Abstract
Collagen vascular diseases (CVDs) are a heterogeneous group of multisystem autoimmune disorders characterized by the presence of autoantibodies. It is generally accepted that the initiation and progression of CVDs, including lupus erythematosus, systemic sclerosis, and dermatomyositis, are caused by the complex interplay between environmental and intrinsic factors. The presence of autoantibodies and autoantigens derived from dying cells, such as keratinocytes in cutaneous lupus erythematosus and dermatomyositis and endothelial cells in systemic sclerosis, is a common pathological feature shared among these diseases, which leads to the activation of interferon-dependent signalings because immune complexes consisting of autoantibodies and autoantigens promote type I interferon production especially from plasmacytoid dendritic cells. Type I interferon potentially induces autoimmunity by activating innate and adaptive immunity. In addition, interferon directly induces apoptosis as well as vascular damage, two histologic hallmarks of CVDs in the skin. Note that recent progress provides new insights into the better understanding of the disease-specific pathological process connecting the initial events, cell death of keratinocytes or endothelial cells, with the progressive tissue damage via innate and adaptive immune responses. In this chapter, the role of skin immunology in the pathogenesis of cutaneous lupus erythematosus, scleroderma, and dermatomyositis is overviewed.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Allanore Y, Saad M, Dieudé P et al (2011) Genome-wide scan identifies TNIP1, PSORS1C1, and RHOB as novel risk loci for systemic sclerosis. PLoS Genet 7:e1002091
Asano Y, Ihn H, Yamane K et al (2005) Increased expression of integrin alpha(v)beta3 contributes to the establishment of autocrine TGF-beta signaling in scleroderma fibroblasts. J Immunol 175:7708–7718
Asano Y, Ihn H, Yamane K et al (2005) Involvement of alphavbeta5 integrin-mediated activation of latent transforming growth factor beta1 in autocrine transforming growth factor beta signaling in systemic sclerosis fibroblasts. Arthritis Rheum 52:2897–2905
Asano Y, Ihn H, Yamane K et al (2006) Increased expression of integrin alphavbeta5 induces the myofibroblastic differentiation of dermal fibroblasts. Am J Pathol 168:499–510
Asano Y, Ihn H, Yamane K et al (2004) Impaired Smad7-Smurf-mediated negative regulation of TGF-beta signaling in scleroderma fibroblasts. J Clin Invest 113:253–264
Asano Y, Ihn H, Yamane K et al (2004) Increased expression levels of integrin alphavbeta5 on scleroderma fibroblasts. Am J Pathol 164:1275–1292
Baroni SS, Santillo M, Bevilacqua F et al (2006) Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis. N Engl J Med 354:2667–2676
Blomberg S, Eloranta ML, Cederblad B et al (2001) Presence of cutaneous interferon-alpha producing cells in patients with systemic lupus erythematosus. Lupus 10:484–490
Chizzolini C (1999) T lymphocyte and fibroblast interactions: the case of skin involvement in systemic sclerosis and other examples. Springer Semin Immunopathol 21:431–450
Chizzolini C, Parel Y, De Luca C et al (2003) Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor alpha. Arthritis Rheum 48:2593–2604
Chizzolini C, Rezzonico R, Ribbens C et al (1998) Inhibition of type I collagen production by dermal fibroblasts upon contact with activated T cells: different sensitivity to inhibition between systemic sclerosis and control fibroblasts. Arthritis Rheum 41:2039–2047
Church LD, Cook GP, McDermott MF (2008) Primer: inflammasomes and interleukin 1beta in inflammatory disorders. Nat Clin Pract Rheumatol 4:34–42
Espinosa A, Dardalhon V, Brauner S et al (2009) Loss of the lupus autoantigen Ro52/Trim21 induces tissue inflammation and systemic autoimmunity by disregulating the IL-23-Th17 pathway. J Exp Med 206:1661–1671
