High levels of osteopontin associated with polymorphisms in its gene are a risk factor for development of autoimmunity/lymphoproliferation

The autoimmune/lymphoproliferative syndrome(ALPS) displays defective functionof Fas, autoimmunities, lymphadenopathy/splenomegaly, and expansion ofCD4/CD8 double-negative (DN) T cells.Dianzani autoimmune/lymphoproliferativedisease (DALD) is an ALPS variantlacking DN cells. Both forms have beenascribed to inherited mutations hittingthe Fas system but other factors may beinvolved. A pilot cDNA array analysis on aDALD patient detected overexpression ofthe cytokine osteopontin (OPN). This observationwas confirmed by enzymelinkedimmunosorbent assay (ELISA) detectionof higher OPN serum levels inDALD patients (n 25) than in controls(n 50). Analysis of the OPN cDNA identified4 polymorphisms forming 3 haplotypes(A, B, and C). Their overall distributionand genotypic combinations weredifferent in patients (N 26) and controls(N 158) (P < .01). Subjects carrying haplotypeB and/or C had an 8-fold higherrisk of developing DALD than haplotypeAhomozygotes. Several data suggest thatthese haplotypes influence OPN levels:(1) in DALD families, high levels cosegregatedwith haplotype B or C; (2) in healthycontrols, haplotype B or C carriers displayedhigher levels than haplotype Ahomozygotes; and (3) in AB and AC heterozygotes,mRNA for haplotype B or Cwas more abundant than that for haplotypeA. In vitro, exogenous OPN decreasedactivation-induced T-cell death,which suggests that high OPN levels areinvolved in the apoptosis defect. (Blood.2004;103:1376-1382)