New Autoantibody Specificities in Systemic Sclerosis and Very Early Systemic Sclerosis.

Roberto Lande,Curdin Conrad,Marius Cadar,Valeria Riccieri,Anna Mennella,Immacolata Pietraforte,Loredana Frasca,Katia Stefanantoni,Raffaella Palazzo

doi:10.3390/antib10020012

Abstract

Chemokine (C-X-C motif) ligand 4 (CXCL4) is a biomarker of unfavorable prognosis in Systemic Sclerosis (SSc), a potentially severe autoimmune condition, characterized by vasculitis, fibrosis and interferon (IFN)-I-signature. We recently reported that autoantibodies to CXCL4 circulate in SSc patients and correlate with IFN-α. Here, we used shorter versions of CXCL4 and CXCL4-L1, the CXCL4 non-allelic variant, to search for autoantibodies exclusively reacting to one or the other CXCL4 form. Moreover, to address whether anti-CXCL4/CXCL4-L1 antibodies were present before SSc onset and predicted SSc-progression, we longitudinally studied two VEDOSS (Very Early Diagnosis of Systemic Sclerosis) patient cohorts, separating SSc-progressors from SSc-non-progressors. We found that anti-CXCL4-specific autoantibodies were present in both SSc and VEDOSS patients (both SSc-progressors and SSc-non-progressors). Anti-CXCL4-L1-specific autoantibodies were especially detected in long-standing SSc (lsSSc). Anti-CXCL4/CXCL4-L1 antibodies correlated with IFN-α and with specific SSc-skin features but only in lsSSc and not in early SSc (eaSSc) or VEDOSS. Thus, a broader antibody response, with reactivity spreading to CXCL4-L1, is characteristic of lsSSc. The early anti-CXCL4 autoantibody response seems qualitatively different from, and likely less pathogenic than, that observed in advanced SSc. Lastly, we confirm that anti-CXCL4 autoantibodies are SSc-biomarkers and uncover that also CXCL4-L1 becomes an autoantigen in lsSSc.

Highlights

Systemic Sclerosis (SSc) is an autoimmune disease characterized by three hallmarks: autoimmunity, fibrosis and vasculopathy [1]
To address whether anti-C-X-C motif ligand 4 (CXCL4) autoantibodies reacted uniquely to the wild type CXCL4 or to the CXCL4 non-allelic variant CXCL4-L1, differing from the wt CXCL4 by three amino acid substitutions at the very COOH-term, we differentiated among patients that responded to both molecules or to either one or the other form
When the patients responded to the entire CXCL4 and/or to the short form of CXCL4, but not to the short form of CXCL4-L1, we considered them only reacting to the wt molecule

Summary

Introduction

Systemic Sclerosis (SSc) is an autoimmune disease characterized by three hallmarks: autoimmunity, fibrosis and vasculopathy [1]. Autoreactive T-cells and autoantibodies expand and participate to SSc pathogenesis; the autoimmune component is of importance in the disease [1,2,3,4]. Dysregulation of the innate immune system in genetically predisposed individuals and aberrant Toll-like receptor (TLR) activation, are likely involved in SSc pathogenesis [3,6]. C-X-C motif ligand 4 (CXCL4) is an SSc biomarker up-regulated in the skin and circulation of SSc patients and is associated with worse disease prognosis [7,8]. CXCL4 is linked to the type I interferon (IFN-I) signature, which is usually present in 50% of SSc patients [1]. An IFN-I signature is linked to a poor SSc prognosis [9,10,11]

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Results

Discussion

Conclusion