A novel autoantigen to differentiate limited cutaneous systemic sclerosis from diffuse cutaneous systemic sclerosis: The interferon‐inducible gene IFI16

Abstract

Objective. To investigate the presence and clinical significance of autoantibodies against the interferoninducible gene IFI16 in systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and other autoimmune diseases.Methods. Immunohistochemical analysis was used to evaluate the expression of IFI16 in skin biopsy specimens obtained from patients with SSc and patients with SLE. Levels of antibodies against IFI16 in sera from 82 patients with SSc and 100 patients with SLE were determined by enzyme-linked immunosorbent assay. Other autoimmune diseases such as primary Sjö-gren's syndrome (SS), rheumatoid arthritis (RA), chronic urticaria, and hepatitis C virus (HCV) infection were also examined.Results. Expression of IFI16 was greatly increased and was ubiquitous in all layers of the epidermis and in the dermal inflammatory infiltrates of lesional skin from both patients with SLE and patients with SSc. Patients with SLE, those with primary SS, and those with SSc exhibited significantly higher anti-IFI16 IgG antibody levels compared with normal controls (for SLE, P < 0.002; for primary SS, P < 0.001; for SSc, P < 0.0005). Anti-IFI16 titers above the ninety-fifth percentile for control subjects were observed in 26% of the patients with SLE, 50% of those with primary SS, and 21% of those with SSc (28% of patients with limited cutaneous SSc [lcSSc] versus 4% of patients with diffuse cutaneous SSc [dcSSc]). In contrast, the prevalence of anti-IFI16 was 4% in patients with RA, 5% in those with chronic urticaria, and 13% in those with HCV infection.Conclusion. The results of this study provide evidence that an IFN-inducible gene, IFI16, may be involved in the pathophysiologic mechanisms of connective tissue disorders such as SSc. Moreover, a strict correlation with lcSSc was also demonstrated, thus providing a novel tool in the differential diagnosis of lcSSc from dcSSc.

Antiviral TRIMs: friend or foe in autoimmune and autoinflammatory disease?

“…The ubiquitination of STING is essential to facilitate dimerisation of the adaptor prior to the recruitment of TBK-1, thus marking TRIM56 as a positive facilitator of this pathway. IFI16 requires STING for its activity and is a well known autoantigen in systemic autoimmune disease [73]. The absolute requirement for STING in the production of IFN-β has come from the recent report of a loss-of-function variant in an American cohort that correlates with an approximate 90% loss of IFN-β inducibility in subjects homozygous for the mutation [74].…”

The interferon‐inducible gene IFI16 secretome of endothelial cells drives the early steps of the inflammatory response

“…The treatment of cells with short hairpin RNA, targeting IFI16 significantly inhibited ICAM-1 induction by IFN-g demonstrating that IFI16 is required for proinflammatory gene stimulation by this cytokine. Moreover, functional analysis of the ICAM-1 promoter demonstrated that NF-kB, one of the main transcription factors activated during inflammation, is the main mediator of IFI16-driven ICAM-1 induction by IFN-g. Additionally, anti-IFI16 autoAb are present at much greater levels in patients with autoimmune diseases, such as cutaneous systemic sclerosis, systemic lupus erythematosus and Sjogren's syndrome, compared with normal controls [10,11].…”

Autoantikörperdiagnostik

“…Riemekasten et al [25] beschrieben stimulatorische Antikörper gegen Typ-I-Rezeptoren von Angiotensin II und gegen Typ-A-Rezeptoren von Endothelin I, die bei SSc, aber auch bei anderen Kollagenosen und rheumatoider Arthritis -allerdings in niedrigeren Titern -vorkommen. Die diagnostische Relevanz dieser stimulatorischen Autoantikörper, zu denen auch Antikörper gegen das Interferon-induzierbare Protein IFI16 zählen [21], bedarf weiterer Untersuchungen.…”