Review article

Innate immunity in systemic sclerosis pathogenesis

Steven O’Reilly


The innate immune system is a critical part of the response to pathogens and overall immunity. Compared with the adaptive immune response, these innate responses are not antigen-specific and recognize patterns in bacteria, viruses and fungi. Chief among these are TLRs (Toll-like receptors). TLRs are PRRs (pattern recognition receptors) that are germ-line-encoded and are also able to recognize endogenous molecules that are released upon cell damage or stress and have been demonstrated to have a key role in numerous autoimmune diseases, including RA (rheumatoid arthritis) and SSc (systemic sclerosis). SSc is an autoimmune disorder in which vascular injury occurs and there is a chronic low-grade inflammation followed by excessive ECM (extracellular matrix) deposition and ultimately fibrosis. The fibrosis ultimately leads to organ dysfunction and death. The preceding vascular damage and activation of the innate immune system leads to mobilization of the innate lymphoid cells and the up-regulation of multiple genes and pro-fibrotic cytokines. These locally released cytokines activate resident fibroblasts to differentiate into myofibroblasts. The aim of the present review is to explore the role of the innate immune system in SSc and TLRs and how these interact with stromal cells to produce fibrosis. Targeting the innate immune system or specific components of the TLR signalling cascade may be a novel therapeutic option in what is an incurable disease.

  • fibrosis
  • innate immune system
  • interleukin-6
  • myeloid differentiation factor 88 (MyD88)
  • systemic sclerosis
  • Toll-like receptor
  • tumour-necrosis-factor-receptor-associated factor (TRAF)

Abbreviations: AIM2, absent in melanoma 2; CCL, CC chemokine ligand; ECM, extracellular matrix; HCV, hepatitis C virus; HMGB, high-mobility group box; HSP, heat-shock protein; IFN, interferon; IL, interleukin; IRAK, IL-1-receptor-associated kinase; LPS, lipopolysaccharide; LBP, LPS-binding protein; MAPK, mitogen-activated protein kinase; MD-2, myeloid differentiation factor-2; MyD88, myeloid differentiation factor 88; NF-κB, nuclear factor κB; NLRP, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing; NOD, nucleotide-binding and oligomerization domain; ODN, oligodeoxynucleotide; PBMC, peripheral blood mononuclear cell; PRR, pattern recognition receptor; RA, rheumatoid arthritis; RIG-I, retinoic acid-inducible gene I; ROS, reactive oxygen species; SLE, systemic lupus erythaematosus; SSc, systemic sclerosis; TGF, transforming growth factor; TIMP, tissue inhibitor of metalloproteinases; TLR, Toll-like receptor; TRIF, TIR (Toll/IL-1 receptor) domain-containing adaptor protein inducing IFNβ

View Full Text

Log in through your institution