Expression profiles of collagens, HSP47, TGF-b1, MMPs and TIMPs in epidermolysis bullosa acquisita Mohammed S. Razzaque a , Suman Kumari a , C. Stephen Foster b , A. Razzaque Ahmed a, * a Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA 02115, USA b Department of Ophthalmology, Immunology and Uveitis Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Received 2 November 2002; received in revised form 14 January 2003; accepted 15 January 2003 Abstract Epidermolysis bullosa acquisita (EBA) is a chronic, uncommon, sub-epidermal blistering disease involving the skin and mucous membranes that heals with scar formation and milia. Collagens, matrix metalloproteinases (MMPs) and tissue inhibitors of metal- loproteinases (TIMPs) are important components that play an essential role(s) in matrix remodeling during scar formation. How- ever, the possible involvement of these components in EBA-induced scarring is not yet known. In the present study, we examined the expression profile of collagens, collagen-binding heat shock protein 47 (HSP47), MMPs and their inhibitory enzymes, TIMPs, in matrix remodeling during conjunctival scarring. The involvement of TGF-b1, a fibrogenic factor, was also studied. Compared to the controls, an increased expression of type I collagen, type III collagen and HSP47 was detected in conjunctival biopsy sections of patient with EBA using immunohistochemistry. Similar increase in the expression of type I collagen, type III collagen and HSP47 was noted in conjunctival fibroblasts obtained from the patient with EBA. Up-regulation in the expression of MMP-1 and MMP-14 was also noted in conjunctival fibroblasts isolated from the patient with EBA, while no significant changes in the expression of MMP-3, MMP-8, MMP-9 and MMP-13 were seen. As for TIMPs, conjunctival fibroblasts isolated from the patient with EBA, grown in vitro, exhibited increased expression of TIMP-1, TIMP-2 and TIMP-3, when compared with fibroblasts grown from con- trol conjunctival tissues, although the expression level varies with different molecules of the same family. Additionally, compared to the control conjunctival fibroblasts, an increased expression of TGF-b1 was detected in fibroblasts isolated from the conjunctival tissues of patient with EBA. This study suggests that there is up-regulation in the production of collagens (type I and III), collagen-binding protein (HSP47), matrix degrading collagenases (MMP-1 and 14), and their inhibitory enzymes (TIMP-1, 2 and 3) during the process of conjunctival matrix remodeling in the patient with EBA. The presented data is preliminary and could serve as a basis for further studies to enhance our understanding about the molecular mechanisms of conjunctival scarring in patients with EBA. Ó 2003 Elsevier Science Ltd. All rights reserved. Keywords: Conjunctiva; Fibroblast; Epidermolysis bullosa acquisita; Collagen; HSP47; Matrix metalloproteinases; Tissue inhibitors of metallo- proteinases 1. Introduction Epidermolysis bullosa acquisita (EBA) is a rare, chronic, sub-epidermal, muco-cutaneous blistering dis- ease characterized by fragility of the affected tissue with spontaneous as well as trauma-induced blisters that heal with scar formation and milia [1]. It is non-hereditary and usually begins in adulthood, although cases of child- hood onset have been described [2]. An association with the HLA-DR2 allele has been shown, with enhanced sus- ceptibility to developing EBA [3]. The diagnostic criteria for EBA include fragility and blistering at affected sites that may be spontaneous but are often trauma-induced. EBA can have a clinical profile similar to that of bullous pemphigoid, and presents with widespread highly inflam- matory vesicles and bullae [4]. An additional clinical pre- sentation is rather similar to cicatricial pemphigoid, and involves mucosa of the eyes, esophagus and ano-genital www.elsevier.com/locate/jnlabr/ycyto * Corresponding author. Fax: +1-617-432-4436. E-mail address: razzaque_ahmed@hms.harvard.edu (A.R. Ahmed). Cytokine 21 (2003) 207–213 1043-4666/03/$ - see front matter Ó 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1043-4666(03)00034-6