Aberrant immune response with consequent vascular and connective tissue remodeling - causal to scleroderma and associated syndromes such as Raynaud phenomenon and other fibrosing syndromes?

Abstract

Purpose of review: Scleroderma and other autoimmune-induced connective tissue diseases are characterized by dysfunctions in the immune system, connective tissue and the vasculature. We are focusing on systemic sclerosis (SSc)-associated pulmonary hypertension, which remains a leading cause of death with only a 50-60% of 2-year survival rate.

Recent findings: Much research and translational efforts have been directed at understanding the immune response that causes SSc and the networked interactions with the connective tissue and the vasculature. One of the unexpected findings was that in some cases the pathogenic immune response in SSc resembles the immune response to helminth parasites. During coevolution, means of communication were developed which protect the host from over-colonization with parasites and which protect the parasite from excessive host responses. One explanation for the geographically clustered occurrence of SSc is that environmental exposures combined with genetic predisposition turn on triggers of molecular and cellular modules that were once initiated by parasites.

Summary: Future research is needed to further understand the parasite-derived signals that dampen the host response. Therapeutic helminth infection or treatment with parasite-derived response modifiers could be promising new management tools for autoimmune connective tissue diseases.

Figure 1

Schematic representation of the similarity of the immune mechanisms that induce severe thickening of the pulmonary artery and increases in right ventricular systolic pressure in response to infection with helminth parasites or exposure with antigen and ambient, urban fine dust (PM2.5). The similarities of the changes in histology (severe pulmonary artery remodeling), physiology (right ventricular systolic pressure), and critical immune cytokines - IL-13 either combined with IL-4 (Schistosome eggs [35]) or IL-17A (antigen & PM2.5 [37]) - are particularly noteworthy. The changes in the lungs and hearts of SSc patients are remarkably similar and cytokine associations have been found that indicate involvements of IL-13 [27,28], IL-4 [28], IL-17A [29] or Interferon [28]. The data schematically represented above were generated using experimental mouse models [33,35,37,79] using cytokine-neutralizing antibodies and KO-mice. It is emphasized that the incidence of clinical pulmonary hypertension associated with Schistosomiasis infection in humans is still not fully known but is estimated at 6–7 % of all infected persons [80]. Two observations are clinically important: A) PH associated with Schistosomiasis generally fails to improve by only giving anti-helminthic treatment [80], emphasizing the significance of the host (immune) response for developing clinical signs of PH. B) A majority of Schistosome infected individuals do not develop PH, indicating the strength of the cross-adaptation between the human host and the helminth parasite.