Abstract
Among the earliest pathologic events in systemic sclerosis (SSc) is the infiltration of mononuclear cells into the skin lesion. This inflammatory cell in filtration precedes the development of fibrosis, suggesting an integral role for the presence of these cells in the fibrotic events observed in the lesion. However, immunosuppressive therapies that are effective in other autoimmune disease have not been successful in the treatment of SSc, making the clinical management of this disease very difficult. The aim of this paper is to review the latest findings regarding the activation and the functional polarization of T cells and their role in the pathogenesis of SSc. Furthermore, the potential role of B cells, a hitherto scantily investigated inflammatory cell in SSc, is discussed. Understanding the interplay between T and B cells, and the processes that promote the fibrotic cytokine pattern seen in these patients is of utmost importance for the development of effective therapies to treat the clinical complications.
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References and Recommended Reading
Prescott RJ, Freemont AJ, Jones CJ, et al.: Sequential dermal microvascular and perivascular changes in the development of scleroderma. J Pathol 1992, 166:255–263.
Chizzolini C, Parel Y, De Luca C, et al.: Systemic sclerosis Th2 cells inhibit collagen production by dermal fibroblasts via membrane-associated tumor necrosis factor alpha. Arthritis Rheum 2003, 48:2593–2604.
Mavilia C, Scaletti C, Romagnani P, et al.: Type 2 helper T-cell predominance and high CD30 expression in systemic sclerosis. Am J Pathol 1997, 151:1751–1758.
Yurovsky V V, Wigley FM, Wise R A, et al.: Skewing of the CD8+ T-cell repertoire in the lungs of patients with systemic sclerosis. Hum Immunol 1996, 48:84–97.
Sakkas LI, Xu B, Artlett CM, et al.: Oligoclonal T cell expansion in the skin of patients with systemic sclerosis. J Immunol 2002, 168:3649–3659.
Farge D, Henegar C, Carmagnat M, et al.: Analysis of immune reconstitution after autologous bone marrow transplantation in systemic sclerosis. Arthritis Rheum 2005, 52:1555–1563. Immune reconstitution after autologous HSCT was analyzed every 3 months in seven patients with SSc. Two groups of patients were retrospectively constituted according to whether they had a favorable clinical response (group A; n = 4) or no response or a relapse of disease (group B; n = 3). It was found that B and T lymphocyte populations remained disturbed for at least 1 year after HSCT in SSc patients, and it was thought that this may reflect the persistence of an underlying disease mechanism.
Tiev KP, Abriol J, Burland MC, et al.: T cell repertoire in patients with stable scleroderma. Clin Exp Immunol 2005, 139:348–354.
Veeraraghavan S, Renzoni EA, Jeal H, et al.: Mapping of the immunodominant T cell epitopes of the protein topoisomerase I. Ann Rheum Dis 2004, 63:982–987.
Ruzek MC, Jha S, Ledbetter S, et al.: A modified model of graft-versus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease. Arthritis Rheum 2004, 50:1319–1331. Many animal models resembling SSc have all but failed to reproduce all the aspects of the disease. This model was novel in that it induced a GVHD response by the introduction of spleen cells from B10.D2 mice into BALB/c mice deficient in mature T and B cells (R AG2 knockout). This modified GVHD model of SSc successfully demonstrated evidence of dermal thickening in the extremities, progressive fibrosis of internal organs, early immune activation, inf lammation in skin and internal organs, and autoantibody generation. Making this one of the most valuable animal models of SSc to date.
Hasegawa M, Fujimoto M, Kikuchi K, et al.: Elevated serum levels of interleukin 4 (IL-4), IL-10, and IL-13 in patients with systemic sclerosis. J Rheumatol 1997, 24:328–332.
