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Objective: Immunization with peptide fragments of autoantigens may lead to an immune response at both the T and B cell level that is directed not only at the immunogen, but also at the autoantigen from which the peptide came. In addition, a complex multicomponent particle may become the target of this expanded immune response. The purpose of this study was to determine the ability of several different peptides from 60-kd Ro to induce expansion of the immune response to the Ro/La RNP particle., Methods: We immunized BALB/c mice with 3 different oligopeptides from human 60-kd Ro (or, SSA)., Results: Animals immunized with peptides either identical to or differing by only 1 amino acid developed autoimmunity to the entire Ro RNP particle. Animals immunized with a human peptide highly divergent from the corresponding mouse sequence developed an immune response to the immunogen only and showed little evidence of epitope spreading. Furthermore, these mice did not have antibodies that bound the poorly conserved mouse homolog peptide, and the antibody response to this peptide did not include IgG1., Conclusion: These data indicate that B lymphocytes specific for the self-peptide that is homologous to the immunogen are a critical determinant for spreading of the immune response to other components of self.

The fine specificity of the Ro and La proteins has been studied by several techniques. In general, there is agreement in a qualitative sense that autoantibodies bind multiple epitopes. For some specific antibody binding, different studies agree quantitatively, for instance, the binding of the carboxyl terminus of 60-kd Ro as described by 2 studies using different techniques and the presence of an epitope within the leucine zipper of 52-kd Ro. In addition, there is general agreement about the location of a prominent epitope at the RRM motif region of the La molecule. On the other hand, the many specific epitope regions of the molecules differ among these studies. These discrepancies are likely the result of using different techniques, sera, and peptide constructs as well as a result of inherent advantages and disadvantages in the individual approaches. Several theories concerning the origin of not only the antibodies, but also the diseases themselves, have been generated from studies of the fine specificity of antibody binding. These include a theory of a primordial foreign antigen for anti-Ro autoimmunity, molecular mimicry with regard to La and CCHB, as well as the association of anti-Ro with HLA. These remain unproven, but are of continuing interest. An explanation for the association of anti-60-kd Ro and anti-52-kd Ro in the sera of patients has sprung from evaluating antibody binding. Data demonstrating multiple epitopes are part of a large body of evidence that strongly suggests an antigen-driven immune response. This means that the autoantigens are directly implicated in initiating and sustaining autoimmunity in their associated diseases. A number of studies have investigated the possibility of differences in the immune response to these antigens in SS and SLE sera. While several differences have been reported, none have been reproduced in a second cohort of patients. Furthermore, none of the reported differences may be sufficiently robust for clinical purposes, such as distinguishing between SS with systemic features and mild SLE, although some might be promising. For instance, in at least 3 groups of SLE patients, no binding of residues spanning amino acids 21-41 of 60-kd Ro has been found. Meanwhile, 1 of those studies found that 41% of sera from patients with primary SS bound the 60-kd Ro peptide 21-41. Perhaps future studies will elaborate a clinical role of such a difference among SS and SLE patients. Study of the epitopes of these autoantigens has, in part, led to a new animal model of anti-Ro and anti-La. Non-autoimmune-prone animals are immunized with proteins or peptides that make up the Ro/La RNP. Such animals develop an autoimmune response to the entire particle, not just the immunogen. This response has been hypothesized to arise from autoreactive B cells. In another, older animal model of disease, the MRL-lpr/lpr mouse, B cells have recently been shown to be required for the generation of abnormal, autoreactive T cells. Thus, there are now powerful data indicating that B cells that produce autoantibodies are directly involved in the pathogenesis of disease above and beyond the formation of immune complexes. Given that the autoreactive B cell is potentially critical to the underlying pathogenesis of disease, then studying these cells will be crucial to further understanding the origin of diseases associated with Ro and La autoimmunity. Hopefully, an increased understanding will eventually lead to improved treatment of patients. Progress in the area of treatment will almost surely be incremental, and studies of the fine specificity of autoantibody binding will be a part of the body of basic knowledge contributing to ultimate advancement. In the future, the animal models will need to be examined with regard to immunology and immunochemistry as well as genetics. The development of these autoantibodies has not been studied extensively because upon presentation to medical care, virtually all patients have a full-

Objective: To characterize the initial events in anti-Ro production by a patient with systemic lupus erythematosus, in whom this autoantibody is developing., Methods: The immune response to the Ro ribonucleoprotein and other autoantigens were studied by enzyme-linked immunosorbent assay for IgG and IgM, by isoelectric focusing, and by inhibition studies to determine apparent avidity., Results: The patient's sera showed an oligoclonal response to Ro that increased in complexity and affinity with time. IgM anti-Ro appeared shortly before IgG anti-Ro, and disappeared as IgG anti-Ro increased in titer and affinity. IgG antiribosomal P autoantibodies also appeared during the patient's course, but in contrast to anti-Ro, were not preceded by IgM antiribosomal P., Conclusion: These data are consistent with the Ro autoantigen being presented and processed in a manner similar to heterologous antigen, and with differences in the mechanisms that lead to the production of IgG anti-Ro autoantibodies as opposed to antiribosomal P autoantibodies.

Objective: To study the serologic manifestations of rheumatoid arthritis (RA) at a United States Public Health Service Hospital that serves numerous tribes in Oklahoma., Methods: Forty-five patients with RA were identified, and serologic studies for antinuclear antibody (ANA), rheumatoid factor, and antibodies to extractable nuclear antigens were performed. Extraarticular manifestations of RA were also evaluated., Results: Twelve of the 45 patients with RA were Kiowa. These patients were significantly more likely to have a positive ANA (75%) than the other patients with RA (28%). In addition, anti-Ro was significantly more common among Kiowa (33%) than among members of other tribes (3%). There was no difference in the extraarticular manifestations of the Kiowa compared with the other Native American tribes., Conclusion: RA can be distinctly characterized by serology among groups of American Indians living in the same geographic area.

Objective: To determine the presence of antibodies that bind vesicular stomatitis virus (VSV) proteins in systemic lupus erythematosus (SLE) patient sera, as well as to examine any relationship between antibodies binding the viral nucleocapsid (N) protein and anti-Ro autoantibodies., Methods: Eighty SLE patient sera, 80 normal control sera, 47 rheumatic disease patient control sera, and 9 sera from Panamanian subjects (6 of whom were infected with VSV) were evaluated by immunoblot of purified VSV proteins., Results: Findings on immunoblots of the Panamanian subjects' sera were consistent with histories of endemic exposure to VSV, as determined by virus neutralization assays. Significantly different binding to viral proteins was seen in the group of 80 SLE patients compared with the normal control group and with the rheumatic disease control group, by a variety of measures. For example, most of the reactivity in the SLE patient sera included binding to the internal viral matrix (M) and N proteins, while the reactivity in the normal control sera was mostly against the surface viral glycoprotein (G) protein alone or the N protein alone. Within this SLE patient cohort, associations were found between binding to N protein and anti-Ro precipitins and between binding to M protein and anti-nuclear RNP autoantibody precipitins., Conclusion: The data are consistent with the original specific hypotheses of a relationship between 60-kd Ro autoantigenicity and VSV, as well as with the suggestion that a rhabdovirus may be important in SLE. They do not, however, make possible any conclusions concerning the role of rhabdoviruses in the development of SLE or of anti-Ro autoimmunity.