Autoantibodies as Biomarker and Therapeutic Target in Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is a rare connective tissue disorder characterized by immune dysregulation evoking the pathophysiological triad of inflammation, fibrosis and vasculopathy. In SSc, several alterations in the B-cell compartment have been described, leading to polyclonal B-cell hyperreactivity, hypergammaglobulinemia and autoantibody production. Autoreactive B cells and autoantibodies promote and maintain pathologic mechanisms. In addition, autoantibodies in SSc are important biomarkers for predicting clinical phenotype and disease progression. Autoreactive B cells and autoantibodies represent potentially promising targets for therapeutic approaches including B-cell-targeting therapies, as well as strategies for unselective and selective removal of autoantibodies. In this review, we present mechanisms of the innate immune system leading to the generation of autoantibodies, alterations of the B-cell compartment in SSc, autoantibodies as biomarkers and autoantibody-mediated pathologies in SSc as well as potential therapeutic approaches to target these.

Copeptin as a Biomarker of Microcirculation Alterations in Systemic Sclerosis

“…Autoantibody profiles in SSc are predictive of disease course and organ involvement. 51 When patients were stratified according to autoantibodies there was a significant increase in copeptin concentration in anti-RNAP III-positive patients. This is in accordance with several observations showing that SSc patients with positive anti-RNAP III antibodies had more frequently rapidly progressive diffuse skin thickening and higher frequency of vascular involvement, such as scleroderma renal crisis, pulmonary hypertension and ischemic damage associated with RP.…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…It is generally accepted that GPCR autoantibodies are produced against the extracellular regions of the receptor. Depending on the epitope to which they specifically bind, and on their type (monovalent, bivalent), autoantibodies are able to either stimulate or suppress the basal or agonist-stimulated activity of a recognized receptor and, thereby, be involved in the pathogenesis of various diseases [99, [235][236][237]. In this regard, it is interesting that in the case of CXCR3 and CXCR4, patterns of autoantibodies have been identified that are specific not only to extracellular regions, but also to their ICLs.…”

“…Endogenous allosteric regulators of PAR1 are autoantibodies produced against its extracellular domains [237,[292][293][294]. A significant proportion of patients with systemic sclerosis have autoantibodies to extracellular regions of PAR1, which are able to activate the receptor, like thrombin, thus acting as allosteric agonists [293].…”

Biomarkers in Systemic Sclerosis: An Overview

“…The original score was developed in 1979 by Rodnan et al [8]. In summary, these are the two main forms into which SSc can be formally classified at present: 1-limited cutaneous form (lcSSc), characterized by predominantly distal skin thickening and the presence of anticentromere antibodies, and 2-diffuse cutaneous form (dcSSc), in which there are diffuse distal and proximal skin changes associated with the presence of anti-topoisomerase antibodies, anti-RNA-III polymerase antibodies, or other antibodies with antinuclear pattern [9][10][11][12][13][14][19][20][21][22][23][24][25]. The most used biomarkers in SSc are autoantibodies, and in this case, they have utility for diagnosis, classification, and prognosis of the disease; it should also be mentioned that biomarkers can be potential therapeutic targets [4,[23][24][25][26][27][28][29][30].…”