Hasegawa M, Sato S, Echigo T, et al.: Up regulated expression of fractalkine/CX3CL1 and CX3CR1 in patients with systemic sclerosis. Ann Rheum Dis 2005, 64:21–28. This study looked at the role of fractalkine and its receptor in SSc. Fractalkine is expressed on endothelial cells mediates activation and adhesion of leukocytes expressing its receptor, CX(3)CR1. Fractalkine was strongly expressed on endothelial cells in the affected skin and lung tissues. Soluble fractalkine levels were significantly raised in sera and were associated with raised erythrocyte sedimentation rates, digital ischaemia, and severity of pulmonary fibrosis.
Scala E, Paganelli R, Sampogna F, et al.: Alpha4beta1 integrin and alpha4beta7 CD4 T cell numbers increase and CLA CD4 T cell numbers decrease in systemic sclerosis. Clin Exp Immunol 2005, 139:551–557. Peripheral blood mononuclear cells were examined from 51 patients with SSc. It was found that alpha4beta1(+) and alpha4beta7(+) cells within the CD4(+) T cell population were significantly increased, while CL A(+) CD4(+) T cells were significantly reduced in SSc, compared with healthy donors. Lung involvement was related to alpha4beta1(+) cell numbers and inversely to alpha4beta7(+) CD4 cell numbers. The findings demonstrate that distinct CD4(+) T cell populations with selective homing properties show changes from normal distribution in SSc and are related to clinical expression and organ involvement.
Stratton RJ, Coghlan JG, Pearson JD, et al.: Different patterns of endothelial cell activation in renal and pulmonary vascular disease in scleroderma. Q J Med 1998, 91:561–566.
Kuryliszyn-Moskal A, Klimiuk PA, Sierakowski S: 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 2005, 24:111–116.
Stummvoll GH, Aringer M, Grisar J, et al.: Increased transendothelial migration of scleroderma lymphocytes. Ann Rheum Dis 2004, 63:569–574.
Kalogerou A, Gelou E, Mountantonakis S, et al.: Early T cell activation in the skin from patients with systemic sclerosis. Ann Rheum Dis 2005, 64:1233–1235.
Brinckmann J, Kim S, Wu J, et al.: Interleukin 4 and prolonged hypoxia induce a higher gene expression of lysyl hydroxylase 2 and an altered cross-link pattern: important pathogenetic steps in early and late stage of systemic scleroderma? Matrix Biology 2005, 24:459–468.
Matsushita M, Yamamoto T, Nishioka K: Upregulation of interleukin-13 and its receptor in a murine model of bleomycin-induced scleroderma. Int Arch Allergy Immunol 2004, 135:348–356.
Sato H, Lagan AL, Alexopoulou C, et al.: The TNF-863A allele strongly associates with anticentromere antibody positivity in scleroderma. Arthritis Rheum 2004, 50:558–564.
Lund FE, Garvy BA, Randall TD, et al.: Regulatory roles for cytokine-producing B cells in infection and autoimmune disease. Curr Dir Autoimmun 2005, 8:25–54. This article gives an excellent review on B cells and their potential role in autoimmune diseases beyond the production of autoantibodies. It covers cytokines produced by B cells, B cell response to T-cell derived signaling and antigen, and the crosstalk between B cells and T cells. It is a very timely, thorough, and provocative review.
Townsend SE, Goodnow CC: Abortive proliferation of rare T cells induced by direct or indirect antigen presentation by rare B cells in vivo. J Exp Med 1998, 187:1611–1621.
Saverino D, Merlo A, Bruno S, et al.: Dual effect of CD85/leukocyte Ig-like receptor-1/Ig-like transcript 2 and CD152 (CTLA-4) on cytokine production by antigen-stimulated human T cells. J Immunol 2002, 168:207–215.
Gabrielli A, Di Loreto C, Taborro R, et al.: Immunohistochemical localization of intracellular and extracellular associated TGF beta in the skin of patients with systemic sclerosis (scleroderma) and primar y Raynaud’s phenomenon. Clin Immunol Immunopathol 1993, 68:340–349.
Sato S, Hasegawa M, Takehara K: Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis. J Dermatol Sci 2001, 27:140–146.
