An update on an immune system that goes awry in systemic sclerosis

This review aims to provide an overview of the recent data that emerged, further substantiating the critical role of innate immunity in systemic sclerosis (SSc).

Driven by the evidence that newly identified SSc susceptibility genes are predominantly involved in immune regulation, we discuss the aberrant antigen presenting cell (APC) activation observed in the course of disease. In particular, we report the alternate activation of 'M1' and 'M2' macrophages reflecting different clinical phenotypes and the aberrant Toll-like receptor (TLR) response, whose effect on cytokine production is mostly evident in the early phases of disease; we especially highlight the increasing importance attributed to TLR3-mediated fibrosis. We next discuss the potential role for interferon (IFN) - producing plasmacytoid dendritic cells (pDCs) in triggering or perpetuating the inflammatory loop caused by TLR hyperactivation, possibly resulting in inflammasome-derived IL-1β-mediated fibrosis and IL-17 producing T helper cells (Th17) skewing.

We propose to approach SSc as a multistep immune-mediated disease that is in need of a therapeutic strategy designed to interfere with one or more of these aberrant molecular pathways. Targeting of DCs could be such a target by which dampening the immune system could modify the course of SSc.