Deregulated Type I IFN Response in TREX1-Associated Familial Chilblain Lupus
2013; Elsevier BV; Volume: 134; Issue: 5 Linguagem: Inglês
10.1038/jid.2013.496
ISSN1523-1747
AutoresKatrin Peschke, Franziska Friebe, Nick Zimmermann, Tom Wahlicht, Tina Schumann, Martin Achleitner, Nicole Berndt, Hella Luksch, Rayk Behrendt, Min Ae Lee‐Kirsch, Axel Roers, Claudia Günther,
Tópico(s)Inflammasome and immune disorders
ResumoAicardi–Goutières syndrome cutaneous lupus activity and severity index revised CLASI systemic lupus erythematosus TO THE EDITOR Familial chilblain lupus is a rare autosomal dominant form of lupus erythematosus with cold-induced bluish red inflammatory infiltrates of acral skin that may ulcerate (Lee-Kirsch et al., 2006Lee-Kirsch M.A. Gong M. Schulz H. et al.Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p.Am J Hum Genet. 2006; 79: 731-737Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar). In contrast to sporadic chilblain lupus that occurs mainly in adolescent and adult patients, familial chilblain lupus manifests in early childhood and is caused by heterozygous mutations of genes encoding TREX1 (3' repair exonuclease) or the phosphohydrolase SAMHD1 (sterile alpha motif domain and HD domain containing protein 1) (Rice et al., 2007Rice G. Newman W.G. Dean J. et al.Heterozygous mutations in TREX1 cause familial chilblain lupus and dominant Aicardi-Goutieres syndrome.Am J Hum Genet. 2007; 80: 811-815Abstract Full Text Full Text PDF PubMed Scopus (299) Google Scholar; Lee-Kirsch et al., 2007Lee-Kirsch M.A. Chowdhury D. Harvey S. et al.A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus.J Mol Med. 2007; 85: 531-537Crossref PubMed Scopus (169) Google Scholar; Gunther et al., 2009Gunther C. Meurer M. Stein A. et al.Familial chilblain lupus - a monogenic form of cutaneous lupus erythematosus due to a heterozygous mutation in TREX1.Dermatology. 2009; 219: 162-166Crossref PubMed Scopus (44) Google Scholar; Ravenscroft et al., 2011Ravenscroft J.C. Suri M. Rice G.I. et al.Autosomal dominant inheritance of a heterozygous mutation in SAMHD1 causing familial chilblain lupus.Am J Med Genet A. 2011; 155A: 235-237Crossref PubMed Scopus (85) Google Scholar). TREX1 represents the major intracellular 3'-5' DNA exonuclease and has a high specificity for single-stranded DNA particularly for single-stranded 3' overhangs of double-stranded DNA (Mazur and Perrino, 2001Mazur D.J. Perrino F.W. Excision of 3' termini by the Trex1 and TREX2 3'—>5' exonucleases. Characterization of the recombinant proteins.J Biol Chem. 2001; 276: 17022-17029Crossref PubMed Scopus (117) Google Scholar). SAMHD1 degrades deoxynucleotides, the building blocks of DNA synthesis and has also 3'-5' exonuclease activity (Lee-Kirsch et al., 2013Lee-Kirsch M.A. Wolf C. Gunther C. Aicardi-Goutieres syndrome: a model disease for systemic autoimmunity.Clin Exp Immunol. 2013; (e-pub ahead of print 21 June 2013; doi:10.1111/cei.12160)Google Scholar). TREX1 deficiency was shown to cause intracellular accumulation of single-stranded DNA which may originate from DNA repair processes or the life cycle of endogenous retroelements (Yang et al., 2007Yang Y.G. Lindahl T. Barnes D.E. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease.Cell. 2007; 131: 873-886Abstract Full Text Full Text PDF PubMed Scopus (419) Google Scholar; Stetson et al., 2008Stetson D.B. Ko J.S. Heidmann T. et al.Trex1 prevents cell-intrinsic initiation of autoimmunity.Cell. 2008; 134: 587-598Abstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar). It is thought that recognition of these inappropriately accumulated nucleic acids by the innate immune system leads to a type I IFN response that subsequently induces autoimmunity. TREX1-deficient mice succumb to circulatory failure due to autoimmune-mediated inflammation of the heart and other organs (Morita et al., 2004Morita M. Stamp G. Robins P. et al.Gene-targeted mice lacking the Trex1 (DNase III) 3'—>5' DNA exonuclease develop inflammatory myocarditis.Mol Cell Biol. 2004; 24: 6719-6727Crossref PubMed Scopus (281) Google Scholar; Gall et al., 2012Gall A. Treuting P. Elkon K.B. et al.Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease.Immunity. 