Search

To assess myocardial involvement in patients with systemic sclerosis (SSc) with no signs or symptoms of cardiac impairment (New York Heart Association functional class I).Fifty patients (45 women, 5 men, age 53.3 +/- 12.9 yrs) who did not complain of serious diseases other than SSc were recruited out of 119 consecutive patients with SSc. Thirty-three were found to have limited cutaneous SSc (lSSc) and 17 diffuse SSc (dSSc). All underwent cardiovascular magnetic resonance imaging (MRI) to determine right and left systolic and diastolic volumes and ventricular ejection fractions (RVEF and LVEF). Thirty-one healthy subjects matched for sex, age, and body surface area (BSA) were studied as controls. Diffusion lung capacity test (DLCO) and high resolution computed tomography were performed to evaluate lung involvement.Disease duration between patients with lSSc (14.1 +/- 11.4 yrs) and those with dSSc (6.9 +/-4.4yrs) was found to be significantly different (p0.003). lSSc patients were older than those with dSSc (54.8 +/- 13.7 yrs vs 50.4 +/- 9.9 yrs, respectively; p0.04). Anticentromere antibodies and Scl-70 were positive in 23 (46%) and 17 patients (34%). Except for the left and right systolic volumes, all unadjusted cardiac MRI measures were significantly reduced in SSc compared to the controls (p0.001 and p0.009). These differences persisted after adjustment for subjects' height and BSA. Raw RVEF data and RVEF data matched for height and BSA were significantly reduced in dSSc patients in comparison to lSSc (p0.03).Compromised RVF was found in patients with asymptomatic SSc. Unlike standard diagnostic techniques, cardiac MRI appears to be a rapid and noninvasive means of determining subclinical right myocardial involvement that is otherwise undetected in patients with SSc.

Fibrotic autoimmune diseases are characterized by an inflammatory process in which fibrogenic cytokines, such as TGFβ and IL6, have a major role. Interestingly, these cytokines are also involved in the generation and function of both an effector T lymphocyte subpopulation, the Th17 cells, and the regulatory T lymphocytes (Treg). These evidences raised the hypothesis that an unbalanced equilibrium induced by the overproduction of the fibrogenic cytokines may have pathogenic relevance in fibrotic autoimmune diseases. On this basis, this review analyzes the available data concerning Th17 and Treg generation and function in two representative fibrotic autoimmune diseases, primary biliary cirrhosis (PBC) and systemic sclerosis (SSc), as models for organ-specific and systemic diseases, respectively. With regard to the Th17 cells, their expansion was found to be a common feature associated with a relative contraction of Th1 immune responses. Concerning to the regulatory T cell compartment, quantitative and qualitative alterations were observed in both diseases. However, while PBC patients showed defects only in the CD8 + Treg subset, SSc patients demonstrated abnormalities regarding to both the CD4 + CD25 + and the CD8 + Treg subpopulations. Hence, the CD8 + Treg subset seems to be the most involved in the pathogenic cascade leading to fibrotic disease onset and maintenance. Collectively, the reviewed data support the concept that altered homeostasis between effector and regulatory T cell circuits is present in fibrotic autoimmune diseases and that the major factors responsible for such disequilibrium are Th17 cells in the effector arm and CD8 + Treg in the regulatory arm. © 2012 Elsevier B.V

The mechanisms that lead to loss of tolerance in autoimmune disease have remained both elusive and diverse, including both genetic predisposition and generic dysregulation of critical mononuclear cell subsets. In primary biliary cirrhosis (PBC), patients exhibit a multilineage response to the E2 component of pyruvate dehydrogenase involving antibody as well as autoreactive CD4 and CD8 responses. Recent data from murine models of PBC have suggested that a critical mechanism of biliary destruction is mediated by liver-infiltrating CD8 cells. Further, the number of autoreactive liver-infiltrating CD4 and CD8 cells is significantly higher in liver than blood in patients with PBC. Based on this data, we have studied the frequencies and phenotypic characterization of both CD4 and CD8 regulatory T cell components in both patients with PBC and age-sex matched controls. Our data is striking and indicate that CD8 Treg populations from PBC patients, but not controls, have significant phenotypic alterations, including increased expression of CD127 and reduced CD39. Furthermore, in vitro induction of CD8 Tregs by incubation with IL10 is significantly reduced in PBC patients. Importantly, the frequencies of circulating CD4+CD25+ and CD8+ and CD28- T cell subpopulations are not significantly different between patients and controls. In conclusion, these data identify the CD8 Treg subset as a regulatory T cell subpopulation altered in patients with PBC. © 2010 Elsevier Ltd

Objective. Ig molecules contain epitopes that can induce T cell-mediated immune responses. B cells can process and present such epitopes and activate T cells. The purpose of the present study was to test our hypothesis that T cells that recognize an Ig consensus sequence presented by B cells will modulate lupus-like disease in mice. Methods. (NZB x NZW)F1 (NZB/NZW) lupus mice received somatic B cell gene transfer of a DNA plasmid encoding a consensus sequence of T cell determinants of murine anti-DNA IgG or control plasmids. Treated animals were monitored for the production of antibody, the development of renal disease, and the phenotype, number, and function of T cells. Results. Treatment of mice with Ig consensus plasmid induced transforming growth factor β-producing CD8+,CD28- T cells that suppressed the antigen-specific stimulation of CD4+ T cells in a cell-contact-independent manner, reduced antibody production, retarded the development of nephritis, and improved survival. Significantly, adoptive transfer of CD8+,CD28- T cells from protected mice into hypergammaglobulinemic NZB/NZW mice effectively protected the transferred mice from the development of renal disease. Conclusion. Gene expression of anti-DNA Ig consensus sequence induces immunoregulatory T cells that delay the development of lupus nephritis by suppressing hypergammaglobulinemia and renal disease. © 2007, American College of Rheumatology.

Treatment of (NZB × NZW)F1 (NZB/W) lupus-prone mice with the anti-DNA Ig-based peptide pConsensus prolongs the survival of treated animals and effectively delays the appearance of autoantibodies and glomerulonephritis. We have previously shown that part of these protective effects associated with the induction of CD4+CD25+Foxp3+ regulatory T cells (Tregs) that suppressed autoantibody responses. Because the effects of pConsensus appeared secondary to qualitative rather than quantitative changes in Tregs, we investigated the molecular events induced by tolerance in Tregs and found that signaling pathways including ZAP70, p27, STAT1, STAT3, STAT6, SAPK, ERK, and JNK were not significantly affected. However, peptide tolerization affected in Tregs the activity of the MAPK p38, whose phosphorylation was reduced by tolerance. The pharmacologic inhibition of p38 with the pyridinyl imidazole inhibitor SB203580 in naive NZB/W mice reproduced in vivo the effects of peptide-induced tolerance and protected mice from lupus-like disease. Transfer experiments confirmed the role of p38 in Tregs on disease activity in the NZB/W mice. These data indicate that the modulation of p38 activity in lupus Tregs can significantly influence the disease activity.