Category: Autoimmune rheumatologic diseases
Background/Purpose. Malondialdehyde-acetaldehyde adducts (MAA) are products of oxidative stress that modify self-proteins and stimulate potent cellular and humoral immune responses. However, mechanism(s) by which citrullinated (Cit) proteins/peptides initiate immune responses are not clear. The purpose of these studies were to evaluate whether co-modification of proteins with MAA and Cit drives anti-Cit autoimmune responses observed in RA.
Methods. DBA/1 mice i.p. weekly x 5 wks with human serum albumin (HSA), or HSA modified with Cit and/or MAA. Serum was evaluated for antibodies to HSA, HSA-MAA, HSA-Cit and HSA-MAA-Cit by ELISA at week 6. Type II collagen (Col) was modified with MAA and/or Cit and mice were immunized as above. CD4+ T cells were evaluated by proliferation against all antigens used for immunization at week 6. Finally, activated peritoneal macrophages were stimulated with Col unmodified or modified with MAA and/or Cit, and assessed for TNF-α secretion.
Results. ACPA concentrations were significantly higher in mice immunized with HSA-MAA-Cit than mice immunized with HSA-Cit. Col-MAA-Cit immunization resulted in increased T cell responses compared to either modification alone. Activated macrophages were shown to increase TNF-α secretion following exposure to Col-MAA-Cit and Col-Cit compared to Col or unimmunized controls.
Conclusion. Co-modification with MAA and Cit serves to increase the immunogenicity of citrullinated proteins to initiate marked antigen specific responses, and the secretion of the pro-inflammatory cytokine TNF-α. Taken together these data suggest that MAA protein adduct formation and resulting immune responses to both MAA and Cit antigen play an important pathogenic role in RA.
Geoffrey Thiele– Professor of Internal Medicine, University of Nebraska Medical Center
Michael Duryee– Instructor, University of Nebraska Medical Center
Lynell Klassen– Professor of Internal Medicine, University of Nebraska Medical Center
James O'Dell– Professor of Internal Medicine, University of Nebraska Medical Center
Bryant England– Assistant Professor, University of Nebraska Medical Center
Ted Mikuls– Professor of Internal Medicine, University of Nebraska Medical Center