title: Antibodies against human cytomegalovirus late protein UL94 in the pathogenesis of scleroderma-like skin lesions in chronic graft-versus-host disease.
abstract: Human cytomegalovirus (hCMV) infection and its reactivation correlate both with the increased risk and with the worsening of graft-versus-host disease (GVHD). Because scleroderma-like skin lesions can occur in chronic GVHD (cGVHD) in allogeneic stem-cell transplant (HCT) patients and hCMV is relevant in the pathogenesis of systemic sclerosis (SSc), we evaluated the possible pathogenetic link between hCMV and skin cGVHD. Plasma from 18 HCT patients was tested for anti-UL94 and/or anti-NAG-2 antibodies, identified in SSc patients, by direct ELISA assays. Both donors and recipients were anti-hCMV IgG positive, without autoimmune diseases. Patients' purified anti-UL94 and anti-NAG-2 IgG binding to human umbilical endothelial cells (HUVECs) and fibroblasts was performed by FACS analysis and ELISA test. HUVECs apoptosis and fibroblasts proliferation induced by patients' anti-NAG-2 antibodies were measured by DNA fragmentation and cell viability, respectively. About 11/18 patients developed cGVHD and all of them showed skin involvement, ranging from diffuse SSc-like lesions to limited erythema. Eight of eleven cGVHD patients were positive for anti-UL94 and/or anti-NAG-2 antibodies. Remarkably, 4/5 patients who developed diffuse or limited SSc-like lesions had antibodies directed against both UL94 and NAG-2; their anti-NAG-2 IgG-bound HUVECs and fibroblasts induce both endothelial cell apoptosis and fibroblasts proliferation, similar to that induced by purified anti-UL94 and anti-NAG-2 antibodies obtained from SSc patients. In conclusion, our data suggest a pathogenetic link between hCMV infection and scleroderma-like skin cGVHD in HCT patients through a mechanism of molecular mimicry between UL94 viral protein and NAG-2 molecule, as observed in patients with SSc.
authors: Hematoncology Division, Bone Marrow Transplant Unit, European Institute of Oncology, Milan, Italy.
authors: Rocco
authors: R
authors: Pastano
authors: Chiara
authors: C
authors: Dell'Agnola
authors: Caterina
authors: C
authors: Bason
authors: Federica
authors: F
authors: Gigli
authors: Cristina
authors: C
authors: Rabascio
authors: Antonio
authors: A
authors: Puccetti
authors: Elisa
authors: E
authors: Tinazzi
authors: Gianluigi
authors: G
authors: Cetto
authors: Fedro
authors: F
authors: Peccatori
authors: Giovanni
authors: G
authors: Martinelli
authors: Claudio
authors: C
authors: Lunardi
mesh_terms: D000328:Adult; D000914:Antibodies, Viral / Q000276:immunology*; D017209:Apoptosis; D036022:Capsid Proteins / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D003429:Cross Reactions; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000150:complications / Q000276:immunology*; D004730:Endothelium, Vascular / Q000276:immunology; D005260:Female; D005347:Fibroblasts / Q000276:immunology; D006086:Graft vs Host Disease / Q000150:complications / Q000276:immunology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D018716:Molecular Mimicry; D012595:Scleroderma, Systemic / Q000150:complications / Q000276:immunology*; D012867:Skin / Q000276:immunology / Q000473:pathology / Q000821:virology; D033581:Stem Cell Transplantation; D059470:Tetraspanins / Q000276:immunology; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D036022:Capsid Proteins; C109139:TSPAN4 protein, human; D059470:Tetraspanins; C415589:UL94 protein, Human cytomegalovirus