- Indian Rheumatology association
Sreejitha KS MBBS, MD, DM (Clinical Immunology & Rheumatology)
Consultant Rheumatologist, Manipal Hospital, Old Airport Road, Bangalore, India
EphB2 Receptor Promotes Dermal Fibrosis in Systemic Sclerosis
Systemic sclerosis (SSc) is characterized by skin and organ fibrosis from excessive extracellular matrix deposition by fibroblasts. Erythropoietin-producing hepatocellular(Eph) receptor tyrosine kinases- Eph A and Eph B- and their corresponding Ephrin ligands expressed in most human tissues were found to cause hepatic and renal fibrosis. The authors hypothesized a role for Eph R-Eph ligand in SSc skin fibrosis.
Overexpression of Eph2R mRNA in dcSSc skin, observed in transcriptomic data from SSc cohorts was assessed in skin biopsies from early dcSSc patients. Immunofluorescence showed that EphB2 and active form phosphoEphB2 were strongly elevated especially in fibroblasts.
A pathogenic role was established by increased gene expression of EphBR and EphB ligands in both bleomycin and tight skin(Tsk) SSc mice models, using rt-qPCR. The corollary was proved by attenuated skin fibrosis in EphB2-knockout mice exposed to bleomycin and Tsk mice with ablated EphB2gene.
The authors proceeded to link the profibrotic TGF-β signalling with Eph, via SMAD-independent EphB2 induction by TGF-β. A dampened TGF-β-–mediated fibroblast-to-myofibroblast transition in EPHB2 knockdown mice showed the requirement of EphB2 for TGF-β action.
The final step was a selective deletion of the EphB2 gene in mice fibroblasts, which reduced fibrosis from subsequent bleomycin.
The study therefore established the role of Eph in SSc skin fibrosis offering a new potential target for treatment.
Calprotectin Impairs Platelet Survival in Patients with Primary Antiphospholipid Syndrome
Thrombocytopenia a common non-criteria manifestation of APS occurs probably from platelet consumption or antiplatelet-glycoprotein antibodies. The role of Neutrophil Extracellular Traps (NETs) in APS has been recognized and the released cytoplasmic component calprotectin (heterodimer of S100A8 and S100A9 calcium-binding proteins) acts as a NETosis biomarker. A potential role of circulating calprotectin in APS was hence hypothesized.
Circulating calprotectin levels were measured by chemiluminescent assay in patients with primary APS (n= 112), asymptomatic aPL-positivity (30), lupus without APS (38), unprovoked aPL-negative venous thrombosis (11) and healthy controls (5). The levels were higher (2–10 μg/mL) in those with primary APS and aPL-positivity. It had a negative correlation with platelet count and a positive correlation with IgG ACL and anti-β2GPI.
A pathogenic role in thrombocytopenia was suggested by the reduced viability of platelets incubated with recombinant calprotectin, which was attenuated by calprotectin inhibitors. Blockade of TLR-4 and NLRP-3 inflammasome reversed reduced platelet survival, whereas APS IgG had a synergistic effect on calprotectin-induced reduced platelet viability and caspase-1 production. Calprotectin increased microparticle generation and phosphatidylserine externalization on the platelet surface promoting thrombosis.
The authors hence establish a pathogenic role of calprotectin, offering a therapeutic target in APS thrombocytopenia, as well as a potential biomarker for thrombocytopenia in primary APS.
