BAFF levels are increased in lesional skin and sera in patients with cutaneous T-cell lymphoma
H. Ohmatsu
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorM. Sugaya
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorT. Miyagaki
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorH. Suga
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorH. Fujita
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorY. Asano
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorY. Tada
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorT. Kadono
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorS. Sato
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorH. Ohmatsu
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorM. Sugaya
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorT. Miyagaki
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorH. Suga
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorH. Fujita
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorY. Asano
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorY. Tada
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorT. Kadono
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorS. Sato
Department of Dermatology, Faculty of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
Search for more papers by this authorFunding sources These studies were supported by grants from the Ministry of Education, Culture, Sports and Technology (Japan).
Conflicts of interest None declared.
Summary
Background B-cell-activating factor belonging to the tumour necrosis factor family (BAFF) is known for its role in the survival and maturation of B cells. It has been recently suggested that BAFF also plays important roles in T-cell activation in T-cell mediated diseases such as psoriasis.
Objectives To investigate the role of BAFF in cutaneous T-cell lymphoma (CTCL).
Methods BAFF messenger RNA (mRNA) expression in skin samples (24 CTCL cases and seven healthy controls) and in skin-derived fibroblasts (five CTCL cases and five healthy controls) was examined by quantitative reverse transcription–polymerase chain reaction. We also performed immunohistochemical staining for BAFF and its receptors. Serum BAFF levels were measured in patients with CTCL (n = 46), atopic dermatitis (n = 36) or psoriasis (n = 27) and 27 healthy controls by enzyme-linked immunosorbent assay.
Results Lesional skin of CTCL contained higher levels of BAFF mRNA than normal skin and the expression levels correlated with disease activity. BAFF mRNA expression levels were elevated in fibroblasts from CTCL skin. Tumour cells in the lesional skin of CTCL expressed BAFF and its receptors, while fibroblasts expressed only BAFF. Serum BAFF levels of CTCL patients were significantly higher than those of healthy controls and correlated with types of skin lesions and clinical stages. They also significantly correlated with serum soluble interleukin-2 receptor and lactate dehydrogenase levels.
Conclusions BAFF expression in CTCL skin and serum BAFF levels are significantly increased and correlate with the severity of CTCL. These results suggest that BAFF may have important roles in the development of CTCL.
References
- 1 Schneider P, MacKay F, Steiner V et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 1999; 189: 1747–56.
- 2 Moore PA, Belvedere O, Orr A et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 1999; 285: 260–3.
- 3 Shu HB, Hu WH, Johnson H. TALL-1 is a novel member of the TNF family that is down-regulated by mitogens. J Leukoc Biol 1999; 65: 680–3.
- 4 Mukhopadhyay A, Ni J, Zhai Y et al. Identification and characterization of a novel cytokine, THANK, a TNF homologue that activates apoptosis, nuclear factor-kappaB, and c-Jun NH2-terminal kinase. J Biol Chem 1999; 274: 15978–81.
- 5 Nardelli B, Belvedere O, Roschke V et al. Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood 2001; 97: 198–204.
- 6 Litinskiy MB, Nardelli B, Hilbert DM et al. DCs induce CD40-independent immunoglobulin class switching through BLyS and APRIL. Nat Immunol 2002; 3: 822–9.
- 7 Craxton A, Magaletti D, Ryan EJ et al. Macrophage- and dendritic cell-dependent regulation of human B-cell proliferation requires the TNF family ligand BAFF. Blood 2003; 101: 4464–71.
- 8 Krumbholz M, Theil D, Derfuss T et al. BAFF is produced by astrocytes and up-regulated in multiple sclerosis lesions and primary central nervous system lymphoma. J Exp Med 2005; 201: 195–200.
- 9 Scapini P, Nardelli B, Nadali G et al. G-CSF-stimulated neutrophils are a prominent source of functional BLyS. J Exp Med 2003; 197: 297–302.
- 10 Ng LG, Sutherland AP, Newton R et al. B cell-activating factor belonging to the TNF family (BAFF)-R is the principal BAFF receptor facilitating BAFF costimulation of circulating T and B cells. J Immunol 2004; 173: 807–17.
- 11 Mackay F, Leung H. The role of the BAFF/APRIL system on T cell function. Semin Immunol 2006; 18: 284–9.
- 12 Chu VT, Enghard P, Riemekasten G et al. In vitro and in vivo activation induces BAFF and APRIL expression in B cells. J Immunol 2007; 179: 5947–57.
- 13 Yamada T, Lizhong S, Takahashi N et al. Poly(I:C) induces BLyS-expression of airway fibroblasts through phosphatidylinositol 3-kinase. Cytokine 2010; 50: 163–9.
- 14 Reyes LI, León F, González P et al. Dexamethasone inhibits BAFF expression in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Cytokine 2008; 42: 170–8.
- 15 Mackay F, Browning JL. BAFF: a fundamental survival factor for B cells. Nat Rev Immunol 2002; 2: 465–75.
