Extracellular vesicles opsonized by monomeric C-reactive protein (CRP) are accessible as autoantigens in patients with systemic lupus erythematosus and associate with autoantibodies against CRP

Jesper Karlsson; Jonas Wetterö; Lawrence A Potempa; Rafael Fernandez-Botran; Yasmine O'Neill; Lina Wirestam; Fariborz Mobarrez; Christopher Sjöwall

doi:10.1016/j.jaut.2023.103073

Extracellular vesicles opsonized by monomeric C-reactive protein (CRP) are accessible as autoantigens in patients with systemic lupus erythematosus and associate with autoantibodies against CRP

J Autoimmun. 2023 Sep:139:103073. doi: 10.1016/j.jaut.2023.103073. Epub 2023 Jun 23.

Authors

Jesper Karlsson¹, Jonas Wetterö², Lawrence A Potempa³, Rafael Fernandez-Botran⁴, Yasmine O'Neill⁵, Lina Wirestam², Fariborz Mobarrez⁵, Christopher Sjöwall²

Affiliations

¹ Department of Biomedical and Clinical Sciences, Division of Inflammation & Infection, Linköping University, Linköping, Sweden. Electronic address: jesper.karlsson@liu.se.
² Department of Biomedical and Clinical Sciences, Division of Inflammation & Infection, Linköping University, Linköping, Sweden.
³ Roosevelt University, College of Science, Health and Pharmacy, Schaumburg, IL, United States.
⁴ Department of Pathology & Laboratory Medicine, University of Louisville, Louisville, KY, United States.
⁵ Department of Medical Sciences, Division of Clinical Chemistry, Uppsala University, Uppsala, Sweden.

PMID: 37356347
DOI: 10.1016/j.jaut.2023.103073

Abstract

The pentraxin C-reactive protein (CRP) is a pentameric protein now known to be able to undergo dissociation into a monomeric, modified isoform, referred to as mCRP. In carefully assessing the bioactivities of each isoform, mCRP has strong pro-inflammatory activities while pCRP has mild anti-inflammatory activities. Systemic lupus erythematosus (SLE) is a disease characterized by a vast number of autoantibodies, including anti-CRP autoantibodies which have been associated with SLE disease activity and lupus nephritis. The origin of these autoantibodies is currently unknown. Extracellular vesicles (EVs) have been implicated in SLE pathogenesis as they can expose nuclear antigens on their outside surface, thereby being a potential adjuvant for the generation of autoantibodies. Herein, we studied exposure of both pCRP and mCRP on EVs in SLE plasma and the implications of each in disease activity, organ damage and clinical manifestations. We used flow cytometry to detect CRP isoforms on EV surfaces in 67 well-characterized SLE patients and 60 sex- and age-matched healthy controls. Autoantibodies against mCRP were measured using ELISA. We found an abundance of both pCRP and mCRP on SLE EVs compared to controls. Furthermore, mCRP⁺ but not pCRP⁺ EVs were elevated in patients with active disease and in anti-CRP positive patients. The proportions of mCRP⁺ EVs were lower in patients with acquired organ damage, especially in patients with lupus nephritis (LN), and displayed an inverse relationship with disease duration in LN and patients with active disease. Speculatively, these data suggest EV-bound mCRP as a relevant factor in SLE pathogenesis, which could contribute to development of anti-CRP autoantibodies by stimulating an immune response.

Keywords: Anti-CRP antibodies; C-reactive protein; Extracellular vesicles; Immune complexes; Systemic lupus erythematosus.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Autoantibodies
Autoantigens
C-Reactive Protein / metabolism
Extracellular Vesicles* / metabolism
Humans
Lupus Erythematosus, Systemic*
Lupus Nephritis* / diagnosis
Protein Isoforms

Substances

C-Reactive Protein
Autoantibodies
Autoantigens
Protein Isoforms