An Autoimmune Basis for Raynaud's Phenomenon: Murine Model and Human Disease

Arthritis Rheumatol. 2018 Sep;70(9):1489-1499. doi: 10.1002/art.40505. Epub 2018 Jul 25.

Abstract

Objective: Raynaud's phenomenon (RP) is common in anti-RNP-positive patients with rheumatic diseases but is not itself known to be caused by autoimmunity. The aim of this study was to assess autoantibodies that could mediate this process.

Methods: Antibodies derived from patient sera and from murine models of anti-RNP autoimmunity were screened for the ability to induce RP-like tissue ischemia and endothelial cell apoptosis in murine models and in vitro systems.

Results: RNP-positive sera from RP patients and murine sera from RNP-positive B cell adoptive transfer recipients induced RP-like tissue ischemia and endothelial cell apoptosis. Proteomic analysis identified cytokeratin 10 (K10) as a candidate autoantigen in RP. Monoclonal anti-K10 antibodies reproduced patterns of ischemic tissue loss and endothelial cell apoptosis; K10 knockout or depletion of anti-K10 activity in serum was protective. Cold exposure enhanced K10 expression and in vivo tissue loss.

Conclusion: Anti-K10 antibodies are sufficient to mediate RP-like ischemia in murine models and are implicated in the pathogenesis of RP in patients with anti-RNP autoimmunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adoptive Transfer
  • Animals
  • Antibodies, Monoclonal / immunology*
  • Autoantibodies / blood*
  • Autoantigens / blood*
  • Autoimmunity / immunology*
  • Disease Models, Animal
  • Humans
  • Keratin-10 / blood
  • Keratin-10 / immunology
  • Mice
  • Mice, Inbred C57BL
  • Proteomics
  • Raynaud Disease / immunology*

Substances

  • Antibodies, Monoclonal
  • Autoantibodies
  • Autoantigens
  • Keratin-10