol 105:749–755 Nagai H, Inagaki N, Tanaka H (1999) Role of IgE for the onset of allergic cutaneous response caused by simple chemical hapten in mice. Int Arch Allergy Immunol 118:285–286 Ray MC, Tharp MD, Sullivan TJ, Tigelaar RE (1983) Contact hypersensitivity reactions to dinitrofluorobenzene mediated by monoclonal IgE anti-DNP antibodies. J Immunol 131:1096–1102 Graziano FM, Gunderson L, Larson L, Askenase PW (1983) IgE antibody-mediated cutaneous basophil hypersensitivity reactions in guinea pigs. J Immunol 131:2675–2681 Matsuda H, Ptak W, Askenase PW (1995) Role of mast cells versus basophils in IgE-dependent local ear skin release of the serotonin required to initiate contact sensitivity in mice. Int Arch Allergy Immunol 107:364 Ptak W, Geba GP, Askenase PW (1991) Initiation of delayed-type hypersensitivity by low doses of monoclonal IgE antibody. Mediation by serotonin and inhibition by histamine. J Immunol 146:3929–3936 Bryce PJ, Miller ML, Miyajima I, Tsai M, Galli SJ, Oettgen HC (2004) Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 20:381–392 Yokozeki H, Wu MH, Sumi K, Igawa K, Miyazaki Y, Katayama I, Takeda K, Akira S, Nishioka K (2003) Th2 cytokines, IgE and mast cells play a crucial role in the induction of para-phenylenediamine-induced contact hypersensitivity in mice. Clin Exp Immunol 132:385–392 Askenase PW, Van Loveren H, Kraeuter-Kops S, Ron Y, Meade R, Theoharides, TC, Nordlund JJ, Scovern H, Gerhson MD, Ptak W (1983) Defective elicitation of delayed-type hypersensitivity in W/Wv and SI/SId mast cell-deficient mice. J Immunol 131:2687–2694 Geba GP, Ptak W, Anderson GM, Paliwal V, Ratzlaff RE, Levin J, Askenase PW (1996) Delayed-type hypersensitivity in mast cell-deficient mice: dependence on platelets for expression of contact sensitivity. J Immunol 157:557–565 Biedermann T, Kneilling M, Mailhammer R, Maier K, Sander CA, Kollias G, Kunkel SL, Hultner L, Rocken M (2000) Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J Exp Med 192:1441–1452 Galli SJ, Wershil BK, Mekori YA (1987) Analysis of mast cell function in biological responses not involving IgE. Int Arch Allergy Appl Immunol 82:269–271 Thomas WR, Schrader JW (1983) Delayed hypersensitivity in mast-cell-deficient mice. J Immunol 130:2565–2567 Galli SJ, Hammel I (1984) Unequivocal delayed hypersensitivity in mast cell-deficient and beige mice. Science 226:710–713 Mekori YA, Galli SJ (1985) Undiminished immunologic tolerance to contact sensitivity in mast cell-deficient W/Wv and Sl/Sld mice. J Immunol 135:879–885 Ha TY, Reed ND, Crowle PK (1986) Immune response potential of mast cell-deficient W/Wv mice. Int Arch Allergy Appl Immunol 80:85–94 Mekori YA, Chang JC, Wershil BK, Galli SJ (1987) Studies of the role of mast cells in contact sensitivity responses. Passive transfer of the reaction into mast cell-deficient mice locally reconstituted with cultured mast cells: effect of reserpine on transfer of the reaction with DNP-specific cloned T cells. Cell Immunol 109:39–52 Seike M, Takata T, Ikeda M, Kodama H, Terui T, Ohtsu H (2005) Histamine helps development of eczematous lesions in experimental contact dermatitis in mice. Arch Dermatol Res 297:68–74 Suto H, Nakae S, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (2006) Mast cell-associated TNF promotes dendritic cell migration. J