Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p.
OBJECTIVE
Systemic lupus erythematosus (SLE) is associated with type I interferons (IFNs) and can be induced by IFNalpha treatment. This study looked for evidence of autoimmunity in a pedigree consisting of 4 family members with a balanced translocation 9;21 and 2 members with an unbalanced translocation resulting in trisomy of the short (p) arm and part of the long (q) arm of chromosome 9. These latter 2 subjects had 3 copies of the IFN gene cluster.


METHODS
Subjects were evaluated clinically and serologically for autoimmune disease. Expression levels of IFNalpha4, IFNbeta, the type I IFN-inducible gene Mx1, the type I IFN receptor, interleukin-6, and tumor necrosis factor alpha were determined by real-time polymerase chain reaction. Circulating plasmacytoid dendritic cells, the main IFN-producing cells, were quantified by flow cytometry.


RESULTS
Both subjects with trisomy of chromosome 9p had a lupus-like syndrome with joint manifestations and antinuclear antibodies: one had anti-RNP and antiphospholipid autoantibodies, and the other had anti-Ro 60. The 3 family members with a balanced translocation 9;21 had no clinical or serologic evidence of autoimmunity, similar to that in relatives who were unaffected by the chromosomal translocation. In the 2 subjects with trisomy of 9p, high levels of IFNalpha/beta (comparable with those found in patients with SLE), increased signaling through the IFN receptor (as indicated by high Mx1 expression), and low levels of circulating plasmacytoid dendritic cells (as observed in patients with SLE) were evident. These abnormalities were not seen in individuals with a balanced translocation.


CONCLUSIONS
Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFNalpha/beta and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE.
Zhuang
Haoyang
H
University of Florida, Gainesville, USA.
Kosboth
Mona
M
Lee
Pui
P
Rice
Amanda
A
Driscoll
Daniel J
DJ
Zori
Roberto
R
Narain
Sonali
S
Lyons
Robert
R
Satoh
Minoru
M
Sobel
Eric
E
Reeves
Westley H
WH
D000293:Adolescent; D000328:Adult; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005260:Female; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis / Q000235:genetics*; D007621:Karyotyping; D008180:Lupus Erythematosus, Systemic / Q000235:genetics; D008297:Male; D005810:Multigene Family; D010375:Pedigree; D014178:Translocation, Genetic; D014314:Trisomy
D007370:Interferon Type I