TY - JOUR
T1 - Immunogenic and inflammatory responses to citrullinated proteins are enhanced following modification with malondialdehyde-acetaldehyde adducts
AU - Thiele, Geoffrey M.
AU - Duryee, Michael J.
AU - Hunter, Carlos D.
AU - England, Bryant R.
AU - Fletcher, Benjamin S.
AU - Daubach, Eric C.
AU - Pospisil, Taylor P.
AU - Klassen, Lynell W.
AU - Mikuls, Ted R.
N1 - Funding Information:
This work was supported by a Veterans Affairs (VA) BLR&D Merit Grant (BX004790). Dr. Mikuls receives additional support from the Rheumatology Research Foundation, NIH/NIGMS (U54GM115458) and NIAAA (R25AA020818).
Funding Information:
This work was supported by a Veterans Affairs (VA) BLR&D Merit Grant (BX004790). Dr. Mikuls receives additional support from the Rheumatology Research Foundation, NIH/NIGMS (U54GM115458) and NIAAA (R25AA020818).
Publisher Copyright:
© 2020 Elsevier B.V.
PY - 2020/6
Y1 - 2020/6
N2 - 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.
AB - 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.
KW - Anti-citrullinated protein antibody (ACPA)
KW - Autoantibody
KW - Citrullination
KW - Malondialdehyde-acetaldehyde
KW - Rheumatoid arthritis
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U2 - 10.1016/j.intimp.2020.106433
DO - 10.1016/j.intimp.2020.106433
M3 - Article
C2 - 32224441
AN - SCOPUS:85082409884
VL - 83
JO - International Immunopharmacology
JF - International Immunopharmacology
SN - 1567-5769
M1 - 106433
ER -