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. DESIGN AND 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

Analysis of TIMP-1 gene polymorphisms in Italian sclerodermic patients.

Systemic sclerosis (SSc) is an autoimmune disease characterized by skin and internal organs fibrosis due to an extracellular matrix (ECM) accumulation of type I collagen. The turnover of the ECM is dependent on the balance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs). The disruption of this balance is involved in SSc because higher serum TIMP-1 levels have been demonstrated in SSc patients than in controls. On this basis, we analyzed three polymorphisms: -19A&rt;G, +261C&rt;T, and +372T&rt;C of the TIMP-1 gene in SSc patients (67 females, eight males) and controls (29 females, nine males). The C allele of the +372T&rt;C single nucleotide polymorphism (SNP) was observed at a higher frequency in male patients than in healthy individuals (P= 0,02), while no differences were observed in the female subjects. Our findings suggest that the +372T&rt;C polymorphism of the TIMP-1 gene is associated with SSc in male individuals. No association with the clinical characteristics of SSc Italian patients and TIMP-1 gene polymorphisms was observed. Thus, the role of TIMP-1 gene in predisposition to SSc remains controversial