2012; 36: 120-131Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar). Genetic ablation of type I IFN signaling in TREX1-deficient mice can fully rescue this phenotype proving a pivotal role of type I IFN activation in the development of autoimmunity (Morita et al., 2004Morita M. Stamp G. Robins P. et al.Gene-targeted mice lacking the Trex1 (DNase III) 3'—>5' DNA exonuclease develop inflammatory myocarditis.Mol Cell Biol. 2004; 24: 6719-6727Crossref PubMed Scopus (281) Google Scholar; Stetson et al., 2008Stetson D.B. Ko J.S. Heidmann T. et al.Trex1 prevents cell-intrinsic initiation of autoimmunity.Cell. 2008; 134: 587-598Abstract Full Text Full Text PDF PubMed Scopus (918) Google Scholar). Type I IFN upregulation is also a typical feature of the rare inflammatory encephalopathy Aicardi–Goutières syndrome (AGS) that clinically resembles intrauterine viral infection (Aicardi and Goutieres, 1984Aicardi J. Goutieres F. A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis.Ann Neurol. 1984; 15: 49-54Crossref PubMed Scopus (371) Google Scholar). AGS phenotypically and genetically overlaps with systemic lupus erythematosus (SLE), and like SLE is also characterized by chronic activation of the type I IFN system (Ramantani et al., 2010Ramantani G. Kohlhase J. Hertzberg C. et al.Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome.Arthritis Rheum. 2010; 62: 1469-1477Crossref PubMed Scopus (153) Google Scholar). AGS is an autosomal recessive disorder caused by biallelic mutations in TREX1, SAMHD1, the three subunits of the RNase H2 complex and adenosin deaminase acting on RNA1 (Lee-Kirsch et al., 2013Lee-Kirsch M.A. Wolf C. Gunther C. Aicardi-Goutieres syndrome: a model disease for systemic autoimmunity.Clin Exp Immunol. 2013; (e-pub ahead of print 21 June 2013; doi:10.1111/cei.12160)Google Scholar). Since all AGS-causing genes encode enzymes which act on nucleic acid substrates, these findings suggests that defects in nucleic acid metabolism can trigger autoimmunity. Given the role of type I IFN in the pathogenesis of SLE and AGS (Wenzel et al., 2005Wenzel J. Worenkamper E. Freutel S. et al.Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus.J Pathol. 2005; 205: 435-442Crossref PubMed Scopus (188) Google Scholar; Lee-Kirsch et al., 2013Lee-Kirsch M.A. Wolf C. Gunther C. Aicardi-Goutieres syndrome: a model disease for systemic autoimmunity.Clin Exp Immunol. 2013; (e-pub ahead of print 21 June 2013; doi:10.1111/cei.12160)Google Scholar), we investigated type I IFN responses in patients with familial chilblain lupus. We analyzed skin and blood of five patients with familial chilblain lupus carrying a heterozygous D18N mutation in TREX1 for expression of type I IFN-induced genes and proteins. In cutaneous lesions from patients with familial chilblain lupus, we detected high expression of the type I IFN inducible myxovirus resistance protein A and CXCL10 (Figure 1a) indicating an ongoing type I IFN response. Interestingly, weak expression of myxovirus resistance protein A was also detectable in non-lesional skin of patients with familial chilblain lupus consistent with a chronic weak type I IFN activation (Figure 1a). Unlike sera from patients with sporadic chilblain lupus or healthy controls, sera of patients with TREX1-associated familial chilblain lupus contained elevated concentrations of the type I IFN inducible chemokine CXCL10 (Figure 1b). We next examined mRNA levels of three type I IFN-induced genes in peripheral blood cells and found them increased in patients with familial compared with sporadic chilblain lupus and healthy controls (Figure 1c). Impairment of the nucleic acid metabolism in patients with TREX1-associated chilblain lupus is present from birth, consistent with the onset of clinical manifestations within the first years of life, which is in contrast to the later manifestation of disease observed in sporadic chilblain lupus. The higher expression of type I IFN-induced genes and CXCL10 in sera of patients with familial compared with polygenic sporadic chilblain lupus may reflect a more sustained chronic activation of the type I IFN system and a more vigorous autoimmune response caused by TREX1 deficiency. Indeed, clinical investigation of patients revealed a more severe phenotype in patients with familial compared with sporadic chilblain lupus. The cutaneous involvement scored by CLASI (cutaneous lupus activity and severity index) or RCLASI (revised CLASI) of patients with TREX1-associated chilblain lupus was more severe compared with sporadic chilblain lupus (Figure 1d) and the patients with TREX1 mutations showed an increased prevalence of systemic involvement including hematologic abnormalities, polyarthritis and antinuclear antibodies (Supplementary Table S1 online). Download .pdf (.3 MB) Help with pdf files Supplementary Information These observations are in keeping with the finding that heterozygous mutations in TREX1 confer an increased risk for SLE (Lee-Kirsch et al., 2007Lee-Kirsch M.A. Gong M. Chowdhury D. et al.Mutations in the gene encoding the 3'-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus.Nat Genet. 