| ironjustice@aol.com 2005-04-24, 5:56 pm |
| Free Radic Biol Med. 2005 Mar 15;38(6):719-28. Related Articles, Links
Modification of lupus-associated 60-kDa Ro protein with the lipid
oxidation product 4-hydroxy-2-nonenal increases antigenicity and
facilitates epitope spreading.
Scofield RH, Kurien BT, Ganick S, McClain MT, Pye Q, James JA,
Schneider RI, Broyles RH, Bachmann M, Hensley K.
Arthritis and Immunology Program, Oklahoma Medical Research Foundation,
Oklahoma City, OK 73104, USA. hal-scofield@omrf.ouhsc.edu
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.
PMID: 15721982 [PubMed - in process]
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