- 16 Mackay F, Schneider P, Rennert P et al. BAFF AND APRIL: a tutorial on B cell survival. Annu Rev Immunol 2003; 21: 231–64.
- 17 Thien M, Phan TG, Gardam S et al. Excess BAFF rescues self-reactive B cells from peripheral deletion and allows them to enter forbidden follicular and marginal zone niches. Immunity 2004; 20: 785–98.
- 18 von Bulow GU, Bram RJ. NF-AT activation induced by a CAML-interacting member of the tumor necrosis factor receptor superfamily. Science 1997; 278: 138–41.
- 19 Wang H, Marsters SA, Baker T et al. TACI-ligand interactions are required for T cell activation and collagen-induced arthritis in mice. Nat Immunol 2001; 2: 632–7.
- 20 Novak AJ, Bram RJ, Kay NE et al. Aberrant expression of B-lymphocyte stimulator by B chronic lymphocytic leukemia cells: a mechanism for survival. Blood 2002; 100: 2973–9.
- 21 Kern C, Cornuel JF, Billard C et al. Involvement of BAFF and APRIL in the resistance to apoptosis of B-CLL through an autocrine pathway. Blood 2004; 103: 679–88.
- 22 Parameswaran R, Muschen M, Kim YM et al. A functional receptor for B-cell-activating factor is expressed on human acute lymphoblastic leukemias. Cancer Res 2010; 70: 4346–56.
- 23 Novak AJ, Darce JR, Arendt BK et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood 2004; 103: 689–94.
- 24 Moreaux J, Legouffe E, Jourdan E et al. BAFF and APRIL protect myeloma cells from apoptosis induced by interleukin 6 deprivation and dexamethasone. Blood 2004; 103: 3148–57.
- 25 Nishio M, Endo T, Tsukada N et al. Nurselike cells express BAFF and APRIL, which can promote survival of chronic lymphocytic leukemia cells via a paracrine pathway distinct from that of SDF-1alpha. Blood 2005; 106: 1012–20.
- 26 Mackay F, Tangye SG. The role of the BAFF/APRIL system in B cell homeostasis and lymphoid cancers. Curr Opin Pharmacol 2004; 4: 347–54.
- 27 Cheema GS, Roschke V, Hilbert DM et al. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum 2001; 44: 1313–19.
- 28 Zhang J, Roschke V, Baker KP et al. Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 2001; 166: 6–10.
- 29 Stohl W, Metyas S, Tan SM et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum 2003; 48: 3475–86.
- 30 Matsushita T, Hasegawa M, Yanaba K et al. Elevated serum BAFF levels in patients with systemic sclerosis: enhanced BAFF signaling in systemic sclerosis B lymphocytes. Arthritis Rheum 2006; 54: 192–201.
- 31 Yamanishi H, Kumagi T, Yokota T et al. Clinical significance of B cell-activating factor in autoimmune pancreatitis. Pancreas 2011; 40: 840–5.
- 32 Groom JR, Fletcher CA, Walters SN et al. BAFF and MyD88 signals promote a lupuslike disease independent of T cells. J Exp Med 2007; 204: 1959–71.
- 33 Sarantopoulos S, Stevenson KE, Kim HT et al. High levels of B-cell activating factor in patients with active chronic graft-versus-host disease. Clin Cancer Res 2007; 13: 6107–14.
- 34 Sarantopoulos S, Stevenson KE, Kim HT et al. Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease. Blood 2009; 113: 3865–74.
- 35 Lavie F, Miceli-Richard C, Quillard J et al. Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sjogren’s syndrome. J Pathol 2004; 202: 496–502.
- 36 Seyler TM, Park YW, Takemura S et al. BLyS and APRIL in rheumatoid arthritis. J Clin Invest 2005; 115: 3083–92.
- 37 Kuwano Y, Fujimoto M, Watanabe R et al. Serum BAFF and APRIL levels in patients with alopecia areata. J Dermatol Sci 2008; 50: 236–9.
- 38 Samoud-El Kissi S, Galai Y, Sghiri R et al. BAFF is elevated in serum of patients with psoriasis: association with disease activity. Br J Dermatol 2008; 159: 765–8.
- 39 Yamaguchi T, Ohshima K, Tsuchiya T et al. The comparison of expression of cutaneous lymphocyte-associated antigen (CLA), and Th1- and Th2-associated antigens in mycosis fungoides and cutaneous lesions of adult T-cell leukemia/lymphoma. Eur J Dermatol 2003; 13: 553–9.
- 40 Kakinuma T, Sugaya M, Nakamura K et al. Thymus and activation-regulated chemokine (TARC/CCL17) in mycosis fungoides: serum TARC levels reflect the disease activity of mycosis fungoides. J Am Acad Dermatol 2003; 48: 23–30.
- 41 Notohamiprodjo M, Segerer S, Huss R et al. CCR10 is expressed in cutaneous T-cell lymphoma. Int J Cancer 2005; 115: 641–7.
