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. 2003 Jun 24;100(13):7503-8.
doi: 10.1073/pnas.0832411100. Epub 2003 Jun 3.

A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen

Dahai Xue  1 , Hong Shi, James D Smith, Xinguo Chen, Dennis A Noe, Tommy Cedervall, Derek D Yang, Elizabeth Eynon, Douglas E Brash, Michael Kashgarian, Richard A Flavell, Sandra L Wolin
Affiliations

A lupus-like syndrome develops in mice lacking the Ro 60-kDa protein, a major lupus autoantigen

Dahai Xue et al. Proc Natl Acad Sci U S A. .

Abstract

Antibodies against a conserved RNA-binding protein, the Ro 60-kDa autoantigen, occur in 24-60% of all patients with systemic lupus erythematosus. Anti-Ro antibodies are correlated with photosensitivity and cutaneous lesions in these patients and with neonatal lupus, a syndrome in which mothers with anti-Ro antibodies give birth to children with complete congenital heart block and photosensitive skin lesions. In higher eukaryotes, the Ro protein binds small RNAs of unknown function known as Y RNAs. Because the Ro protein also binds misfolded 5S rRNA precursors, it is proposed to function in a quality-control pathway for ribosome biogenesis. Consistent with a role in the recognition or repair of intracellular damage, an orthologue of Ro in the radiation-resistant eubacterium Deinococcus radiodurans contributes to survival of this bacterium after UV irradiation. Here, we show that mice lacking the Ro protein develop an autoimmune syndrome characterized by anti-ribosome antibodies, anti-chromatin antibodies, and glomerulonephritis. Moreover, in one strain background, Ro-/- mice display increased sensitivity to irradiation with UV light. Thus, one function of this major human autoantigen may be to protect against autoantibody development, possibly by sequestering defective ribonucleoproteins from immune surveillance. Furthermore, the finding that mice lacking the Ro protein are photosensitive suggests that loss of Ro function could contribute to the photosensitivity associated with anti-Ro antibodies in humans.

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Figures

Fig. 1.
Fig. 1.
Disruption of the Ro gene. (A) Diagram showing the Ro gene locus, the targeting construct, and the recombined mutant allele. The first two exons are indicated by filled boxes, and the translation initiation site is indicated (arrow). (B) Southern analysis of PstI-digested DNA from wild-type (lanes 1 and 2), Ro+/– (lanes 3 and 4), and Ro–/–(lanes 5 and 6) mice. (C) Western blots of brain extracts with a rabbit anti-Ro serum. The blot was reprobed to detect Uch-L5, which runs as a doublet (Middle), and actin (Bottom). (D) Northern blot analyses of brain RNA reveal that Y RNAs are reduced in Ro+/– and Ro–/– mutant mice.
Fig. 2.
Fig. 2.
Glomerulonephritis in Ro–/– mice. Light (A, B, E, F, I, and J; ×200) and electron (C, D, G, H, K, and L; ×5,000) microscopy of kidneys from Ro–/– mice and age-matched controls. Ro–/– and wild-type mice from the original hybrid strain (A–D) were examined at 16.5 months, and backcrossed mice were examined at 7 (E–H) and 12.5 (I–L) months. Age-matched controls show essentially normal histology. The hybrid Ro–/– mice show glomerular hypercellularity with large eosinophilic capillary deposits (B, arrow), which correspond to subendothelial immune complexes (D, arrow). Lesions in the backcrossed mice are less severe, with mesangial immune complexes at 7 months (H, arrow) and larger subendothelial complexes at 12.5 months (L, arrow).
Fig. 3.
Fig. 3.
Autoantibodies in Ro mutant mice. NIH 3T3 cells were stained with sera (diluted 1:1,000) from 6- to 7-month-old Ro–/– mice (A–C) and a 12-month-old wild-type mouse (D). (E) Reference sera (lanes 1 and 2) and sera from Ro–/– mice were used to probe Western blots of L1210 cell extracts. *, Doublet detected by most sera containing anti-ribosomal antibodies. (F) Reference sera (lanes 2–4) and sera from 129/Sv × C57BL/6 hybrid mice were used to immunoprecipitate from L1210 cell extracts. RNAs in immunoprecipitates were labeled with [32P]pCp. *, Band identified as U1 RNA by cDNA sequencing.
Fig. 4.
Fig. 4.
Ro–/– mice are more sensitive to UVB irradiation. (A) After six backcrosses to C57BL/6 mice, the backs of wild-type (n = 8) and Ro–/– (n = 6) mice were shaved and exposed to the indicated doses of UVB. After 24 h, apoptotic keratinocytes (sunburn cells) were counted. (B) The backs of mice from the original hybrid 129/Sv × C57BL/6 strain were shaved and exposed to UVB, and apoptotic keratinocytes were counted. For the 1,000-J/m2 dose, 14 wild-type and 13 Ro–/– mice were examined.
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