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.
Chiocchetti
Annalisa
A
Interdisciplinary Center for Research of Autoimmune Diseases and Department of Medical Science, A. Avogadro University of Eastern Piedmont, I-28100 Novara, Italy.
Indelicato
Manuela
M
Bensi
Thea
T
Mesturini
Riccardo
R
Giordano
Mara
M
Sametti
Selina
S
Castelli
Luca
L
Bottarel
Flavia
F
Mazzarino
Maria Clorinda
MC
Garbarini
Letizia
L
Giacopelli
Francesca
F
Valesini
Guido
G
Santoro
Claudio
C
Dianzani
Irma
I
Ramenghi
Ugo
U
Dianzani
Umberto
U
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