Systemic lupus erythematosus (SLE) and
mixed connective tissue disease (
MCTD) are autoimmune illnesses characterized by the presence of high titers of
autoantibodies directed against a wide range of 'self '
antigens.
Proteins of the
U1 small nuclear ribonucleoprotein particle (
U1 snRNP) are among the most immunogenic molecules in patients with SLE and
MCTD. The recent release of a crystallized
U1 snRNP provides a unique opportunity to evaluate the effects of tertiary and quaternary structures on autoantigenicity within the
U1 snRNP. In the present study, an
epitope map was created using the
U1 snRNP crystal structure. A total of 15
peptides were tested in a cohort of 68 patients with SLE, 29 with
MCTD and 26 healthy individuals and mapped onto the
U1 snRNP structure. Antigenic sites were detected in a variety of structures and appear to include RNA binding domains, but mostly exclude regions necessary for
protein-
protein interactions. These data suggest that while some
autoantibodies may target
U1 snRNP proteins as monomers or apoptosis-induced,
protease-digested fragments, others may recognize
epitopes on assembled
protein subcomplexes of the
U1 snRNP. Although nearly all of the
peptides are strong predictors of autoimmune illness, none were successful at distinguishing between SLE and
MCTD. The antigenicity of some
peptides significantly correlated with several clinical symptoms. This investigation implicitly highlights the complexities of autoimmune
epitopes, and autoimmune illnesses in general, and demonstrates the variability of
antigens in patient populations, all of which contribute to difficult clinical diagnoses.