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THU0058 B Cell Receptor Editing in Scleroderma Patients Generates Pathogenic Anti-PDGFR Autoantibodies
  1. G. Moroncini1,
  2. A. Grieco1,
  3. G. Nacci2,
  4. C. Paolini1,
  5. C. Tonnini1,
  6. K. N. Pozniak1,
  7. S. Mori1,
  8. S. Svegliati1,
  9. E. Avvedimento3,
  10. A. Funaro2,
  11. A. Gabrielli1
  1. 1Scienze Cliniche e Molecolari, Università Politecnica Marche, Ancona
  2. 2Scienze Mediche, Università di Torino, Torino
  3. 3Biologia e Patologia Molecolare e Cellulare, Università Federico II, Napoli, Italy


Background Systemic sclerosis or scleroderma (SSc) is a clinically heterogeneous disease of the connective tissue characterized by vascular, immune/inflammatory and fibrotic manifestations. We have hypothesized that the serum of SSc patients contains stimulatory auto-antibodies (auto-abs) directed to the PDGF receptor (PDGFR) that elicit reactive oxygen species (ROS) and collagen production in human fibroblasts1.

Objectives Aim of this study was to analyze the native immune repertoire of SSc patients.

Methods Memory B cells of two SSc patients were immortalized and screened for PDGFR-autoreactive clones. RNA was extracted from each PDGFR-autoreactive B cell line, reverse-transcribed, and amplified with a set of primers designed to analyze the human immunoglobulin (Ig) gene repertoire. Ig variable (V) regions identified in these clones were expressed as human IgG monoclonal abs and characterized through binding and functional assays.

Results PCR analysis of rearranged Ig genes suggested the presence of a large panel of V heavy (H) and light (L) chain subgroups. However, subsequent sequencing showed a small panel of VH and VL chains in each B cell line: the same variable Ig sequences were recovered repeatedly from independent PCR amplifications of different VH and VL subgroups and displayed a high frequency of somatic mutations in the complementarity determining regions (CDRs). Ab engineering revealed that 4 different VL chains identified in one SSc patient conferred diverse biological properties to the unique VH chain identified in the same patient: loss of high affinity binding; PDGFR binding without signaling; PDGFR binding with ROS induction; PDGFR binding with ROS and collagen gene induction. This gain in autoreactivity from the nonbinding monoclonal antibody up to the fully agonistic antibody corresponded to a progressive enrichment in positive charge and higher isoelectric point (pI) of the CDRs. These data are consistent with the notion that B cell receptor editing governs B cell tolerance to endogenous antigens, and suppresses autoreactivity by pairing potentially reactive Ig H chains with non-autoreactive L chains.

Conclusions The repertoire of PDGFR-autoreactive SSc B cells is restricted and somatically mutated. This suggests the hypothesis of a polarization of the immune response towards the autologous PDGFRa under the influence of a strong antigenic drive, the nature of which awaits identification. Stimulatory and non-stimulatory anti-PDGFRa auto-abs coexist in the same SSc patient, they share a common VH chain and have, therefore, a common origin. The CDRs of the shared VH framework might represent a common trait of SSc patients’ IgG, and be used as novel biomarkers of this disease.


  1. Baroni SS, NEJM 2006.

Disclosure of Interest None Declared

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