Espinosa A, Hennig J, Ambrosi A et al (2011) Anti-Ro52 autoantibodies from patients with Sjögren’s syndrome inhibit the Ro52 E3 ligase activity by blocking the E3/E2 interface. J Biol Chem 286:36478–36491
Espinosa A, Zhou W, Ek M et al (2006) The Sjogren’s syndrome-associated autoantigen Ro52 is an E3 ligase that regulates proliferation and cell death. J Immunol 176:6277–6285
Flier J, Boorsma DM, van Beek PJ et al (2001) Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation. J Pathol 194:398–405
Frank MB, Itoh K, Fujisaku A et al (1993) The mapping of the human 52-kD Ro/SSA autoantigen gene to human chromosome 11, and its polymorphisms. Am J Hum Genet 52:183–191
Fu Q, Zhao J, Qian X et al (2011) Association of a functional IRF7 variant with systemic lupus erythematosus. Arthritis Rheum 63:749–754
Giacomelli R, Matucci-Cerinic M, Cipriani P et al (1998) Circulating Vdelta1+ T cells are activated and accumulate in the skin of systemic sclerosis patients. Arthritis Rheum 41:327–334
Graham RR, Kozyrev SV, Baechler EC et al (2006) A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet 38:550–555
Grassi M, Capello F, Bertolino L et al (2009) Identification of granzyme B-expressing CD-8-positive T cells in lymphocytic inflammatory infiltrate in cutaneous lupus erythematosus and in dermatomyositis. Clin Exp Dermatol 34:910–914
Gruschwitz M, Müller PU, Sepp N et al (1990) Transcription and expression of transforming growth factor type beta in the skin of progressive systemic sclerosis: a mediator of fibrosis? J Invest Dermatol 94:197–203
Hamaguchi Y, Kuwana M, Hoshino K et al (2011) Clinical correlations with dermatomyositis-specific autoantibodies in adult Japanese patients with dermatomyositis: a multicenter cross-sectional study. Arch Dermatol 147:391–398
Higgs R, Lazzari E, Wynne C et al (2010) Self protection from anti-viral responses – Ro52 promotes degradation of the transcription factor IRF7 downstream of the viral toll-like receptors. PLoS One 5:e11776
Higgs R, Ní Gabhann J, Ben Larbi N et al (2008) The E3 ubiquitin ligase Ro52 negatively regulates IFN-beta production post-pathogen recognition by polyubiquitin-mediated degradation of IRF3. J Immunol 181:1780–1786
Hill MB, Phipps JL, Cartwright RJ et al (1996) Antibodies to membranes of endothelial cells and fibroblasts in scleroderma. Clin Exp Immunol 106:491–497
Ihn H, Sato S, Fujimoto M et al (1997) Circulating intercellular adhesion molecule-1 in the sera of patients with systemic sclerosis: enhancement by inflammatory cytokines. Br J Rheumatol 36:1270–1275
Ihn H, Sato S, Fujimoto M et al (1998) Increased serum levels of soluble vascular cell adhesion molecule-1 and E-selectin in patients with systemic sclerosis. Br J Rheumatol 37:1188–1192
Järvinen TM, Hellquist A, Koskenmies S et al (2010) Tyrosine kinase 2 and interferon regulatory factor 5 polymorphisms are associated with discoid and subacute cutaneous lupus erythematosus. Exp Dermatol 19:123–131
Kahaleh MB, Fan PS, Otsuka T (1999) Gammadelta receptor bearing T cells in scleroderma: enhanced interaction with vascular endothelial cells in vitro. Clin Immunol 91:188–195
Kalogerou A, Gelou E, Mountantonakis S et al (2005) Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis 64:1233–1235
Kim D, Peck A, Santer D et al (2008) Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: association of higher interferon-alpha activity with lung fibrosis. Arthritis Rheum 58:2163–2173
Kim JS, Bashir MM, Werth VP (2012) Gottron’s papules exhibit dermal accumulation of CD44 variant 7 (CD44v7) and its binding partner osteopontin: a unique molecular signature. J Invest Dermatol 132:1825–1832