2007; 39: 1065-1067Crossref PubMed Scopus (518) Google Scholar). Therefore, clinicians should be aware of systemic manifestations of lupus erythematosus in patients with familial chilblain lupus. Furthermore, our findings also suggest a common pathogenesis of TREX1-associated cutaneous lupus erythematosus and TREX1-associated SLE. To further investigate this hypothesis, we examined TREX1-deficient mice (Morita et al., 2004Morita M. Stamp G. Robins P. et al.Gene-targeted mice lacking the Trex1 (DNase III) 3'—>5' DNA exonuclease develop inflammatory myocarditis.Mol Cell Biol. 2004; 24: 6719-6727Crossref PubMed Scopus (281) Google Scholar), which develop type I IFN-dependent systemic autoimmune disease, for signs of cutaneous inflammation. Macroscopic inspection of 3–8–weeks-old homozygous TREX1-deficient mice revealed variable erythema or erythematous infiltrates with fine scaling in up to 50% of cases (Figure 2a and b). These lesions were not detected in wild-type littermate controls but also occurred in one of nine heterozygous mice. Differences in penetrance and expressivity or the necessity of additional disease-promoting genetic or environmental factors might explain the lower rate of cutaneous involvement in heterozygous mice compared with patients with dominant familial chilblain lupus. The coat of TREX1-deficient animals appeared less glossy and dense. In addition, two animals developed localized diffuse alopecia, which was not observed in controls. Histologically skin lesions showed marked acanthosis, hyperkeratosis, increased leukocyte infiltration of the dermis and localized vacuolar degeneration of the basal cell layer (Figure 2c). Less pronounced but similar histological changes were also frequently detected in non-lesional skin of TREX1- deficient mice. The dermal cellular infiltrate contained increased numbers of MHC class II positive antigen presenting cells, whereas CD3+ lymphocytes were mainly located in the epidermis and only marginally increased in TREX1-deficient mice (Figure 2d, Supplementary Figure S1 online). Along the basement membrane zone, immunofluorescence staining revealed enhanced deposition of immune complexes (IgG and IgM) and complement C3 in mutant versus wild-type littermate controls (Supplementary Figure S1 online), a feature consistent with immune activation in these animals. Skin of TREX1-deficient mice showed enhanced expression of the type I IFN-induced genes Ifit1, Ifi44 and Cxcl10 suggestive of type I IFN mediated induction (Figure 2e). The cellular source of type I IFN within cutaneous lesions could be either non-hematopoietic or hematopoietic cells. Gall et al. suggested non-hematopoietic cells as an important source of the pathogenic type I IFN in TREX1-deficient heart (Gall et al., 2012Gall A. Treuting P. Elkon K.B. et al.Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease.Immunity. 2012; 36: 120-131Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar). As TREX1 is ubiquitously expressed, this would be in support of a cell-intrinsic origin of type I IFN activation. In addition, external triggers including cold may modulate the local immune response. Taken together, the finding of spontaneous type I IFN-dependent cutaneous pathology in TREX1-deficient mice illustrates common pathogenetic pathways in cutaneous as well as systemic TREX1-associated lupus erythematosus. This study was supported by grants from the Deutsche Forschungsgemeinschaft (KFO 249/GU1212/1-1 to CG, KFO 249/LE1074/4-1 to ML-K, KFO 249/AR2133/6-1 to AR) and a MEDDRIVE-grant from the faculty of Medicine, Technical University of Dresden to CG. Supplementary material is linked to the online version of the paper at http://www.nature.com/jid Correction to: Journal of Investigative Dermatology (2014) 134, 1456–1459; doi:10.1038/jid.2013.496; published online 19 December 2013Journal of Investigative DermatologyVol. 134Issue 9PreviewDeregulated Type I IFN Response in TREX1-Associated Familial Chilblain Lupus Full-Text PDF Open Archive
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