Rheumatology Advance Access originally published online on February 13, 2008
Rheumatology 2008 47(4):558-559; doi:10.1093/rheumatology/ken018
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Comment on: The candidate lupus susceptibility gene Ifi202a is largely dispensable for B-cell function
Department of Environmental Health, University of Cincinnati, Cincinnati, OH, USA
Correspondence to: D. Choubey. Department of Environmental Health, University of Cincinnati, 3223 Eden Avenue, Kettering Laboratory, PO Box 670056, Cincinnati, OH, USA. E-mail: Divaker.choubey{at}uc.edu
SIR, We read with interest the letter by Bupp et al. [1] concerning the candidate lupus susceptibility gene Ifi202a. They conclude that the Ifi202a gene is largely dispensable for B-cell function. However, we feel that Bupp et al. provided incomplete information in their letter concerning Ifi202 genes. Moreover, before we conclude that the Ifi202a gene is largely dispensable for B-cell function, we feel there are a number of observations that need to be considered.
A study by Wang et al. [2] revealed that Ifi202a gene is a member of the Ifi202 gene subfamily. The subfamily includes Ifi202a, Ifi202b and Ifi202c genes. The Ifi202a gene encodes p202a protein and the Ifi202b gene encodes p202b protein. The p202b protein differs from the p202a protein in only 7 of 445 amino acids [2]. This observation suggested that p202a and p202b proteins are highly related to each other. The study also reported that co-expression of Ifi202a and Ifi202b mRNA is detectable in several cells and tissues in wild-type mice. Interestingly, ratios of Ifi202a and Ifi202b mRNAs differ among various organs and tissues and the ratio is 1 : 1.2 in the spleen [2]. These observations suggest that in splenic cells from the wild-type mice the steady state levels of the Ifi202b mRNA are relatively higher than the Ifi202a.
Importantly, the study by Wang et al. [2] reported that the Ifi202a knockout (Ifi202a–/–) mice do not have any phenotype. This is in part because in organs (including the spleen) and in mouse embryonic fibroblasts (MEFs) from the knockout mice the Ifi202b mRNA and protein levels are detectable. Interestingly, there is a post-transcriptional compensatory increase in p202b protein levels in the Ifi202a–/– MEFs. Therefore, Wang et al. [2] concluded that compensatory increases in p202b protein levels in Ifi202a knockout mice may explain the lack of phenotype.
Because increased expression of Ifi202 gene in B6.Nba2 congenic (congenic for Nba2 locus derived from New Zealand Black (NZB) mice on C57BL/6 background) mice is associated with development of lupus-like disease [3], we compared steady state levels of Ifi202a and Ifi202b mRNA by RT-PCR in splenocytes from young (
10 week old) female NZB, C57BL/6 (B6) and B6.Nba2 mice using primer sets specific for either Ifi202a or Ifi202b gene, as described by Wang et al. [2]. In these experiments, we noted that expression of Ifi202a and Ifi202b mRNA was detectable in NZB mice (data not shown). However, in contrast to the previous report [2], levels of Ifi202a mRNA were relatively higher than Ifi202b. Moreover, consistent with our previous observations [3], expression of Ifi202a mRNA was not detectable in B6 mice (data not shown). However, relatively low levels of Ifi202b mRNA were detectable. Because expression of p202 (both p202a and p202b) protein is not detectable in cells from the B6 mice [3], our observations raise the possibility that post-transcriptional mechanisms contribute to the lack of detection of p202b protein in B6 mice. Furthermore, expression of both Ifi202a and Ifi202b was detectable in B6.Nba2 mice and levels of Ifi202a mRNA were relatively higher than Ifi202b (data not shown). Together, our observations are consistent with the idea that Ifi202a and Ifi202b genes are co-expressed in splenic cells of certain strains of mice, including the B6.Nba2 congenic mice.
Because Ifi202a knockout mice express structurally and functionally-related protein p202b [2], it is not surprising that Ifi202a gene is dispensable for B-cell functions. Moreover, based on observations by Wang et al. [2], it is conceivable that a compensatory increase in expression levels of p202b protein in splenic B cells from the Ifi202a knockout mice could account for suppression of B-cell function noted by Bupp et al. [1]. Furthermore, in the text and in figure of the letter [1], the authors incorrectly used the term Ifi202 (instead of Ifi202a). In light of the observations by Wang et al. [2] and our observations described above, the conclusion by Bupp et al. and some statements in the letter are open for more than one interpretation, therefore, the letter is confusing.
Expression of Ifi202 genes (most likely both Ifi202a and Ifi202b) is also regulated in IFN-independent manner [4]. This could account for our observation that p202 (possibly both p202a and p202b) levels are unaffected in NZB mice that are deficient in the type-I IFN receptor despite their overall protection from disease [5]. Because the type-I IFN is needed for nuclear localization of p202 (possibly both p202a and p202b) protein [6], it seems likely that in cells from the type-I IFN receptor-deficient NZB mice, the protein p202 is not localized in the nucleus. Therefore, the p202 protein is predicted to be non-functional. This could account for overall protection from the disease in the NZB mice that are deficient in the type-I IFN receptor.
Currently available antibodies to p202 protein cannot distinguish between p202a and p202b proteins (our unpublished observations). Therefore, further studies are needed to determine whether increased expression of the p202a or the p202b (or both p202a and p202b proteins) in B6.Nba2 mice accounts for the B-cell phenotype observed in our studies [3]. Moreover, because expression levels of p202 protein in certain cells are regulated by transcriptional and post-transcriptional mechanisms [4], generation of double knockout (Ifi202–/– and Ifi202b–/–) mice may allow us to determine whether the Ifi202 genes are dispensable for B-cell functions.
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The author thanks H. Xin for technical help and Drs S. Rozzo and B. Kotzin for providing mouse splenocytes.
Funding: Research work was supported by a grant from the National Institutes of Health (NIH; R01 AI066261).
Disclosure statement: The author has declared no conflicts of interest.
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- Bupp MRG, Li M, Pashine A, Aud D, Peng SL. The candidate lupus susceptibility gene Ifi202a is largely dispensable for B-cell function. Rheumatology (2008) 47:103–4.
[Free Full Text] - Wang H, Chatterjee G, Meyer JJ, et al. Characteristics of three homologous 202 genes (Ifi202a, Ifi202b, and Ifi202c) from the murine interferon-activatable gene 200 cluster. Genomics (1999) 60:281–94.[CrossRef][Web of Science][Medline]
- Rozzo SJ, Allard JD, Choubey D, et al. Evidence for an interferon-inducible gene, Ifi202, in the susceptibility to systemic lupus. Immunity (2001) 15:435–43.[CrossRef][Web of Science][Medline]
- Choubey D, Kotzin BL. Interferon-inducible p202 in the susceptibility to systemic lupus. Front Biosci (2002) 7:e252–62.[Web of Science][Medline]
- Satiago-Raber ML, Baccala R, Haraldsson KM, et al. Type-I interferon receptor deficiency reduces lupus-like disease in NZB mice. J Exp Med (2003) 197:777–88.
[Abstract/Free Full Text] - Choubey D, Pramanik R, Xin H. Subcellular localization and mechanisms of nucleo-cytoplasmic distribution of p202, an interferon-inducible candidate for lupus susceptibility. FEBS Lett (2003) 553:245–9.[CrossRef][Web of Science][Medline]
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