Immunogenic and inflammatory responses to citrullinated proteins are enhanced following modification with malondialdehyde-acetaldehyde adducts

Geoffrey M. Thiele, Michael J. Duryee, Carlos D. Hunter, Bryant R. England, Benjamin S. Fletcher, Eric C. Daubach, Taylor P. Pospisil, Lynell W. Klassen, Ted R. Mikuls

Research output: Contribution to journalArticle

Abstract

Background/Objective: Malondialdehyde-acetaldehyde adducts (MAA) act as potent immune adjuvants and co-localize with citrullinated antigens in tissues effected by rheumatoid arthritis (RA). We sought to examine the role of MAA-adducts in promoting RA-related autoimmunity and inflammation. Methods: DBA/J1 mice were immunized with human serum albumin (HSA), HSA-MAA, citrullinated HSA (HSA-Cit), or HSA-MAA-Cit with subsequent measurement of serum anti-citrullinated protein antibody (ACPA) and anti-Cit T cell responses. Cellular binding of the same antigens was examined using THP-1 monocytes and Chinese Hamster Ovary (CHO) cells transfected with specific scavenger receptors (SRs: TLR4, SR-B2, SREC-1). The effects of these antigens on THP-1 activation were then examined by quantifying plate adherence, pro-inflammatory (TNFα, IL-1β, IL-10) cytokine release, and SR (CD14, SR-B2)/co-stimulatory molecule (CD80, HLA-DR) expression. Comparisons were completed using one-way ANOVA with Tukey's post-hoc test. Results: Mice immunized with co-modified HSA produced significantly higher ACPA concentrations than all other groups whereas T cell responses to citrullinated proteins were highest following immunization with HSA-MAA. Both transfected CHO and THP-1 cells demonstrated significantly higher binding of HSA-MAA-Cit vs. HSA or HSA-Cit. THP-1 cells exposed to HSA-MAA-Cit expressed significantly higher concentrations of TNFα, IL-1β, and IL-10 vs. all other groups. Furthermore, THP-1 cells demonstrated significantly increased plate adherence and higher expression of CD14, SR-B2, and HLA-DR following incubation with HSA-MAA-Cit vs. HSA or HSA-Cit. Conclusion: These studies demonstrate that MAA-adduction of citrullinated antigen greatly enhances immune and cellular responses, potentially acting as a key co-factor in RA pathogenesis.

Original languageEnglish (US)
Article number106433
JournalInternational Immunopharmacology
Volume83
DOIs
StatePublished - Jun 2020

Keywords

  • Anti-citrullinated protein antibody (ACPA)
  • Autoantibody
  • Citrullination
  • Malondialdehyde-acetaldehyde
  • Rheumatoid arthritis

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Pharmacology

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