Immunol 176:4102–4112 Johnson EE, Irons JS, Patterson R, Roberts M (1974) Serum IgE concentration in atopic dermatitis. Relationship to severity of disease and presence of atopic respiratory disease. J Allergy Clin Immunol 54:94–99 Soter NA (1989) Morphology of atopic eczema. Allergy 44(Suppl 9):16–19 Irani AM, Sampson HA, Schwartz LB (1989) Mast cells in atopic dermatitis. Allergy 44(Suppl 9):31–34 Ring J, Thomas P (1989) Histamine and atopic eczema. Acta Derm Venereol Suppl (Stockh) 144:70–77 Obara W, Kawa Y, Ra C, Nishioka K, Soma Y, Mizoguchi M (2002) T cells and mast cells as a major source of interleukin-13 in atopic dermatitis. Dermatology 205:11–17 Horsmanheimo L, Harvima IT, Jarvikallio A, Harvima RJ, Naukkarinen A, Horsmanheimo M (1994) Mast cells are one major source of interleukin-4 in atopic dermatitis. Br J Dermatol 131:348–353 Spergel JM, Mizoguchi E, Oettgen H, Bhan AK, Geha RS (1999) Roles of TH1 and TH2 cytokines in a murine model of allergic dermatitis. J Clin Invest 103:1103–1111 Groneberg DA, Bester C, Grutzkau A, Serowka F, Fischer A, Henz BM, Welker P (2005) Mast cells and vasculature in atopic dermatitis—potential stimulus of neoangiogenesis. Allergy 60:90–97 Cox HE, Moffatt MF, Faux JA, Walley AJ, Coleman R, Trembath RC, Cookson WO, Harper JI (1998) Association of atopic dermatitis to the beta subunit of the high affinity immunoglobulin E receptor. Br J Dermatol 138:182–187 Badertscher K, Bronnimann M, Karlen S, Braathen LR, Yawalkar N (2005) Mast cell chymase is increased in chronic atopic dermatitis but not in psoriasis. Arch Dermatol Res 296:503–506 Mao XQ, Shirakawa T, Yoshikawa T, Yoshikawa K, Kawai M, Sasaki S, Enomoto T, Hashimoto T, Furuyama J, Hopkin JM, Morimoto K (1996) Association between genetic variants of mast-cell chymase and eczema. Lancet 348:581–583 Alenius H, Laouini D, Woodward A, Mizoguchi E, Bhan AK, Castigli E, Oettgen HC, Geha RS (2002) Mast cells regulate IFN-gamma expression in the skin and circulating IgE levels in allergen-induced skin inflammation. J Allergy Clin Immunol 109:106–113 Tam SY, Tsai M, Snouwaert JN, Kalesnikoff J, Scherrer D, Nakae S, Chatterjea D, Bouley DM, Galli SJ (2004) RabGEF1 is a negative regulator of mast cell activation and skin inflammation. Nat Immunol 5:844–852 Watanabe N, Tomimori Y, Saito K, Miura K, Wada A, Tsudzuki M, Fukuda Y (2002) Chymase inhibitor improves dermatitis in NC/Nga mice. Int Arch Allergy Immunol 128:229–234 Vigo PG, Girgis KR, Pfuetze BL, Critchlow ME, Fisher J, Hussain I (2006) Efficacy of anti-IgE therapy in patients with atopic dermatitis. J Am Acad Dermatol 55:168–170 Wintroub BU, Mihm MC Jr, Goetzl EJ, Soter NA, Austen KF (1978) Morphologic and functional evidence for release of mast-cell products in bullous pemphigoid. N Engl J Med 298:417–421 Dvorak AM, Mihm MC Jr, Osage JE, Kwan TH, Austen KF, Wintroub BU (1982) Bullous pemphigoid, an ultrastructural study of the inflammatory response: eosinophil, basophil and mast cell granule changes in multiple biopsies from one patient. J Invest Dermatol 78:91–101 Baba T, Sonozaki H, Seki K, Uchiyama M, Ikesawa Y, Toriisu M (1976) An eosinophil chemotactic factor present in blister fluids of bullous pemphigoid patients. J Immunol 116:112–116 Katayama I, Doi T, Nishioka K (1984) High histamine level in the blister fluid of bullous