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.
Interdisciplinary Center for Research of Autoimmune Diseases and Department of Medical Science, A. Avogadro University of Eastern Piedmont, I-28100 Novara, Italy.
Annalisa
A
Chiocchetti
Manuela
M
Indelicato
Thea
T
Bensi
Riccardo
R
Mesturini
Mara
M
Giordano
Selina
S
Sametti
Luca
L
Castelli
Flavia
F
Bottarel
Maria Clorinda
MC
Mazzarino
Letizia
L
Garbarini
Francesca
F
Giacopelli
Guido
G
Valesini
Claudio
C
Santoro
Irma
I
Dianzani
Ugo
U
Ramenghi
Umberto
U
Dianzani
D000293:Adolescent; D000328:Adult; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D005838:Genotype; D006801:Humans; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin; D011110:Polymorphism, Genetic; D012307:Risk Factors; D012795:Sialoglycoproteins / Q000097:blood / Q000235:genetics*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology
C506895:SPP1 protein, human; D012795:Sialoglycoproteins; D053495:Osteopontin