The immunopathogenesis of fibrosis in systemic sclerosis

Abstract

Summary Systemic sclerosis (SSc) is an idiopathic systemic autoimmune disease. It is characterized by a triad of hallmarks: immune dysfunction, fibrosis and vasculopathy. Immune dysfunction in SSc is characterized by the activation and recruitment of immune cells and the production of autoantibodies and cytokines. How immune abnormalities link the fibrosis and vasculopathy in SSc is poorly understood. A plethora of immune cell types are implicated in the immunopathogenesis of SSc, including T cells, B cells, dendritic cells, mast cells and macrophages. How these different cell types interact to contribute to SSc is complicated, and can involve cell‐to‐cell interactions and communication via cytokines, including transforming growth factor (TGF)‐β, interleukin (IL)‐6 and IL‐4. We will attempt to review significant and recent research demonstrating the importance of immune cell regulation in the immunopathogenesis of SSc with a particular focus on fibrosis.

Differential expression of Toll-like receptors 1 and 3 in patients with systemic lupus erythematosus and systemic sclerosis

“…It has been hypothesized that complexes of self-RNA and antimicrobial peptides can activate TLR3 [28]. Previous research has revealed that interferon-α2 increases the TLR3-induced production of interleukin-6 in dermal broblasts and overexpression of TLR3 in human skin, particularly in dermal broblasts present in the connective tissue of the dermis [25]. Our ndings can be used as a reference to further investigate the association between TLR3 and skin brosis.…”

“…SSc affects the gastrointestinal tract, resulting in its progressive dysfunction. For example, small bowel disease occurs with smooth muscle atrophy, followed by the nal stage of muscle brosis [25]. As bowel movements change, the gut microbiota also changes, which may provoke an immune response, e.g., via TLR1, in patients with SSc.…”

“…A typical feature of SSc is that vascular injury causes Raynaud's phenomenon and results in the release of endogenous TLR ligands during in ammation and local tissue damage [32]. Induction of intracellular signaling pathways may be one of the mechanisms that initiate brosis [25]. Studies have shown the importance of TLRs in the pathogenesis of SSc, with both TLRs and their ligands showing increased expression [24,25].…”

“…Induction of intracellular signaling pathways may be one of the mechanisms that initiate brosis [25]. Studies have shown the importance of TLRs in the pathogenesis of SSc, with both TLRs and their ligands showing increased expression [24,25].…”

Inhibition of effector B cells by ibrutinib in systemic sclerosis

“…On the other hand, while a beneficial impact of ibrutinib in autoimmune diseases like rheumatoid arthritis or SSc has been proposed from the very beginning, the transition to a clinical application in this field is incomplete [18]. In SSc, B cells are assumed to be important players in disease onset and progression [19,20]. B cells of patients with SSc show elevated expression levels of the regulatory surface molecule CD19, which reduces the threshold of BCR signaling, thereby importantly influencing B cell activation and survival [21].…”