pemphigoid. Arch Dermatol Res 276:126–127 Brockow K, Abeck D, Hermann K, Ring J (1996) Tryptase concentration in skin blister fluid from patients with bullous skin conditions. Arch Dermatol Res 288:771–773 D’Auria L, Pietravalle M, Cordiali-Fei P, Ameglio F (2000) Increased tryptase and myeloperoxidase levels in blister fluids of patients with bullous pemphigoid: correlations with cytokines, adhesion molecules and anti-basement membrane zone antibodies. Exp Dermatol 9:131–137 Kaminska R, Helisalmi P, Harvima RJ, Naukkarinen A, Horsmanheimo M, Harvima IT (1999) Focal dermal–epidermal separation and fibronectin cleavage in basement membrane by human mast cell tryptase. J Invest Dermatol 113:567–573 Arbesman CE, Wypych JI, Reisman RE, Beutner EH (1974) IgE levels in sera of patients with pemphigus or bullous pemphigoid. Arch Dermatol 110:378–381 Dopp R, Schmidt E, Chimanovitch I, Leverkus M, Brocker EB, Zillikens D (2000) IgG4 and IgE are the major immunoglobulins targeting the NC16A domain of BP180 in Bullous pemphigoid: serum levels of these immunoglobulins reflect disease activity. J Am Acad Dermatol 42:577–583 Dimson OG, Giudice GJ, Fu CL, Van den Bergh F, Warren SJ, Janson MM, Fairley JA (2003) Identification of a potential effector function for IgE autoantibodies in the organ-specific autoimmune disease bullous pemphigoid. J Invest Dermatol 120:784–788 Fairley JA, Fu CL, Giudice GJ (2005) Mapping the binding sites of anti-BP180 immunoglobulin E autoantibodies in bullous pemphigoid. J Invest Dermatol 125:467–472 Liu Z, Diaz LA, Troy JL, Taylor AF, Emery DJ, Fairley JA, Giudice GJ (1993) A passive transfer model of the organ-specific autoimmune disease, bullous pemphigoid, using antibodies generated against the hemidesmosomal antigen, BP180. J Clin Invest 92:2480–2488 Liu Z, Giudice GJ, Swartz SJ, Fairley JA, Till GO, Troy JL, Diaz LA (1995) The role of complement in experimental bullous pemphigoid. J Clin Invest 95:1539–1544 Liu Z, Giudice GJ, Zhou X, Swartz SJ, Troy JL, Fairley JA, Till GO, Diaz LA (1997) A major role for neutrophils in experimental bullous pemphigoid. J Clin Invest 100:1256–1263 Chen R, Ning G, Zhao ML, Fleming MG, Diaz LA, Werb Z, Liu Z (2001) Mast cells play a key role in neutrophil recruitment in experimental bullous pemphigoid. J Clin Invest 108:1151–1158 Hawkins RA, Claman HN, Clark RA, Steigerwald JC (1985) Increased dermal mast cell populations in progressive systemic sclerosis: a link in chronic fibrosis? Ann Intern Med 102:182–186 Nishioka K, Kobayashi Y, Katayama I, Takijiri C (1987) Mast cell numbers in diffuse scleroderma. Arch Dermatol 123:205–208 Seibold JR, Giorno RC, Claman HN (1990) Dermal mast cell degranulation in systemic sclerosis. Arthritis Rheum 33:1702–1709 Irani AM, Gruber BL, Kaufman LD, Kahaleh MB, Schwartz LB (1992) Mast cell changes in scleroderma. Presence of MCT cells in the skin and evidence of mast cell activation. Arthritis Rheum 35:933–939 Akimoto S, Ishikawa O, Igarashi Y, Kurosawa M, Miyachi Y (1998) Dermal mast cells in scleroderma: their skin density, tryptase/chymase phenotypes and degranulation. Br J Dermatol 138:399–406 Green MC, Sweet HO, Bunker LE (1976) Tight-skin, a new mutation of the mouse causing excessive growth of connective tissue and skeleton. Am J Pathol 82:493–512 Menton DN, Hess RA (1980) The