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.