Role of tissue inhibitor of metalloproteinases-1 in the development of autoimmune lymphoproliferation.
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.
Boggio
Elena
E
Department of Medical Sciences, Interdisciplinary Research Center of Autoimmune Diseases, A AvogadroUniversity of Eastern Piedmont, Novara, Italy.
Indelicato
Manuela
M
Orilieri
Elisabetta
E
Mesturini
Riccardo
R
Mazzarino
Maria Clorinda
MC
Campagnoli
Maria Francesca
MF
Ramenghi
Ugo
U
Dianzani
Umberto
U
Chiocchetti
Annalisa
A
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
D019715:Tissue Inhibitor of Metalloproteinase-1; D053495:Osteopontin