New Autoantibody Specificities in Systemic Sclerosis and Very Early Systemic Sclerosis

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.

Type 1 interferon activation in systemic sclerosis: a biomarker, a target or the culprit

“…Recently, CXCL4 itself was found to behave as a self-antigen, maintaining a vicious cycle by promoting T1 IFN activation via pDCs and anti-CXCL4 antibodies by B cells, sustaining the SSc IFN signature [ 19 ]. Further work with CXCL4 has interestingly shown that the anti-CXCL4 antibodies were present in patients with VEDOSS (very early diagnosis of systemic sclerosis), suggesting that this mechanism can intervene very early in the pathogenesis of disease, before clinically apparent tissue damage [ 20 ].…”

Heparin-Independent and Heparin-Dependent Anti-CXCL4 Antibodies Have a Reciprocal Expression in a Systemic Sclerosis Patients’ Cohort

“…Importantly, CXCL4 and IFN-I are closely linked via the process of triggering the nucleic sensor TLRs that leads to the IFN-I signature. In addition to that, we have previously shown that CXCL4 also acts as B-cell autoantigen in SSc patients [ 11 , 12 ]. This could be the result of formation of large CXCL4-DNA complexes in SSc patients, which could contribute to the immunogenicity of CXCL4.…”

“…Indeed, we have previously shown that CXCL4-DNA complexes circulate in SSc patients, correlate with IFN-I and are also present in SSc-affected skin where they co-localize with an IFN-I induced gene [ 5 ]. Anti-CXCL4 antibodies were higher in patients with pulmonary fibrosis and digital ulcers and were associated with disease activity [ 11 , 12 ].…”

“…However, it is well known that CXCL4 is a heparin-binding protein [ 13 , 14 ], and heparin-dependent anti-CXCL4 antibodies have been described in another rheumatic disease, systemic lupus erythematosus (SLE) [ 12 ].…”

“…Importantly, the activation of platelets is also characteristic of SSc; thus, whether heparin-dependent antibodies are more frequent in SSc than in the healthy population is of interest [ 16 ]. Anti-CXCL4 antibodies that we have previously described in SSc were likely heparin-independent [ 11 , 12 ].…”