Distinct Functions of Autoantibodies Against Interferon in Systemic Lupus Erythematosus: A Comprehensive Analysis of Anticytokine Autoantibodies in Common Rheumatic Diseases

Abstract

Background Anticytokine autoantibodies occur across a range of hematologic, pulmonary and infectious diseases, however, systematic investigation of their presence and significance in autoimmune diseases is lacking. Methods Serum samples from patients with systemic lupus erythematosus (SLE) (n=199), primary Sjögren’s syndrome (SS) (n=150), rheumatoid arthritis (RA) (n=149) and healthy controls (n=200) were screened for 24 anticytokine autoantibodies using a multiplex bead-based assay. To evaluate biological activity of anticytokine autoantibodies, their ability to block cytokine-induced signal transduction or protein expression was measured. RNA sequencing was performed on whole blood in subset of controls and SLE patients. Results SLE and SS patients had striking excess of autoantibodies against interferons and the interferon-responsive chemokine interferon-inducible-protein-10 (IP-10). Only autoantibodies against type I interferon, interleukin (IL)-12 and IL-22 exhibited neutralizing activity. In SLE, anti-interferon-γ autoantibodies tracked with more disease activity, anti-double-stranded-DNA antibodies, and elevated expression of interferon-α/β-inducible genes. Conversely, SLE patients with blocking anti-interferon-α autoantibodies normalized their type I interferon gene expression signature. Anti-type III interferons (λ2, λ3), and anti-IP-10 autoantibodies were newly recognized and autoantibodies against macrophage-colony stimulating factor, IL-4, IL-7, IL-17 and IL-22, that have not been previously identified in rheumatologic conditions, were discovered. Conclusions Anticytokine autoantibodies were associated with distinct patterns of SLE, SS and RA. Anti-interferon autoantibodies were overrepresented in SLE and SS and fall into distinct functional classes with only a subset of anti-type I interferon antibodies exhibiting neutralizing activity. Anti-interferon-γ autoantibodies correlated with increased disease activity and interferon-related gene expression, suggesting that they may contribute to the pathogenesis of SLE.

Associations of B cell-activating factor (BAFF) and anti-BAFF autoantibodies with disease activity in multi-ethnic Asian systemic lupus erythematosus patients in Singapore

“…Neutralizing anti-IFN-a antibodies detected in approximately 25% of lupus patients by Morimoto et al were associated with decreased bioactivity of IFN-a and lower disease activity and severity [12]. Contrary to this, the recent study by Gupta et al [13] found that of their 12 SLE patients (of a total of 199) who had anti-IFN-a antibodies, only 50% of these samples demonstrated functional activity. Moreover, there were no significant differences in clinical disease activity, hypocomplementaemia or anti-dsDNA antibody titres between those with and without anti-IFN-a antibodies.…”

“…Contrary to this, the recent study by Gupta et al . found that of their 12 SLE patients (of a total of 199) who had anti‐IFN‐α antibodies, only 50% of these samples demonstrated functional activity. Moreover, there were no significant differences in clinical disease activity, hypocomplementaemia or anti‐dsDNA antibody titres between those with and without anti‐IFN‐α antibodies.…”

Clinical features of Sjögren's syndrome patients with autoantibodies against interferons

“…Based on a previous study of anticytokine autoantibodies in SS [29], a select LIPS panel of five autoantigen targets was employed. The five cytokine targets included GM-CSF, IFN-γ, IFN-λ1, IFN-ω and IFN-α1 and have been previously described [20,25,28].…”

“…Using an established in vitro assay [20,25,29,37,44,45], the neutralizing capacity of specific anti-interferon autoantibodies, were evaluated using control peripheral blood mononuclear cells (PBMC). In these experiments, PBMC were incubated in the presence of 10% healthy volunteer or patient sera and left unstimulated or stimulated with the cytokine recognized by the specific anticytokine autoantibody found in the serum samples.…”

“…Increasing evidence suggests that neutralizing anticytokine autoantibodies, in some cases, may also alter autoimmune disease activity. Notably, SLE patients harboring high levels of anti-interferon-α autoantibodies demonstrate less severe disease activity [26][27][28][29]. Furthermore, a subset of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients exhibiting anticytokine autoantibodies did not develop type I diabetes [30].…”