SYSTEMIC SCLEROSIS AND CHRONIC GRAFT-VERSUS-HOST DISEASE SCLERODERMA-LIKE HAVE OTHER SIMILAR PATHOGENETIC MECHANISMS THAN STIMULATORY AUTOANTIBODIES TO PDGFR?

Background: Chronic graft-versus-host disease (cGVHD), a major complication of allogeneic hematopoietic stem cell transplantation, is a complex multisystem syndrome with overlapping features of immunodeficiency and several of the naturally occurring autoimmune diseases. In particular, scleroderma-like cGVHD may well resemble systemic sclerosis (SSc) in skin and lung involvement. Recent studies suggested that both these diseases are driven by stimulatory autoantibodies to platelet-derived growth factor receptor (PDGFR), which in turn stimulates the production of reactive oxygen species and collagen by fibroblasts. Several case reports, case series and uncontrolled studies on patients with SSc and in sclerodermatous cGvHD describe regression of fibrosis and good tolerability after therapy with Imatinib mesylate, a compound that inhibits PDGFR kinases. Objectives: The aim of this study was to evaluate the role of T-cell clonality in the pathogenesis of SSc and scleroderma-like cGVHD. Methods: We studied 11 female patients affected by SSc and 9 patients (5 male, 4 female) with scleroderma-like cGVHD. Clonality was assessed by analyzing the rearrangement of the T-cell receptor (TCR) gamma gene (region VJA and VJB). Additionally, the lysates prepared from peripheral blood mononuclear cells were studied to detect constitutive phosphorylation of ERK1/2 kinases. We analyzed also expression profiles of genes involved in apoptosis, including BCL2A1, CASP1, CASP6, EGR1, EGR2, FAS, FOS, TNF, TNFRSF1A, transduction signals (IKB, NFkB), intercellular adhesion (ICAM-1), and immune regulation (Fox-p3, CD52, CD83, CXCL1, CCL2, CCL5, IL-10, IL-17). Results: Ten patients (90.9%) with SSc and 5 patients (55.6%) with cGVHD had oligoclonal T-cell expansion. ERK-autophosphorylation was detected in 5 of 10 (50.0%) patients with SSc and in 2 of 5 (22.2%) patients affected by cGVHD. Phosphorylation of ERK1/2 kinases in the other 3 patients with sclerodermatous cGVHD is not available. In addition, we found that expression profiles of several genes implicated in the Th1/Tregs/Th17 responses were similar in patients with SSc or cGVHD, while expression profiles of other genes, particularly those associated with the Th2 response, were different. Conclusions: In conclusion, we think that expanded clonal T-cells could play a critical role in the pathogenetic mechanisms of both SSc and scleroderma-like cGVHD, probably in some cases by the activation of the same gene expression profiles and the same signal transduction pathways. Further studies are needed to confirm these preliminary data and to better explain similarities and differences between these two clinical conditions.