sphingosine-1-phosphate and Scleroderma--Systemic

Systemic sclerosis (SSc) is a complex fibrosing autoimmune disease that has variable clinical manifestations and morbidity/mortality secondary to organ damage due to vasculopathy and/or fibrosis. Initial events in the pathogenesis are manifested by fibroproliferative vasculopathy that compromises delivery of blood to critical organs. There is evidence of autoimmunity early in the disease which persists and is accompanied by fibrotic processes that leave large accumulations of collagen and other matrix components in the intima of blood vessels and extracellularly in the connective tissue of organs affected by the disease. It has recently been realized that the lysophospholipids -- lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), which are elevated in sera of SSc patients, are capable of producing many of the abnormalities observed in the vasculature, immune system, and connective tissue of patients with this disease. This article reviews key abnormalities of the vasculature, immune system, and connective tissue in SSc that could be mediated by LPA/S1P.

Topics: Autoimmunity; Blood Vessels; Fibrosis; Humans; Lysophospholipids; Scleroderma, Systemic; Sphingosine

Pulmonary arterial hypertension (PAH) is a frequent extracutaneous manifestation of systemic sclerosis (SSc). PAH is characterized by increased vasomotor tone, progressive remodeling of pulmonary arteries and arterioles, consequentially increased pulmonary vascular resistance, right heart hypertrophy, and eventually right ventricular failure. Autoimmunity against G-protein coupled receptors (GPCRs) has been implicated in the development of SSc-associated PAH. Sphingosine-1-phosphate (S1P) receptors (S1PR) present a potential, yet so far untested antigen for PAH autoimmunity, given the documented role of S1P/S1PR signaling in PAH pathogenesis.. We hypothesized that S1P receptors (S1PR) may constitute autoantigens in human patients, and that the prevalence of autoantibodies (aAb) to S1PR1, S1PR2 and S1PR3 is elevated in SSc patients and associated with PAH.. For this exploratory study, serum samples from 158 SSc patients, 58 of whom with PAH, along with 333 healthy control subjects were screened for S1PR-aAb. S1PR1-3 were expressed as fusion proteins with luciferase in human embryonic kidney cells and used to establish novel. All three assays showed dose-dependent signal intensities when tested with S1PR-subtype specific commercial antibodies. Natural aAb to each S1PR were detected in healthy controls with a prevalence of <10% each, i.e., 2.7% for S1PR1-aAb, 3.6% for S1PR2-aAb, and 8.3% for S1PR3. The respective prevalence was higher in the cohort of SSc patients without PAH, with 17.1% for S1PR1-aAb, 19.0% for S1PR2-aAb, and 21.5% for S1PR3. In the subgroup of SSc patients with PAH, prevalence of aAb to S1PR2 and S1PR3 was further elevated to 25.9% for S1PR2-aAb, and 27.6% for S1PR3. Notably, the majority of patients with positive S1PR2-aAb (60.7%) or S1PR3-aAb (71.9%) displayed interstitial lung disease.. S1PR1-3 can constitute autoantigens in humans, particularly in SSC patients with PAH. The potential pathophysiological significance for the etiology of the disease is currently unknown, but the elevated prevalence of S1PR2-aAb and S1PR3-aAb in SSC patients with PAH merits further mechanistic investigations.

Topics: Autoantigens; Autoimmunity; Humans; Lysophospholipids; Pulmonary Arterial Hypertension; Receptors, Lysosphingolipid; Scleroderma, Systemic; Sphingosine; Sphingosine-1-Phosphate Receptors

Systemic sclerosis (SSc) is an often fatal disease characterized by autoimmunity and inflammation, leading to widespread vasculopathy and fibrosis. Lysophosphatidic acid (LPA), a bioactive phospholipid in serum, is generated from lysophospholipids secreted from activated platelets in part by the action of lysophospholipase D (lysoPLD). Sphingosine 1-phosphate (S1P), a member of the bioactive lysophospholipid family, is also released from activated platelets. Because activated platelets are a hallmark of SSc, we wanted to determine whether subjects with SSc have altered serum lysophospholipid levels or lysoPLD activity. Lysophospholipid levels were measured using mass spectrometric analysis. LysoPLD activity was determined by quantifying choline released from exogenous lysophosphatidylcholine (LPC). The major results were that serum levels of arachidonoyl (20:4)-LPA and S1P were significantly higher in SSc subjects versus controls. Furthermore, serum LPA:LPC ratios of two different polyunsaturated phospholipid molecular species, and also the ratio of all species combined, were significantly higher in SSc subjects versus controls. No significant differences were found between other lysophospholipid levels or lysoPLD activities. Elevated 20:4 LPA, S1P levels and polyunsaturated LPA:LPC ratios may be markers for and/or play a significant role in the etiology of SSc and may be future pharmacological targets for SSc treatment.

Topics: Adult; Case-Control Studies; Female; Humans; Lysophospholipids; Middle Aged; Phosphoric Diester Hydrolases; Scleroderma, Systemic; Sphingosine; Young Adult