Graft-versus-host disease (GVHD) is a frequent complication following haematopoietic stem cell transplantation. GVHD reveals various skin lesions, such as maculo-papular rash, brownish pigmentation, and scleroderma (1). Although GVHD may present subepidermal blisters caused by vacuolar degeneration of basal cells, the association of bullous pemphigoid (BP) and GVHD is extremely rare (1).We report here a case of BP that developed 4 months after allogeneic bone marrow transplantation (BMT). Interestingly, histopathology revealed necrotic keratinocytes scattered in the spongiotic epidermis, composed of subepidermal blister roof. We further investigated the necrotic keratinocytes for the presence of apoptotic cells and cleaved caspase 3.
CASE REPORTA 57-year-old Japanese woman was diagnosed with acute myelogenous leukaemia in November 2002. She achieved complete remission after chemotherapy with cytarabine, daunorubicin and gemcitabine. In June 2004, the patient underwent allogeneic BMT from her human leukocyte antigen (HLA)-identical older sister. GVHD prophylaxis was attempted with cyclosporine and short-term treatment with methotrexate. Complete remission of the acute myelogenous leukaemia and 100% donor chimerism were confirmed. In October 2004 (4 months after BMT), extensive exudative erythemas with blisters appeared over the patient's entire body surface (Fig. 1a). A biopsy from a fresh vesicle showed subepidermal blistering and moderate infiltration of both eosinophils and lymphocytes in both the dermis and the bulla (Fig. 1b). Dyskeratotic keratinocytes were observed in the epidermis at the roof of the bulla with spongiosis (Fig. 1b, c). Shrunken keratinocytes were also demonstrated in the blister roof of different blisters (Fig. 1d). Direct immunofluorescence of skin biopsy showed linear immunoglobulin G (IgG) deposition in the epidermal basement membrane zone (BMZ). Indirect immunofluorescence of normal human skin revealed circulating IgG anti-BMZ antibodies. Indirect immunofluorescence of 1 M sodium chloride (NaCl)-split skin sections showed IgG reactivity with the epidermal side of the split (Fig. 1e). No circulating anti-BMZ antibodies were detected in the older sister. BP180 and BP230 enzyme-linked immunosorbent assays (ELISAs) of the sera from the patient and her sister were negative. Immunoblot analysis of normal human epidermal extracts did not detect IgG antibodies to either BP180 or BP230. Immunoblot analysis of recombinant proteins of NC16a and C-terminal domains of BP180 showed negative results. Oral prednisolone, 1 mg/kg/day, was started, leading to complete disappearance of the skin lesions within one month. Oral prednisolone was discontinued 6 months later. One year later, the patient died from brain metastasis of leukaemia and progressive renal failure. In order to characterize the necrotic keratinocytes in the blister roof, we conducted transferase dUTP nick end labelling (TUNEL) staining with the ApopTag Plus Fluorescein In Situ Apoptosis Detection Kit (Merck Millipore, Darmstadt, Germany)...