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 function of Fas, autoimmunities, lymphadenopathy/splenomegaly, and expansion of CD4/CD8 double-negative (DN) T cells. Dianzani autoimmune/lymphoproliferative disease (DALD) is an ALPS variant lacking DN cells. Both forms have been ascribed to inherited mutations hitting the Fas system but other factors may be involved. A pilot cDNA array analysis on a DALD patient detected overexpression of the cytokine osteopontin (OPN). This observation was confirmed by enzyme-linked immunosorbent assay (ELISA) detection of higher OPN serum levels in DALD patients (n = 25) than in controls (n = 50). Analysis of the OPN cDNA identified 4 polymorphisms forming 3 haplotypes (A, B, and C). Their overall distribution and genotypic combinations were different in patients (N = 26) and controls (N = 158) (P <.01). Subjects carrying haplotype B and/or C had an 8-fold higher risk of developing DALD than haplotype A homozygotes. Several data suggest that these haplotypes influence OPN levels: (1) in DALD families, high levels cosegregated with haplotype B or C; (2) in healthy controls, haplotype B or C carriers displayed higher levels than haplotype A homozygotes; and (3) in AB and AC heterozygotes, mRNA for haplotype B or C was more abundant than that for haplotype A. In vitro, exogenous OPN decreased activation-induced T-cell death, which suggests that high OPN levels are involved in the apoptosis defect.