Kim JS, Werth VP (2011) Identification of specific chondroitin sulfate species in cutaneous autoimmune disease. J Histochem Cytochem 59:780–790
Kong HJ, Anderson DE, Lee CH et al (2007) Cutting edge: autoantigen Ro52 is an interferon inducible E3 ligase that ubiquitinates IRF-8 and enhances cytokine expression in macrophages. J Immunol 179:26–30
Kono H, Rock KL (2008) How dying cells alert the immune system to danger. Nat Rev Immunol 8:279–289
Kuhn A, Herrmann M, Kleber S et al (2006) Accumulation of apoptotic cells in the epidermis of patients with cutaneous lupus erythematosus after ultraviolet irradiation. Arthritis Rheum 54:939–950
Kulozik M, Hogg A, Lankat-Buttgereit B et al (1990) Co-localization of transforming growth factor beta 2 with alpha 1(I) procollagen mRNA in tissue sections of patients with systemic sclerosis. J Clin Invest 86:917–922
Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S (2005) Soluble adhesion molecules (sVCAM-1, sE-selectin), vascular endothelial growth factor (VEGF) and endothelin-1 in patients with systemic sclerosis: relationship to organ systemic involvement. Clin Rheumatol 24:111–116
Loetscher M, Gerber B, Loetscher P et al (1996) Chemokine receptor specific for IP10 and mig: structure, function, and expression in activated T-lymphocytes. J Exp Med 184:963–969
Magro CM, Segal JP, Crowson AN et al (2010) The phenotypic profile of dermatomyositis and lupus erythematosus: a comparative analysis. J Cutan Pathol 37:659–671
Matsushita T, Hasegawa M, Hamaguchi Y et al (2006) Longitudinal analysis of serum cytokine concentrations in systemic sclerosis: association of interleukin 12 elevation with spontaneous regression of skin sclerosis. J Rheumatol 33:275–284
Mavalia C, Scaletti C, Romagnani P et al (1997) Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis. Am J Pathol 151:1751–1758
Meller S, Winterberg F, Gilliet M et al (2005) Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment: an amplification cycle triggering cutaneous lupus erythematosus. Arthritis Rheum 52:1504–1516
Mimura Y, Ihn H, Jinnin M et al (2005) Constitutive thrombospondin-1 overexpression contributes to autocrine transforming growth factor-beta signaling in cultured scleroderma fibroblasts. Am J Pathol 166:1451–1463
Muñoz LE, Lauber K, Schiller M et al (2010) The role of defective clearance of apoptotic cells in systemic autoimmunity. Nat Rev Rheumatol 6:280–289
Nakashima T, Jinnin M, Yamane K et al (2012) Impaired IL-17 signaling pathway contributes to the increased collagen expression in scleroderma fibroblasts. J Immunol 188:3573–3583
Nishijima C, Hayakawa I, Matsushita T et al (2004) Autoantibody against matrix metalloproteinase-3 in patients with systemic sclerosis. Clin Exp Immunol 138:357–363
Oke V, Vassilaki I, Espinosa A et al (2009) High Ro52 expression in spontaneous and UV-induced cutaneous inflammation. J Invest Dermatol 129:2000–2010
Prescott RJ, Freemont AJ, Jones CJ et al (1992) Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 166:255–263
Querfeld C, Eckes B, Huerkamp C et al (1999) Expression of TGF-beta 1, -beta 2 and -beta 3 in localized and systemic scleroderma. J Dermatol Sci 21:13–22
Radstake TR, Gorlova O, Rueda B et al (2010) Genome-wide association study of systemic sclerosis identifies CD247 as a new susceptibility locus. Nat Genet 42:426–429
Rhodes DA, Ihrke G, Reinicke AT et al (2002) The 52 000 MW Ro/SS-A autoantigen in Sjögren’s syndrome/systemic lupus erythematosus (Ro52) is an interferon-gamma inducible tripartite motif protein associated with membrane proximal structures. Immunology 106:246–256
Rosen A, Casciola-Rosen L (1999) Autoantigens as substrates for apoptotic proteases: implications for the pathogenesis of systemic autoimmune disease. Cell Death Differ 6:6–12
