The Immune Pathogenesis of Scleroderma: Context Is Everything
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The fundamental mechanisms that drive the pathogenesis of systemic sclerosis (SSc) remain elusive, despite over 50 years of investigation. Here, we review recent progress in the understanding of the immunopathogenesis of SSc. In particular, we consider interleukin-13 (IL13), and its upstream and downstream pathways, as an example of an immune system-derived mediator involved in fibrotic and vascular pathology. Emerging results linking pattern-recognition receptors and interferon pathways to SSc are also stressed. We discuss genetic data linking the immune system to SSc risk and efforts to apply animal models to subsets of patients recently resolved by gene expression profiling. These developments will help build a context for better understanding of previous observations and design of the next generation of studies that may eventually lead to effective treatment.
KeywordsScleroderma Systemic sclerosis Animal models Interleukin-13 Interleukin-33 Toll-like receptor 3 Interferon Immune Pathogenesis
Dr Aliprantis is supported by grants from the Burroughs Wellcome Fund and the National Institutes of Health (K08 AR 054859 and R01 AR060363). Dr Aliprantis’ work relevant to SSc was previously supported by the Scleroderma Research Foundation and Sanofi pharmaceuticals. The authors thank Drs Julia Charles, Susan Ritter, and Joerg Ermann for their thoughtful review and discussion of this manuscript.
No potential conflicts of interest relevant to this article were reported.
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- 6.•• Radstake TR, Gorlova O, Rueda B, et al. Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet. 2010;42(5):426–9. This paper reports the findings of a large GWAS study of SSc, identifying the CD247 locus as involved and confirming previous observations regarding the MHC locus, IRF5, and STAT4.PubMedCrossRefGoogle Scholar
- 7.• Allanore Y, Saad M, Dieude P, et al. Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet. 2011;7(7):e1002091. This GWAS study of SSc confirms the linkage with MHC and identifies the TNIP1, RHOB, and PSORS1C1 loci as involved.PubMedCrossRefGoogle Scholar
- 18.•• Pendergrass SA, Lemaire R, Francis IP, et al. Intrinsic gene expression subsets of diffuse cutaneous systemic sclerosis are stable in serial skin biopsies. J Invest Dermatol. 2012;132(5):1363–73. This work extends the results of Milano et al., furnishing evidence that the SSc subsets identified are stable and may not simply reflect different stages during the development of SSc.PubMedCrossRefGoogle Scholar
- 25.•• Greenblatt MB, Sargent JL, Farina G, et al. Interspecies comparison of human and murine scleroderma reveals IL-13 and CCL2 as disease subset-specific targets. Am J Pathol. 2012;180(3):1080–94. Here we describe the contribution of IL-13 to the SclGVHD model, including the cellular sources and effects of IL-13. Also, molecular profiling of the SclGVHD model is used to map it to the inflammatory subset of SSc patients.PubMedCrossRefGoogle Scholar
- 34.Bellinghausen I, Brand P, Bottcher I, et al. Production of interleukin-13 by human dendritic cells after stimulation with protein allergens is a key factor for induction of T helper 2 cytokines and is associated with activation of signal transducer and activator of transcription-6. Immunology. 2003;108(2):167–76.PubMedCrossRefGoogle Scholar
- 37.• Neill DR, Wong SH, Bellosi A, et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature. 2010;464(7293):1367–70. With Refs.  and , this paper identifies nuocytes as a novel IL-13-producing, IL-25 and IL33-responsive, innate immune cell.PubMedCrossRefGoogle Scholar
- 39.• Price AE, Liang HE, Sullivan BM, et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc Natl Acad Sci USA. 2010;107(25):11489–94. With Refs.  and , this paper identifies systemically dispersed lineage negative cell that secretes IL-13 in response to IL-25 and IL33.PubMedCrossRefGoogle Scholar
- 49.Fichtner-Feigl S, Young CA, Kitani A et al.: IL-13 signaling via IL-13R alpha2 induces major downstream fibrogenic factors mediating fibrosis in chronic TNBS colitis. Gastroenterology 2008, 135(6):2003–2013, 2013 e2001-2007.Google Scholar
- 87.•• Farina GA, York MR, Di Marzio M, et al. Poly(I:C) drives type I IFN- and TGFbeta-mediated inflammation and dermal fibrosis simulating altered gene expression in systemic sclerosis. J Invest Dermatol. 2010;130(11):2583–93. This paper identifies expression of type I interferon and TGFβ target genes in the skin of SSc patients and demonstrates that chronic subcutaneous infusion of type I interferon eliciting poly I:C stimulates inflammation and fibrosis.PubMedCrossRefGoogle Scholar