- 42 Vowels BR, Lessin SR, Cassin M et al. Th2 cytokine mRNA expression in skin in cutaneous T-cell lymphoma. J Invest Dermatol 1994; 103: 669–73.
- 43 Dummer R, Heald PW, Nestle FO et al. Sezary syndrome T-cell clones display T-helper 2 cytokines and express the accessory factor-1 (interferon-gamma receptor beta-chain). Blood 1996; 88: 1383–9.
- 44 Saed G, Fivenson DP, Naidu Y et al. Mycosis fungoides exhibits a Th1-type cell-mediated cytokine profile whereas Sezary syndrome expresses a Th2-type profile. J Invest Dermatol 1994; 103: 29–33.
- 45 Chong BF, Wilson AJ, Gibson HM et al. Immune function abnormalities in peripheral blood mononuclear cell cytokine expression differentiates stages of cutaneous T-cell lymphoma/mycosis fungoides. Clin Cancer Res 2008; 14: 646–53.
- 46 Krejsgaard T, Ralfkiaer U, Clasen-Linde E et al. Malignant cutaneous T-cell lymphoma cells express IL-17 utilizing the Jak3/Stat3 signaling pathway. J Invest Dermatol 2011; 131: 1331–8.
- 47 Miyagaki T, Sugaya M, Suga H et al. IL-22, but not IL-17, dominant environment in cutaneous T-cell lymphoma. Clin Cancer Res 2011; 17: 7529–38.
- 48 Miyagaki T, Sugaya M, Fujita H et al. Eotaxins and CCR3 interaction regulates the Th2 environment of cutaneous T-cell lymphoma. J Invest Dermatol 2010; 130: 2304–11.
- 49 Willemze R, Jaffe ES, Burg G et al. WHO-EORTC classification for cutaneous lymphomas. Blood 2005; 105: 3768–85.
- 50 Olsen E, Vonderheid E, Pimpinelli N et al. Revisions to the staging and classification of mycosis fungoides and Sezary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the European Organization of Research and Treatment of Cancer (EORTC). Blood 2007; 110: 1713–22.
- 51 Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1980; 92: 44–7.
- 52 Takashima A. Establishment of fibroblast cultures. In: Current Protocols in Cell Biology. ( JS Bonifacino, M Darso, JB Harford, J Lippincott-Schwartz, KM Yamada, eds.), New Jersey, NJ: John Wiley & Sons, 2001; 2.1.1–2.1.12.
- 53 Marti RM, Estrach T, Reverter JC et al. Prognostic clinicopathologic factors in cutaneous T-cell lymphoma. Arch Dermatol 1991; 127: 1511–16.
- 54 Zachariae C, Larsen CS, Kaltoft K et al. Soluble IL2 receptor serum levels and epidermal cytokines in mycosis fungoides and related disorders. Acta Derm Venereol 1991; 71: 465–70.
- 55 Wasik MA, Vonderheid EC, Bigler RD et al. Increased serum concentration of the soluble interleukin-2 receptor in cutaneous T-cell lymphoma clinical and prognostic implications. Arch Dermatol 1996; 132: 42–7.
- 56 Asano Y, Ihn H, Yamane K et al. Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts. J Clin Invest 2004; 113: 253–64.
- 57 Dobbeling U, Dummer R, Laine E et al. Interleukin-15 is an autocrine/paracrine viability factor for cutaneous T-cell lymphoma cells. Blood 1998; 92: 252–8.
- 58 Chen J, Petrus M, Bryant BR et al. Autocrine/paracrine cytokine stimulation of leukemic cell proliferation in smoldering and chronic adult T-cell leukemia. Blood 2010; 116: 5948–56.
- 59 Miyagaki T, Sugaya M, Murakami T et al. CCL11–CCR3 interactions promote survival of anaplastic large cell lymphoma cells via ERK1/2 activation. Cancer Res 2011; 71: 2056–65.
- 60 Schiemann B, Gommerman JL, Vora K et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 2001; 293: 2111–14.
- 61 Gross JA, Johnston J, Mudri S et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature 2000; 404: 995–9.
- 62 Avery DT, Kalled SL, Ellyard JI et al. BAFF selectively enhances the survival of plasmablasts generated from human memory B cells. J Clin Invest 2003; 112: 286–97.
- 63 Novak AJ, Grote DM, Stenson M et al. Expression of BLyS and its receptors in B-cell non-Hodgkin lymphoma: correlation with disease activity and patient outcome. Blood 2004; 104: 2247–53.
- 64 Matsushita T, Fujimoto M, Echigo T et al. Elevated serum levels of APRIL, but not BAFF, in patients with atopic dermatitis. Exp Dermatol 2008; 17: 197–202.
- 65 Hallermann C, Kaune KM, Tiemann M et al. High frequency of primary cutaneous lymphomas associated with lymphoproliferative disorders of different lineage. Ann Hematol 2007; 86: 509–15.
