Background/Purpose: Autoantibodies targeting to nuclear antigens are serological hallmarks of SLE, however, the processing of autoantibody production during the transition from normal to autoimmunity and the pathogenicity of the autoantibodies related with the disease activities are still unclear.

Methods: In this study, we first measured the serum anti-nuclear antibody (ANA) in 2,353 healthy controls (HC) and 500 SLE patients by ELISA. We then screened the levels of IgG and IgM autoantibodies (autoAbs) targeting to a broad range of nuclear and non-nuclear antigens using proteomic microarrays bearing 95 autoantigens, in a cohort of 121 well defined SLE patients and the same number of matched HCs. For a subset of samples, we also measured the IgA subtype of AutoAbs using autoantigen arrays.

Results: ANA testing showed a positivity of 92.5% in SLE, in which 78% with high ANA titers (>40 AU) and 14.5% with moderate to low ANA (20-40 AU). About 25% of HCs also exhibited positive ANA among which 9% with high titer (>40 AU). Autoantigen array analysis revealed high prevalence of IgG autoAbs in SLE patients, the average number of positive IgG autoAbs in SLE were 28.5 and over 95% of SLE harbor more than 5 autoAbs, comparing with average of 3 IgG autoAbs with only 25% have more than 5 autoAbs in HCs (p<0.05). A group of 19 IgG autoAbs targeting to various nuclear antigens (dsDNA, chromatin, nucleosome, histone, Sm/RNP, PCNA, CENP-B, etc.) were identified to be significantly enriched in SLE patients by clustering analysis. The presence of IgG autoantibodies against DNA antigens (dsDNA, ssDNA, chromatin, nucleosome, histone) were most significantly associated with disease activity (SLEDAI) and lupus nephritis (r=0.56, p<0.001) in SLE. Among the normal populations, the young females (age 20-45) with high ANA (>20) tend to carry more IgG autoAbs than other groups, however, majority of the IgG autoAbs identified in HCs were those targeting to non-nuclear antigens, such as cell matrix (collagens, alpha-actinin, heparin sulfate, etc) and phospholipid proteins (cardiolipin). The ANA negative NCs showed low positivity for both IgG and IgM autoAbs, however, the ANA positive NC exhibited higher IgM specificities targeting to 33 non-nuclear and nuclear antigens  whereas in SLE the IgM autoAb reaction were relatively lower.   Interestingly we noticed a subgroup of SLE       patients who have active disease (SLIDAI>10) with lupus nephritis exhibited strong positivity for both IgG and IgM autoantibodies again DNA-associated antigens (dsDNA, ssDNA, chromatin, nucleosome, histone). IgA autoabs were detected in 17 (out of 30) SLEs, preferentially targeting to RNA-associated antigens (Ro, La, Sm/RNP and Ribo phophoproteins). Interestingly, 3 of the ANA- SLE who have no IgG autoAbs showed positive IgA autoantibodies.

Conclusion: Breach in immune tolerance in normal population was usually accompanied by production of autoantibodies against non-nuclear antigens and the transition from IgM to IgG autoAbs was an indication of increased pathogenicity of the autoantibodies. IgG autoantibodies against nuclear antigens especially DNA associated antigens were closely related with the disease activitity and renal damage in SLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/profiling-a-broad-range-of-autoantibodies-in-healthy-and-systemic-lupus-erythematosis-revealed-autoantibody-patterns-associated-with-autoantibody-transition-and-disease-activity/