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

•Post translational modification of proteins increase immune response.•Co-modification of MAA and Citrulline enhance the cellular responses.•Scavenger receptors on macrophage bind these dual modified proteins.•Co-stimulatory molecules are increased in response to MAA and Citrulline Binding. Malondia...

Full description

Saved in:

Bibliographic Details
Published in:	International immunopharmacology Vol. 83; p. 106433
Main Authors:	Thiele, Geoffrey M., Duryee, Michael J., Hunter, Carlos D., England, Bryant R., Fletcher, Benjamin S., Daubach, Eric C., Pospisil, Taylor P., Klassen, Lynell W., Mikuls, Ted R.
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier B.V 01-06-2020 Elsevier BV
Subjects:	Acetaldehyde Acetaldehyde - chemistry Acetaldehyde - immunology Adducts Adjuvants Adjuvants, Immunologic - chemistry Animals Anti-Citrullinated Protein Antibodies - blood Anti-Citrullinated Protein Antibodies - immunology Anti-citrullinated protein antibody (ACPA) Antibodies Antigens Arthritis Arthritis, Rheumatoid - immunology Autoantibody Autoimmunity Binding CD14 antigen CD80 antigen CHO Cells Citrullination Citrullination - immunology Citrulline Cricetulus Cytokines Cytokines - metabolism Histocompatibility antigen HLA Human serum albumin Humans IL-1β Immunization Immunogenicity Immunogenicity, Vaccine Inflammation Inflammation - metabolism Interleukin 10 Lymphocytes Lymphocytes T Male Malondialdehyde Malondialdehyde - chemistry Malondialdehyde - immunology Malondialdehyde-acetaldehyde Mice, Inbred DBA Monocytes Monocytes - metabolism Pathogenesis Proteins Receptors, Scavenger - metabolism Rheumatoid arthritis Scavenger receptors Serum albumin Serum Albumin, Human - chemistry Serum Albumin, Human - immunology T-Lymphocytes - immunology T-Lymphocytes - metabolism THP-1 Cells TLR4 protein Toll-like receptors Tumor necrosis factor-α Variance analysis Citrullination Autoantibody Malondialdehyde-acetaldehyde Rheumatoid arthritis Anti-citrullinated protein antibody (ACPA)
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	•Post translational modification of proteins increase immune response.•Co-modification of MAA and Citrulline enhance the cellular responses.•Scavenger receptors on macrophage bind these dual modified proteins.•Co-stimulatory molecules are increased in response to MAA and Citrulline Binding. 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. 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. 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1567-5769 1878-1705
DOI:	10.1016/j.intimp.2020.106433