ultrastructure of collagen in the dermis of tight-skin (Tsk) mutant mice. J Invest Dermatol 74:139–147 Walker M, Harley R, Maize J, DeLustro F, LeRoy EC (1985) Mast cells and their degranulation in the Tsk mouse model of scleroderma. Proc Soc Exp Biol Med 180:323–328 Walker MA, Harley RA, LeRoy EC (1987) Inhibition of fibrosis in TSK mice by blocking mast cell degranulation. J Rheumatol 14:299–301 Walker M, Harley R, LeRoy EC (1990) Ketotifen prevents skin fibrosis in the tight skin mouse. J Rheumatol 17:57–59 Everett ET, Pablos JL, Harley RA, LeRoy EC, Norris JS (1995) The role of mast cells in the development of skin fibrosis in tight-skin mutant mice. Comp Biochem Physiol A Physiol 110:159–165 Wang HW, Tedla N, Hunt JE, Wakefield D, McNeil HP (2005) Mast cell accumulation and cytokine expression in the tight skin mouse model of scleroderma. Exp Dermatol 14:295–302 Kihira C, Mizutani H, Asahi K, Hamanaka H, Shimizu M (1998) Increased cutaneous immunoreactive stem cell factor expression and serum stem cell factor level in systemic scleroderma. J Dermatol Sci 20:72–78 Yamamoto T, Takagawa S, Katayama I, Yamazaki K, Hamazaki Y, Shinkai H, Nishioka K (1999) Animal model of sclerotic skin. I: local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol 112:456–462 Yamamoto T, Takahashi Y, Takagawa S, Katayama I, Nishioka K (1999) Animal model of sclerotic skin. II. Bleomycin induced scleroderma in genetically mast cell deficient WBB6F1-W/W(V) mice. J Rheumatol 26:2628–2634 Yamamoto T (2006) The bleomycin-induced scleroderma model: what have we learned for scleroderma pathogenesis? Arch Dermatol Res 297:333–344 Gruber BL (1995) Mast cells: accessory cells which potentiate fibrosis. Int Rev Immunol 12:259–279 Jeong WI, Lee CS, Park SJ, Chung JY, Jeong KS (2002) Kinetics of macrophages, myofibroblasts and mast cells in carbon tetrachloride-induced rat liver cirrhosis. Anticancer Res 22:869–877 Toth T, Toth-Jakatics R, Jimi S, Ihara M, Urata H, Takebayashi S (1999) Mast cells in rapidly progressive glomerulonephritis. J Am Soc Nephrol 10:1498–1505 Kondo S, Kagami S, Kido H, Strutz F, Muller GA, Kuroda Y (2001) Role of mast cell tryptase in renal interstitial fibrosis. J Am Soc Nephrol 12:1668–1676 Claman HN (1989) On scleroderma. Mast cells, endothelial cells, and fibroblasts. JAMA 262:1206–1209 Gruber BL (2003) Mast cells in the pathogenesis of fibrosis. Curr Rheumatol Rep 5:147–153 Jordana M, Befus AD, Newhouse MT, Bienenstock J, Gauldie J (1988) Effect of histamine on proliferation of normal human adult lung fibroblasts. Thorax 43:552–558 Hatamochi A, Fujiwara K, Ueki H (1985) Effects of histamine on collagen synthesis by cultured fibroblasts derived from guinea pig skin. Arch Dermatol Res 277:60–64 Gruber BL, Kew RR, Jelaska A, Marchese MJ, Garlick J, Ren S, Schwartz LB, Korn JH (1997) Human mast cells activate fibroblasts: tryptase is a fibrogenic factor stimulating collagen messenger ribonucleic acid synthesis and fibroblast chemotaxis. J Immunol 158:2310–2317 Cairns JA, Walls AF (1997) Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. J Clin Invest 99:1313–1321 Abe M, Kurosawa M, Igarashi Y, Ishikawa O, Miyachi Y (2000) Influence of IgE-mediated activation of cultured human mast cells on proliferation and type I collagen production by human dermal fibroblasts. J