Rheumatology Advance Access originally published online on November 22, 2007
Rheumatology 2008 47(1):103-104; doi:10.1093/rheumatology/kem259
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LETTERS TO THE EDITOR |
The candidate lupus susceptibility gene Ifi202a is largely dispensable for B-cell function
Roche Palo Alto, Palo Alto, CA, USA
Correspondence to: S. L. Peng, 3431 Hillview Ave., M/S A2-259, Palo Alto, CA 94304, USA. E-mail: stanford.peng{at}roche.com
SIR, The transcriptional modulator Ifi202 has been implicated in the pathogenesis of lupus via genetic studies in the vicinity of the Nba2 locus [1]. It is a member of the interferon-inducible Ifi200 cluster of genes located on mouse chromosome 1, which bears homology to a cluster of three human chromosome 1 genes (MNDA, IFI 16 and AIM2 [2]), all of which share a largely conserved 
200 amino acid domain and have been implicated in multiple cellular processes, including cellular proliferation and apoptosis, by virtue of their ability to modulate the activity of relevant transcriptional regulators such as p53 [3], Rb, E2F [4] and NF-
B [5]. In lupus, Ifi202 has been proposed to regulate apoptosis in B-cells, perhaps via modulation of p53 [1, 6], thereby contributing to the underlying B-cell hyperactivity that causes disease. In addition, Ifi202 appears to be up-regulated in response to IL-6, which has also been implicated in lupus pathogenesis [7], and may be a target of the lupus autoantibody response, at least in mice [8]. However, much of the evidence linking Ifi202 and lupus pathogenesis has remained largely correlative and is based upon studies with Nba2 congenic mice, where a non-coding single-nucleotide polymorphism (SNP) appears to modulate the expression of Ifi202 [1, 6].
To explore the role of Ifi202 in immunity, we examined the B-cell phenotype of Ifi202a-deficient (Ifi202KO) mice [9], expecting to observe attenuated B-cell activation, correlating with the findings in Nba2 animals, which exhibit elevated Ifi202 expression [1]. This study was approved by and performed according to International Animal Care and Use Committee (IACUC)-approved guidelines and protocols. Compared with wild-type littermates (Ifi202WT), Ifi202KO animals developed normal B-cell populations and subpopulations, including marginal zone, B1 and transitional cells, as judged by appropriate B220, CD5, CD11b, CD23, CD21, immunoglobin (Ig)M and IgD staining of splenocytes and lymph node cells in flow cytometry (data not shown). Surprisingly, however, Ifi202KO B-cells exhibited largely normal apoptotic, proliferative and class switching/Ig secretion (of all Ig isotypes) phenotypes in vitro, in response to anti-IgM, anti-CD40 or lipopolysaccharide, in the presence or absence of IL-4, IFN-
or TGF-β (Fig. 1A–C and data not shown). Indeed, if anything, Ifi202KO B-cells appeared to demonstrate hyper-activity under some conditions, such as in response to anti-IgM + IL-4 (Fig. 1A). In addition, Ifi202KO mice exhibited normal humoral responses to immunization with the T-dependent antigen, NP-KLH, as judged by total anti-NP IgM, IgG and IgG isotype analyses (Fig. 1D and data not shown). Thus, Ifi202a is grossly dispensable for B-cell functions and, if anything, suppresses B-cell function, at least as judged by B-cell proliferation and Ig production in vitro (Fig. 1A and C).
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These findings question the role of Ifi202 in the pathogenesis of lupus. In this sense, it is interesting to note that therapeutic interventions in some mouse lupus models fail to correlate with effects on Ifi202 activity and/or expression—e.g. Ifi202 levels are unaffected in NZB animals deficient in the type I IFN receptor despite their overall protection from disease [10]. The present findings suggest that at least under some conditions, Ifi202 actually suppresses B-cell activation and/or proliferation, perhaps through its previously described ability to suppress cellular growth and activity via Rb, E2F [4] and/or NF-
B [5]. Thus the physiological functions of Ifi202 may be context-dependent, questioning its utility as a pathogenic target or disease biomarker in lupus. At the same time, it should be emphasized that the Ifi200 cluster does include additional members, such as Ifi203 and Ifi204, whose functions may be redundant with Ifi202. As such, although it seems clear from the present studies that Ifi202a is not necessary for normal B-cell homeostasis and function, making unlikely the possibility that its up-regulated expression accounts for the B-cell phenotype associated with the Nba2 locus [1], future studies will hopefully continue to explore the relative roles of the Ifi200 family members in lupus and B cells and perhaps other cell types, such as T-cells, which express Ifi202, with increased attention to the potentially overlapping and/or distinct roles of different family members.
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Acknowledgements |
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We thank Peter Lengyel for the gracious provision of Ifi202a-deficient mice.
Funding: This work was supported in part by a grant from the National Institutes of Health (NIH) (R01 AI057571) to S.L.P.
Disclosure statement: The authors have declared no conflicts of interest.
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TopAcknowledgementsReferences |
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[Abstract/Free Full Text]
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  D. Choubey Comment on: The candidate lupus susceptibility gene Ifi202a is largely dispensable for B-cell function Rheumatology, April 1, 2008; 47(4): 558 - 559. [Full Text] [PDF]
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