IFI16 Antibodies Associated With Severity of Sjögren Syndrome

Anti-interferon-inducible protein-16 (anti-IFI16) antibodies were found to be more prevalent in patients with markers of severe  primary Sjögren syndrome (SS), as defined by a Schirmer’s test of tear production  <5 mm wetting over 5 minutes, ANA titer> 1:320, hypergammaglobulinemia (IgG >1,445 mg/dl), and germinal center–like structures in the labial salivary gland lymphocytic infiltrates, according to research published in Arthritis Care & Research.

Among patients with positive Ro/SSA and La/SSB serology, the presence of IFI16 antibodies was associated significantly with hypergammaglobulinemia and an abnormal Schirmer’s test, which is suggestive of an independent association of IFI16 antibodies as markers for the diagnosis of severe SS phenotypes.

“Emerging evidence supports a role for IFI16 in the pathogenesis of several autoimmune disorders, both through the generation of high levels of proinflammatory cytokines and its recognition as an autoantigen,” the authors wrote. “We demonstrate for the first time that anti-IFI16 antibodies associate with markers of more severe Sjögren’s syndrome.”

In order to evaluate the frequency, phenotypic characteristics, and clinical associations of anti-IFI16 antibodies in patients with primary Sjögren syndrome, Alan Baer, MD, from the Johns Hopkins University School of Medicine and colleagues studied sera from participants with primary Sjögren syndrome (n=133), from healthy controls (n=47), and from patients with systemic lupus erythematosus as disease controls (n=132).

Anti-IFI16 antibodies were assessed by enzyme-linked immunosorbent assay (ELISA). The researchers quantified expression of IFI16 in salivary gland lysates by immunoblotting. They found that anti-IFI16 antibodies were present in the sera of 38 of the 133 participants with Sjögren syndrome (29%) compared with 1 of 47 healthy participants (2.1%) and 31 of 132 participants with lupus (24%).

In participants with Sjögren syndrome, anti-IFI16 antibodies were associated with an abnormal Schirmer test (P = .003), hyperglobulinemia (P = .02), antinuclear antibody ≥1:320 (P = .01), germinal center-like structures in labial salivary gland lymphoid infiltrates (P = .01), and higher focus scores (3.4 vs 2.4; P = .005). High-titer IFI16 antibodies were directed against an epitope outside the N-terminus in 69% of participants with Sjögren syndrome, and IFI16 was expressed in 80% of participants with Sjögren syndrome and 17% of labial salivary glands in control participants.

Thus, IFI16 is expressed at higher levels in the salivary glands of individuals with Sjögren syndrome compared to controls. These high levels in disease target tissue may contribute to the ongoing anti-IFI16 immune response.

The researchers suggest that “while the mechanisms that make IFI16 a prominent target of the autoimmune response in [lupus] and [Sjögren syndrome] await elucidation, elevated IFI16 levels, in the setting of DNA binding and apoptosis, may create the potential for initiating autoimmunity.”

Summary and Clinical Applicability

Researchers in this study used an immunoblotting approach to quantify levels of  IFI16 salivary gland expression, finding that IFI16 expression was low or absent in salivary gland lysates from control subjects, and increased in patients with SS.  This suggests that elevated autoantigen expression in SS is likely one mechanism for initiating and/or propagating the abnormal immune response responsible for pathogenesis of SS.

Reference

Baer AN, Petri M, Sohn J, Rosen A, Casciola-Rosen L. Association of antibodies to interferon-inducible protein-16 with markers of more severe disease in primary Sjögren’s syndrome. Arthritis Care Res. 2016;68(2):254-260. doi:10.1002/acr.22632.