Allergy Clin Immunol 106:S72–S77 Claman HN (1990) Mast cells and fibrosis. The relevance to scleroderma. Rheum Dis Clin North Am 16:141–151 Sullivan KM, Shulman HM, Storb R, Weiden PL, Witherspoon RP, McDonald GB, Schubert MM, Atkinson K, Thomas ED (1981) Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 57:267–276 Jaffee BD, Claman HN (1983) Chronic graft-versus-host disease (GVHD) as a model for scleroderma. I. Description of model systems. Cell Immunol 77:1–12 Claman HN, Jaffee BD, Huff JC, Clark RA (1985) Chronic graft-versus-host disease as a model for scleroderma. II. Mast cell depletion with deposition of immunoglobulins in the skin and fibrosis. Cell Immunol 94:73–84 Claman HN, Choi KL, Sujansky W, Vatter AE (1986) Mast cell “disappearance” in chronic murine graft-vs-host disease (GVHD)-ultrastructural demonstration of “phantom mast cells”. J Immunol 137:2009–2013 Choi KL, Giorno R, Claman HN (1987) Cutaneous mast cell depletion and recovery in murine graft-vs-host disease. J Immunol 138:4093–4101 Levi-Schaffer F, Mekori YA, Segal V, Claman HN (1990) Histamine release from mouse and rat mast cells cultured with supernatants from chronic murine graft-vs-host splenocytes. Cell Immunol 127:146–158 Levi-Schaffer F, Goldenhersh MA, Segal V, Nagler A (1997) Nedocromil sodium ameliorates skin manifestations in a murine model of chronic graft-versus-host disease. Bone Marrow Transplant 19:823–828 Murphy GF, Sueki H, Teuscher C, Whitaker D, Korngold R (1994) Role of mast cells in early epithelial target cell injury in experimental acute graft-versus-host disease. J Invest Dermatol 102:451–461 Levi-Schaffer F, Segal V, Mekori YA, Claman HN, Hammel I (1991) Morphological evidence for chronic mast cell activation after prolonged exposure with supernatants from chronic graft-versus-host splenocytes. Immunol Lett 27:13–18 Geha RS, Rappaport JM, Twarog FJ, Parkman R, Rosen FS (1980) Increased serum immunoglobulin E levels following allogeneic bone marrow transplantation. J Allergy Clin Immunol 66:78–81 Heyd J, Donnenberg AD, Burns WH, Saral R, Santos GW (1988) Immunoglobulin E levels following allogeneic, autologous, and syngeneic bone marrow transplantation: an indirect association between hyperproduction and acute graft-v-host disease in allogeneic BMT. Blood 72:442–446 Claman HN, Spiegelberg HL (1990) Immunoglobulin dysregulation in murine graft-vs-host disease: a hyper-IgE syndrome. Clin Immunol Immunopathol 56:46–53 Doutrelepont JM, Moser M, Leo O, Abramowicz D, Vanderhaegen ML, Urbain J, Goldman M (1991) Hyper IgE in stimulatory graft-versus-host disease: role of interleukin-4. Clin Exp Immunol 83:133–136 Ushiyama C, Hirano T, Miyajima H, Okumura K, Ovary Z, Hashimoto H (1995) Anti-IL-4 antibody prevents graft-versus-host disease in mice after bone marrow transplantation. The IgE allotype is an important marker of graft-versus-host disease. J Immunol 154:2687–2696 Korngold R, Jameson BA, McDonnell JM, Leighton C, Sutton BJ, Gould HJ, Murphy GF (1997) Peptide analogs that inhibit IgE–Fc epsilon RI alpha interactions ameliorate the development of lethal graft-versus-host disease. Biol Blood Marrow Transplant 3:187–193 Kovarova M, Rivera J (2004) A molecular understanding of mast cell activation and the promise of anti-allergic therapeutics. Curr Med Chem 11:2083–2091