Rosenbaum J, Pottinger BE, Woo P et al (1988) Measurement and characterisation of circulating anti-endothelial cell IgG in connective tissue diseases. Clin Exp Immunol 72:450–456
Salojin KV, Le Tonquèze M, Saraux A et al (1997) Antiendothelial cell antibodies: useful markers of systemic sclerosis. Am J Med 102:178–185
Sato S, Fujimoto M, Hasegawa M et al (2004) Altered B lymphocyte function induces systemic autoimmunity in systemic sclerosis. Mol Immunol 41:1123–1133
Sato S, Hasegawa M, Takehara K (2001) Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci 27:140–146
Sato S, Hayakawa I, Hasegawa M et al (2003) Function blocking autoantibodies against matrix metalloproteinase-1 in patients with systemic sclerosis. J Invest Dermatol 120:542–547
Scharffetter K, Lankat-Buttgereit B, Krieg T (1988) Localization of collagen mRNA in normal and scleroderma skin by in-situ hybridization. Eur J Clin Invest 18:9–17
Sfikakis PP, Tesar J, Baraf H et al (1993) Circulating intercellular adhesion molecule-1 in patients with systemic sclerosis. Clin Immunol Immunopathol 68:88–92
Sgonc R, Gruschwitz MS, Boeck G et al (2000) Endothelial cell apoptosis in systemic sclerosis is induced by antibody-dependent cell-mediated cytotoxicity via CD95. Arthritis Rheum 43:2550–2562
Sgonc R, Gruschwitz MS, Dietrich H et al (1996) Endothelial cell apoptosis is a primary pathogenetic event underlying skin lesions in avian and human scleroderma. J Clin Invest 98:785–792
Shahin AA, Anwar S, Elawar AH et al (2000) Circulating soluble adhesion molecules in patients with systemic sclerosis: correlation between circulating soluble vascular cell adhesion molecule-1 (sVCAM-1) and impaired left ventricular diastolic function. Rheumatol Int 20:21–24
Strandberg L, Ambrosi A, Espinosa A et al (2008) Interferon-alpha induces up-regulation and nuclear translocation of the Ro52 autoantigen as detected by a panel of novel Ro52-specific monoclonal antibodies. J Clin Immunol 28:220–231
Tan FK, Zhou X, Mayes MD et al (2006) Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford) 45:694–702
Tian J, Avalos AM, Mao SY et al (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8:487–496
Torchia D, Caproni M, Volpi W et al (2010) The Fas/Fas ligand system, rather than granzyme B, may represent the main mediator of epidermal apoptosis in dermatomyositis. Clin Exp Dermatol 35:669–670
Urbonaviciute V, Fürnrohr BG, Meister S et al (2008) Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J Exp Med 205:3007–3018
Wenzel J, Zahn S, Mikus S et al (2007) The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets. Br J Dermatol 157:752–757
Whitfield ML, Finlay DR, Murray JI et al (2003) Systemic and cell type-specific gene expression patterns in scleroderma skin. Proc Natl Acad Sci U S A 100:12319–12324
Wong D, Kea B, Pesich R et al (2012) Interferon and biologic signatures in dermatomyositis skin: specificity and heterogeneity across diseases. PLoS One 7:e29161
Zhou X, Lee JE, Arnett FC et al (2009) HLA-DPB1 and DPB2 are genetic loci for systemic sclerosis: a genome-wide association study in Koreans with replication in North Americans. Arthritis Rheum 60:3807–3814
Zhou X, Tan FK, Milewicz DM et al (2005) Autoantibodies to fibrillin-1 activate normal human fibroblasts in culture through the TGF-beta pathway to recapitulate the “scleroderma phenotype”. J Immunol 175:4555–4560
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2016 Springer Japan
About this chapter
Cite this chapter
Asano, Y. (2016). Collagen Vascular Disease. In: Kabashima, K. (eds) Immunology of the Skin. Springer, Tokyo. https://doi.org/10.1007/978-4-431-55855-2_31
Download citation
DOI: https://doi.org/10.1007/978-4-431-55855-2_31
Published:
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-55853-8
Online ISBN: 978-4-431-55855-2
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)