title: Role of tissue inhibitor of metalloproteinases-1 in the development of autoimmune lymphoproliferation.
abstract: BACKGROUND
  Inherited defects decreasing function of the Fas death receptor cause autoimmune lymphoproliferative syndrome and its variant Dianzani's autoimmune lymphoproliferative disease. Analysis of the lymphocyte transcriptome from a patient with this latter condition detected striking over-expression of osteopontin and tissue inhibitor of metalloproteinases-1. Since previous work on osteopontin had detected increased serum levels in these patients, associated with variations of its gene, the aim of this work was to extend the analysis to tissue inhibitor of metalloproteinases-1.
  
  
  METHODS
  Tissue inhibitor of metalloproteinases-1 levels were evaluated in sera and culture supernatants from patients and controls by enzyme-linked immunosorbent assay. Activation- and Fas-induced cell death were induced, in vitro, using anti-CD3 and anti-Fas antibodies, respectively.
  
  
  RESULTS
  Tissue inhibitor of metalloproteinases-1 levels were higher in sera from 32 patients (11 with autoimmune lymphoproliferative syndrome and 21 with Dianzani's autoimmune lymphoproliferative disease) than in 50 healthy controls (P<0.0001), unassociated with variations of the tissue inhibitor of metalloproteinases-1 gene. Both groups of patients also had increased serum levels of osteopontin. In vitro experiments showed that osteopontin increased tissue inhibitor of metalloproteinases-1 secretion by peripheral blood monocytes. Moreover, tissue inhibitor of metalloproteinases-1 significantly inhibited both Fas- and activation-induced cell death of lymphocytes.
  
  
  CONCLUSIONS
  These data suggest that high osteopontin levels may support high tissue inhibitor of metalloproteinases-1 levels in autoimmune lymphoproliferative syndrome and Dianzani's autoimmune lymphoproliferative disease, and hence worsen the apoptotic defect in these diseases.
authors.affiliation: Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases, A AvogadroUniversity of Eastern Piedmont, Novara, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Boggio
authors.forename: Manuela
authors.initials: M
authors.lastname: Indelicato
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orilieri
authors.forename: Riccardo
authors.initials: R
authors.lastname: Mesturini
authors.forename: Maria Clorinda
authors.initials: MC
authors.lastname: Mazzarino
authors.forename: Maria Francesca
authors.initials: MF
authors.lastname: Campagnoli
authors.forename: Ugo
authors.initials: U
authors.lastname: Ramenghi
authors.forename: Umberto
authors.initials: U
authors.lastname: Dianzani
authors.forename: Annalisa
authors.initials: A
authors.lastname: Chiocchetti
mesh_terms: D000293:Adolescent; D017209:Apoptosis / Q000235:genetics; D056735:Autoimmune Lymphoproliferative Syndrome / Q000097:blood / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D014644:Genetic Variation; D006801:Humans; D008297:Male; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood* / Q000235:genetics
chemical_list: D019715:Tissue Inhibitor of Metalloproteinase-1; D053495:Osteopontin