60 kD Ro and nRNP A frequently initiate human lupus autoimmunity

Abstract

Systemic lupus erythematosus (SLE) is a clinically heterogeneous, humoral autoimmune disorder. The unifying feature among SLE patients is the production of large quantities of autoantibodies. Serum samples from 129 patients collected before the onset of SLE and while in the United States military were evaluated for early pre-clinical serologic events. The first available positive serum sample frequently already contained multiple autoantibody specificities (65%). However, in 34 SLE patients the earliest pre-clinical serum sample positive for any detectable common autoantibody bound only a single autoantigen, most commonly 60 kD Ro (29%), nRNP A (24%), anti-phospholipids (18%) or rheumatoid factor (15%). We identified several recurrent patterns of autoantibody onset using these pre-diagnostic samples. In the serum samples available, anti-nRNP A appeared before or simultaneously with anti-nRNP 70 K in 96% of the patients who had both autoantibodies at diagnosis. Anti-60 kD Ro antibodies appeared before or simultaneously with anti-La (98%) or anti-52 kD Ro (95%). The autoantibody response in SLE patients begins simply, often binding a single specific autoantigen years before disease onset, followed by epitope spreading to additional autoantigenic specificities that are accrued in recurring patterns.

Figure 1. Autoantibodies precede lupus classification and occur in linked subsets.

Kaplan-Maier survival curves for the onset of each autoantibody specific as measured by a solid phase, bead-based assay are presented. Anti-60 kD Ro, anti-La and anti-52 kD Ro are among the earliest specificities detected by this method. In contrast, anti-68 kD nRNP and nRNP A specificities are frequently detected closer to the time of lupus classification.

Figure 2. Initial autoantibody targets in the pre-diagnosis cohort.

(A) The front (black) bars show the number of patients developing antibodies to respective antigen as their initial single autoantibody specificity. The middle (dark gray) bars show the number of patients with antibodies to the respective antigen in their first positive sample, which includes individuals who had multiple autoantibody specificities in their earliest positive serum. The back (light gray) bars show the total number of patients ever positive for each specificity. (B) Initial autoantibody profiles detected in 34 patients with a single initial specificity and (C) the final autoantibody profile for the patients with a later sample available. Colorimetric changes represent autoantibody concentration, ranging from green showing lower reactivity to bright red for high binding.

Figure 3. The order of onset of protein-specific autoantibodies within the linked systems.

Antibodies to nRNP A commonly appeared prior to anti-70 K (A) while a variable onset was seen between Sm and nRNP A (B). Anti-60 kD antibodies virtually always precede anti-La antibodies (C). The order of appearance did not favor anti-dsDNA or anti-chromatin when compared to each other (D).

Figure 4. Potential mechanism for development of autoantibodies through a common environmental etiology.

While potential structural mimics are known with EBNA-1 for Ro, Sm B, Sm D, nRNP A, nRNP C and nRNP 70 K, no such structural relationship is known for a heteroimmune response operating to generate anti-dsDNA, anti-chromatin or anti-ribosomal P.