Hoshino K, Takeuchi O, Kawai T, et al.: Cutting edge: tolllike receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the LPS gene product. J Immunol 1999, 162:3749–3752.
Krop I, Shaffer AL, Fearon DT, et al.: The signaling activity of murine CD19 is regulated during cell development. J Immunol 1996, 157:48–56.
Sato S, Fujimoto M, Hasegawa M, et al.: Altered blood B lymphocyte homeostasis in systemic sclerosis. Arthritis Rheum 2004, 50:1918–1927.
Sato S, Hasegawa M, Fujimoto M, et al.: Quantitative genetic variation in CD19 expression correlates with autoimmunity. J Immunol 2000, 165:6635–6643.
Tedder TF, Sato S, Poe JC, et al.: CD19 and CD22 regulate a B lymphocyte signal transduction pathway that contributes to autoimmunity. Keio J Med 2000, 49:1–13.
Tsuchiya N, Kuroki K, Fujimoto M, et al.: Association of a functional CD19 polymorphism with susceptibilit y to systemic sclerosis. Arthritis Rheum 2004, 50:4002–4007. This study investigates the role of functional CD19 polymorphisms in 134 patients with SSc and 96 healthy controls. CD19 expression levels in the peripheral blood naive and memory B cells from SSc patients were also examined. It was found that the carrier frequencies of the -499T allele in the promoter were significantly increased as was the (GT)(14) repeat. These alleles were in linkage disequilibrium, but the -499T allele seemed to play a primary role.
Kaufman J, Sime PJ, Phipps RP: Expression of CD154 (CD40 ligand) by human lung fibroblasts: differential regulation by INF-γ and IL-13, and implications for fibrosis. J Immunol 2004, 172:1862–1871. The CD40-CD40 ligand (CD40L) system (CD154) is one central means of immune cell communication crucial for immunoglobulin class switching and enhanced antigen presentation. It has been found that disruption of the CD40-CD40L pathway reduces lung inflammation and fibrosis, autoimmune disease and atherosclerosis. This study, demonstrates that human lung fibroblasts derived from normal and scarred lung express CD40L mRNA and protein. Importantly, fibroblast strains from human idiopathic pulmonary fibrosis tissue expressed increased levels of CD40L compared with fibroblasts from nonscarred lung. Fibroblast-derived CD40L may play a role in promoting fibroblast activation by the interaction with CD40 bearing cells.
Flaxenburg JA, Melter M, Lapchak PH, et al.: The CD40-induced signaling pathway in endothelial cells resulting in the overexpression of vascular endothelial grow th factor involves Ras and phosphatidylinositol 3-kinase. J Immunol 2004, 172:7503–7509. CD40 induces the e xpression of several proinf lammator y c y tokines as well as angiogenic factors, such as vascular endothelial growth factor. Despite the impor tance of CD40 in cell-mediated immunity, little is known about its signaling pathways in endothelial cells. This study f inds that Ras and PI3K are intermediaries in CD40-induced regulation of vascular endothelial growth factor in endothelial cells.
Komura K, Sato S, Hasegawa M, et al.: Elevated circulating CD40L concentrations in patients with systemic sclerosis. J Rheumatol 2004, 31:514–519.
Gentiletti J, McCloskey LJ, Artlett CM, et al.: Demonst ration of autoimmunit y in t he tight skin-2 mouse: a model for scleroderma. J Immunol 2005, 175:2418–2426. The tight skin-2 (Tsk2/+) mouse has been proposed as an animal model of SSc because this animal exhibits increased collagen synthesis and accumulation in the dermis. This study reports that Tsk2/+ mice harbor numerous autoantibodies in their plasma including some, which are similar to those, present in SSc patients. The high frequency of anti-Scl70 and anti-centromere autoantibodies indicates that Tsk2/+ mice display some humoral immune alterations which are similar to those found in patients with SSc. However, the Tsk2/+ mice also develop autoantibodies to dsDNA and a majority of the mice develop multiple autoantibody specificities (anti-Scl70, anti-CENP-B, and anti-dsDNA) indicating that the mouse may be a useful model to study autoimmunity in a wider spectrum of connective tissue diseases.
