Anti-RNP Antibodies May Induce Interferon Without Decreasing Complement Levels in SLE

Unlike anti-dsDNA autoantibodies, anti-RNP autoantibodies form immune complexes that may induce interferon without complement fixation in patients with systemic lupus erythematosus (SLE), according to study results published in Annals of the Rheumatic Diseases.

Antinuclear antibodies can target dsDNA and RNA-binding proteins (RBPs), forming immune complexes that induce type I interferon. Anti-dsDNA are also known to decrease complement levels. While anti-dsDNA antibodies are markers for SLE classification and disease activity, anti-RBP antibodies do not noticeably change with disease activity and their role in SLE pathogenesis is not as clear.

In the current study, researchers evaluated the association between anti-dsDNA and anti-RBP antibodies (including anti-RNP, anti-Sm, anti-SSA, and anti-SSB antibodies), interferon gene signatures, and complement components C3 and C4 in patient samples from 2 clinical trials of tabalumab in patients with SLE. These associations were compared between patients of African and European ancestry. Analyses included statistical hypothesis testing, linear regression, and classification and regression trees analysis.

Patients of African vs European ancestry were more likely to have multiple autoantibodies and higher anti-RNP levels. Ancestry also influenced the association between antinuclear antibodies, complement, and the interferon gene signatures. Although anti-RNP autoantibodies were associated with the interferon gene signature in both ancestries, anti-dsDNA autoantibodies were only associated with the interferon gene signature in patients of European ancestry. The researchers suggested this may have been due to ancestral differences in the biologic functions of autoantibodies.

In all patients, anti-RNP autoantibodies were identified as the strongest predictor of interferon gene signature expression. In addition, an inverse relationship was found between interferon gene signatures and C3/C4 for anti-dsDNA autoantibodies but not anti-RNP autoantibodies. This indicated that anti-RNP autoantibodies may not be related to depression of complement.

In patients with a positive interferon gene signature, 82.41% tested positive for antinuclear antibody-positive compared with 54.48% who tested negative for interferon gene signature. Therefore, the researchers noted that autoantibodies may be required for the induction of interferon, but that interferon gene signature was not required for the production of autoantibodies.

The main limitation of the study was the inability to generalize results due to narrow clinical trial enrollment criteria.

The researchers concluded, “There is a complex relationship between autoantibodies and the interferon gene signature, with anti-RNP associated in African ancestry and both anti-dsDNA and RNP associated in European ancestry. Moreover, there was a difference in the relationship between anti-dsDNA, but not anti-RBP, with complement levels. The lack of a relationship of anti-RNP with C3 and C4 suggests that anti-RNP immune complexes (ICs) may drive the interferon gene signature without complement fixation, whereas anti-dsDNA ICs involve complement consumption.”

Disclosure: Several study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

Hubbard EL, Pisetsky DS, Lipsky PE. Anti-RNP antibodies are associated with the interferon gene signature but not decreased complement levels in SLE. Ann Rheum Dis. Published online February 3, 2022. doi:10.1136/annrheumdis-2021-221662