Deregulated PSGL-1 Expression in B Cells and Dendritic Cells May Be Implicated in Human Systemic Sclerosis Development

Abstract

Systemic sclerosis (SSc) is an autoimmune disorder with high morbidity and mortality, is difficult to diagnose early, and has no curative treatment. PSGL-1 is a leukocyte receptor whose deficiency in mice promotes an SSc-like disease. ADAM8, a metalloprotease that cleaves PSGL-1, is implicated in inflammatory processes. Our goal was to evaluate whether PSGL-1 and ADAM8 contribute to the pathogenesis of human SSc. We found that patients with SSc presented increased PSGL-1 expression on monocytes, dendritic cells, and T cells and decreased expression of PSGL-1 on B cells. PSGL-1 on monocytes from SSc patients failed to induce Syk phosphorylation or IL-10 production after interaction with P-selectin. Up to 60% of the IL-10-producing B cells expressed PSGL-1, pointing to a regulatory role for PSGL-1 in B cells, and PSGL-1 B cells from SSc patients had decreased IL-10 production. ADAM8 expression was increased on antigen-presenting cells and T lymphocytes of SSc patients. Patients treated with calcium antagonists had lower levels of ADAM8 on APCs and T lymphocytes. Multivariate analysis indicated that the high percentage of ADAM8-expressing plasmacytoid dendritic cells discriminated patients from healthy donors. High PSGL-1 expression on dendritic cells was associated with the presence of interstitial lung disease.

Relevance of PSGL-1 Expression in B Cell Development and Activation

“…It was recently described that less than 10% of human circulating B cells expressed PSGL-1 in human healthy donors (31). In this work, the proportion of human circulating B cells expressing different types of Igs was analyzed in healthy donors and, as expected, most B cells were naïve (IgD + IgM + ) and only a small percentage presented isotype switching (IgG + or IgA + ) ( Figure 6A).…”

“…Interestingly, PSGL-1 expression is decreased in peripheral blood B cells from SSc patients compared with age-matched healthy controls and these PSGL-1 + B cells from SSc patients present decreased IL-10 production. Moreover, PSGL-1 fails to induce Syk phosphorylation and IL-10 production in monocytes from SSc patients after interaction with P-selectin, thus highlighting the loss of PSGL-1 regulatory role in SSc (31).…”

“…In the case of P-selectin deficient mice (P-sel −/− ), lack of PSGL-1/P-selectin interaction results in a systemic lupus erythematosus (SLE)-like syndrome, characterized by the production of SLE-specific autoantibodies such as anti-dsDNA or anti-RNP, reduced dermal T effector/Treg ratio, and lung and renal involvement (28). Remarkably, in humans, up to 60% of the IL-10-producing B cells express PSGL-1, pointing to a regulatory role for PSGL-1 in B cells (31). Interestingly, PSGL-1 expression is decreased in peripheral blood B cells from SSc patients compared with age-matched healthy controls and these PSGL-1 + B cells from SSc patients present decreased IL-10 production.…”

Systemic Sclerosis Associated Interstitial Lung Disease: A Comprehensive Overview

“…74 The immune system is clearly implicated in the pathogenesis and progression of SSc-ILD, although the mechanisms linking immune-mediated inflammation to fibrosis remain unclear. [75][76][77][78][79][80] Downstream of the initiating disease-specific pathogenetic events, the fibrotic process is similar in many ways to other fibrotic ILDs, with multiple profibrotic pathways leading to the activation of mesenchymal cells including fibroblasts and myofibroblasts, excessive formation and insufficient degradation of extracellular matrix with progressive deposition of fibrosis, and destruction of the normal lung architecture. 40,81 Interestingly, the immune system dysregulation clearly continues to play a role even when lung fibrosis is extensive, as suggested by the findings of the SLS-I trial.…”

Novel insights into dendritic cells in the pathogenesis of systemic sclerosis

“…Another factor which might be involved in the development of SSc is P‐selectin glycoprotein ligand‐1 (PSGL‐1) . Increased expression of PSGL‐1 specifically in SSc cDCs was associated with the presence and severity of interstitial lung disease (ILD), although the precise role of DCs in ILD development is not clear.…”