Siracusa LD, McGrath R, Ma Q, et al.: A tandem duplication within the.brillin 1 gene is associated with the mouse tight skin mutation. Genome Res 1996, 6:300–313.
Bona C, Rothfield N: Autoantibodies in scleroderma and tight skin mice. Curr Opin Immunol 1994, 6:931–937.
Samarkos M, Vaiopoulos G: Role of infections in the pathogenesis of autoimmune diseases. Curr Drug Targets Inflamm Allergy 2005, 14:694–698.
Asano N, Fujimoto M, Yazawa N, et al.: B lymphocyte signaling established by the CD19/CD22 loop regulates autoimmunity in the tight-skin mouse. Am J Pathol 2004, 165:641–650.
Saito E, Fujimoto M, Hasegawa M, et al.: CD19-depepdent B lymphocyte signaling thresholds influence skin.brosis and autoimmunity in the tight skin mouse. J Clin Invest 2002, 109:1453–1462.
Santos MM, de Sousa M, Rademakers LH, et al.: Iron overload and heart.brosis in mice deficient for both beta2-microglobulin and Rag1. Am J Pathol 2000, 157:1883–1892.
Hart TK, Blackburn MN, Brigham-Burke M, et al.:Preclinical efficacy and safety of pascolizumab (SB 240683): a humanized anti-interleukin-4 antibody with therapeutic potential in asthma. Clin Exp Immunol 2002, 130:93–100.
Ong C, Wong C, Roberts CR, et al.: Anti-IL-4 treatment prevents dermal collagen deposition in the tight-skin mouse model of scleroderma. Eur J Immunol 1998, 28:2619–2629.
Nishimoto N, Yoshizaki K, Miyasaka N, et al.: Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebocontrolled trial. Arthritis Rheum 2004, 50:1761–1769.
Ito H: Treatment of Crohn’s disease with anti-IL-6 receptor antibody. J Gastroenterol 2005, 40(Suppl 16):32–34.
Kitani A, Hara M, Hirose T, et al.: Autostimulatory effects of IL-6 on excessive B cell differentiation in patients with systemic lupus erythematosus: analysis of IL-6 production and IL-6R expression. Clin Exp Immunol 1992, 88:75–83.
Kong HH, Prose NS, Ware RE, et al.: Successful treatment of refractory childhood Pemphigus Vulgaris with anti- CD20 monoclonal antibody (rituximab). Pediatr Dermatol 2005, 22:461–464.
Goebeler M, Herzog S, Broker EB, et al.: Rapid response of treatment-resistant pemphigus foliaceua to the anti-CD20 antibody rituximab. Br J Dermatol 2003, 149:899–901.
Arin MJ, Engert A, Krieg T, et al.: Anti-CD20 monoclonal antibody (rituximab) in the treatement of pemphigus. Br J Dermatol 2005, 153:620–625.
Ratanatharathorn V, Ayash L, Reynolds C, et al.: Treatment of chronic graft-versus-host disease with anti-CD20 chimeric monoclonal antibody. Biol Blood Marrow Transplant 2003, 9:505–511.
Gollob JA, Mier JW, Veenstra K, et al.: Phase I trial of twice-weekly intravenous interleukin 12 in patients with metastatic renal cell cancer or malignant melanoma: ability to maintain IFN-gamma induction is associated with clinical response. Clin Cancer Res 2000, 6:1678–1692.
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Galdo, F.D., Artlett, C.M. T cells and B cells in the pathogenesis of systemic sclerosis: Recent insights and therapeutic opportunities. Curr Rheumatol Rep 8, 123–130 (2006). https://doi.org/10.1007/s11926-006-0052-0
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DOI: https://doi.org/10.1007/s11926-006-0052-0