Association of endogenous anti–interferon‐α autoantibodies with decreased interferon‐pathway and disease activity in patients with systemic lupus erythematosus

Abstract

Objective Numerous observations implicate interferon-α (IFNα) in the pathophysiology of systemic lupus erythematosus (SLE); however, the potential impact of endogenous anti-IFNα autoantibodies (AIAAs) on IFN-pathway and disease activity is unclear. The aim of this study was to characterize IFN-pathway activity and the serologic and clinical profiles of AIAA-positive patients with SLE. Methods Sera obtained from patients with SLE (n = 49), patients with rheumatoid arthritis (n = 25), and healthy control subjects (n = 25) were examined for the presence of AIAAs, using a biosensor immunoassay. Serum type I IFN bioactivity and the ability of AIAA-positive sera to neutralize IFNα activity were determined using U937 cells. Levels of IFN-regulated gene expression in peripheral blood were determined by microarray, and serum levels of BAFF, IFN-inducible chemokines, and other autoantibodies were measured using immunoassays. Results AIAAs were detected in 27% of the serum samples from patients with SLE, using a biosensor immunoassay. Unsupervised hierarchical clustering analysis identified 2 subgroups of patients, IFNlow and IFNhigh, that differed in the levels of serum type I IFN bioactivity, IFN-regulated gene expression, BAFF, anti-ribosomal P, and anti-chromatin autoantibodies, and in AIAA status. The majority of AIAA-positive patients had significantly lower levels of serum type I IFN bioactivity, reduced downstream IFN-pathway activity, and lower disease activity compared with the IFNhigh patients. AIAA-positive sera were able to effectively neutralize type I IFN activity in vitro. Conclusion Patients with SLE commonly harbor AIAAs. AIAA-positive patients have lower levels of serum type I IFN bioactivity and evidence for reduced downstream IFN-pathway and disease activity. AIAAs may influence the clinical course in SLE by blunting the effects produced by IFNα.

Emerging clinical phenotypes associated with anti-cytokine autoantibodies

“…IFNα plays a central role in the pathophysiology of SLE and an increased expression of type I IFN-regulated genes, the so-called "type I IFN signature", has been implicated in the pathogenic processes of the disease [51]. In a study involving 49 SLE patients, anti-IFNα neutralizing AAbs were detected in 27% of the patients [52]. In agreement with the pathogenic role of IFNα in SLE, the presence of neutralizing anti-IFNα AAbs in these patients was associated with a decreased bioactivity of the IFNα in the serum, a reduced downstream IFN-pathway activity and a lower disease severity.…”

Protein microarray analysis reveals BAFF-binding autoantibodies in systemic lupus erythematosus

“…Abs targeting cytokines, chemokines, and growth factors have been described in SLE, pulmonary alveolar proteinosis, chronic mycobacterial infection, autoimmune polyendocrine syndrome type 1 (APS-1), Felty's syndrome, thymic malignancy, and other immune disorders (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Here, we use the term serum factors to encompass cytokines, chemokines, growth factors, and other circulating components in the blood and lymph that have the ability to influence the immune response.…”

Lupus Nephritis: The Evolving Role of Novel Therapeutics

“…In 49 patients with SLE, 22% were found to have naturally occurring anti–IFN-α antibodies and a lower IFN-α gene signature than patients without such antibodies. 101 These antibody-positive patients also tended to have a lower SLEDAI (Systemic Lupus Erythematosus Disease Activity Index) score, fewer positive lupus serologic test results, and higher complement levels than patients with the high IFN-α signature. However, ~35% of this cohort were low IFN-α signature but did not have anti–IFN-α autoantibodies, suggesting that not all patients will benefit from exogenous anti–IFN-α therapy.…”