Modification of lupus-associated 60-kDa Ro protein with the lipid oxidation product 4-hydroxy-2-nonenal increases antigenicity and facilitates epitope spreading
RH Scofield, BT Kurien, S Ganick, MT McClain… - Free Radical Biology …, 2005 - Elsevier
Free Radical Biology and Medicine, 2005•Elsevier
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with autoantibodies
as a near universal feature of the disease. The Ro ribonucleoprotein particle, composed of a
60-kDa protein noncovalently associated with human cytoplasmic RNA, is the target of
antibodies in 25–40% of lupus patients. Purified human 60-kDa Ro was found to be
oxidatively modified. Earlier investigations from our laboratory revealed increased oxidative
damage in SLE patients. Therefore we hypothesized that oxidation by-products, such as 4 …
as a near universal feature of the disease. The Ro ribonucleoprotein particle, composed of a
60-kDa protein noncovalently associated with human cytoplasmic RNA, is the target of
antibodies in 25–40% of lupus patients. Purified human 60-kDa Ro was found to be
oxidatively modified. Earlier investigations from our laboratory revealed increased oxidative
damage in SLE patients. Therefore we hypothesized that oxidation by-products, such as 4 …
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with autoantibodies as a near universal feature of the disease. The Ro ribonucleoprotein particle, composed of a 60-kDa protein noncovalently associated with human cytoplasmic RNA, is the target of antibodies in 25–40% of lupus patients. Purified human 60-kDa Ro was found to be oxidatively modified. Earlier investigations from our laboratory revealed increased oxidative damage in SLE patients. Therefore we hypothesized that oxidation by-products, such as 4-hydroxy-2-nonenal (HNE), could lead to neoantigens like HNE-modified 60-kDa Ro, which could in turn initiate autoimmunity or drive epitope spreading. To test this hypothesis we immunized rabbits with either HNE-modified 60-kDa Ro or the unmodified Ro. Intramolecular epitope spreading within the Ro molecule and intermolecular epitope spreading to La, double-stranded DNA, nRNP, and Sm occurred preferentially in HNE–Ro-immunized animals. Nonspecific anti-HNE antibody, generated by immunization with HNE–keyhole limpet hemocyanin conjugate, did not significantly bind to these autoantigens. These data may suggest a hitherto unappreciated mechanism by which oxidative stress facilitates epitope spreading in SLE.
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