MOLECULAR CHARACTERIZATION OF THE SM SNRNP POLYPEPTIDES

From a biological point of view the U1 snRNP is a ubiquitous nuclear
ribonucleoprotein particle that plays a crucial role in the processing of
pre-messenger RNA. In terms of human disease, apparently normal U1 snRNP
particles act as a central focal point for humoral autoimmune responses
that are especially prominent in systemic lupus erythematosus and overlap
syndromes. For example it has recently become clear that anti-U1 RNP
antibodies bind the U1 snRNP polypeptides 70K, A, B'/B and C while anti-Sm
antibodies recognize polypeptides B'/B and D. We have directed our
attention to the B'/B polypeptides because they are at the crossroads of
these responses. In the present project a cDNA encoding one or both of he closely related
B'/B polypeptides has been cloned and sequenced. A colleague, Dr. Michael
Lerner, has cloned and sequenced a cDNA for polypeptide N, a brain and
heart specific variant of B'/B that provides a potential mechanisms for
tissue specific alternative mRNA splicing mechanisms. The proposed work
will identify the precise regions on B'/B and N that are recognized by
antibodies from patients with SLE and related connective tissue disease and
correlate these regions with structural changes that occur in B'/B and N
during evolution. These efforts will permit a test of the hypothesis that
he degree of evolutionary stability is a major determinant of autoantigenic
epitopes. The ability to compare autoantigenic epitopes on B'/B and N
offers the potential for discovering autoimmune responses that are
generated in specific tissues. The importance of this work is that it will provide new knowledge of the
structure of the U series of snRNP and how they evolved. Moreover, the
precise identification of the most prominent and characteristic
autoantigenic epitopes of SLE, combined with insight into the forces that
nominate them for autoimmune responses, will provide the foundation for
future studies that will assess directly how selected "self" antigens
interact with specific surface receptors on cells of the immune system.