gms | German Medical Science

Background: Systemic sclerosis (SSc) is a rare autoimmune multisystemic disease with a significant disease burden and impact on life quality and survival. Disease specific, diagnostic and prognostic antibodies (ab) are known such as Scl70 and centromer (ACA) ab [1] or recently endothelin or angiotensin receptors [2]. Functional ab can bind G protein-coupled receptors (GPCR) regulating immune function and were reported in the pathogenesis of various inflammatory and non-inflammatory diseases [3].

We analyzed 31 ab against GPCRs and growth factors in a retrospective cohort of 71 SSc patients compared to 196 sera from healthy controls (HC). Ab levels were related to disease manifestations such as sex, age, SSc phenotype in order to hypothesize functional ab and new pathogenic targets in SSc.

Methods: The retrospective clinical characterization of 14 male and 57 female SSc patients (26-82 years) included mRSS, organ involvement assessed by laboratory tests, spirometry and imaging such as CT-scan or echocardiography. 30/71 had active disease (EUSTAR activity score). Ab were measured by ELISA and normalized to a standard serum. Median ab levels from SSc were compared to HC (Mann Whitney Test). Ab patterns were analyzed using different statistical approaches (factor analysis, principal component analysis (PCA), linear discriminant analysis (LDA), cluster analysis and biserial correlation.

Results: Clinical SSc subgroups (diffuse/limited cutaneous, male/female) differ in ab levels and form separate clusters (LDA method). Moreover, 5 resp. 7 latent factors group ab and clinical disease manifestations. Factor analysis reveals VEGFR2 and YBX1 ab to be more unique with the lowest communalities. The biserial correlation shows moderate associations between ab patterns and SSc specific symptoms such as Raynaud’s, calcinosis or akroosteolysis but also unspecific symptoms such as polyneuropathy. Compared to association of ETAR ab with Raynaud’s and skin sclerosis HGFR ab are inversely correlated. In HC most ab levels against GPCR and growth factors are higher than in SSc except for YBX1 which has the highest ab levels in SSc patients. In HC ab levels against YBX1 ab are associated with male sex and family history of rheumatic diseases. Yet, ADRB2 ab are linked to the absence of GI symptoms or depression and ab against ENG, ETAR, PAR2, PAR1 with normal troponine levels (absence of heart involvement).

Conclusion: We describe 31 new ab against GPCR and growth factors in SSc. Ab as well as SSc disease manifestations could be clustered by latent factors. Most ab titers in SSc were lower than in HC. Some ab were linked to the absence of SSc manifestations. Thus, we postulate that a dysbalance of functionally protective autoantibodies, that can be found in healthy individuals, and the appearance of SSc specific ab such as Scl70 contribute to its pathogenesis. Considering the preliminary character of our data, the functional impact of ab against GPCR and growth factors has to be validated in vitro and statistical correlations to be confirmed in a prospective independent patient cohort.