Type I IFN signature in primary Sjögren’s syndrome patients

Abstract

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disease characterized by lymphocytic infiltrates in salivary and lacrimal glands. Clinical manifestations range from ocular and oral dryness to vasculitis and severe fatigue. pSS is a disease with heterogeneous symptoms and a variable response to the available treatment. Recently, a key role for Interferon (IFN) type I has been implicated in the pathogenesis of pSS. As type I IFN consists of 17 different subtypes, it cannot be easily assessed using a conventional ELISA. Therefore the expression of type I IFN inducible genes – the so-called type I IFN signature – is assessed in salivary gland tissue and blood from patients as a readout for type I IFN activity. In this review we discuss the potential of type I IFN as a novel biomarker for disease activity, subclassification of patients, prediction of therapy response and most importantly as a target for therapeutic intervention.

Keywords::

• BAFF
• monocyte
• plasmacytoid dendritic cell
• Sjögren’s syndrome
• Th17
• type I interferon

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The development of primary Sjögren's syndrome (pSS)-like symptoms was noted upon treatment with interferon (IFN) type I in hepatitis and melanoma patients.

• Type I IFN consists of 13 different members of IFNα as well as IFNβ, IFNε, IFNκ and IFNω, resulting in the technical challenge that type I IFN cannot be easily assessed by the use of a conventional ELISA.

• The expression of type I IFN-inducible genes, the so-called type I IFN signature, is assessed in salivary gland tissue, peripheral blood mononuclear cells, isolated blood monocytes and whole blood from pSS patients as a readout for type I IFN activity. For the assessment of type I IFN activity in pSS serum and/or plasma, the epithelium-derived WISH reporter cell line can be used.

• Increased expression of IFN-inducible genes has been found both locally in the glands of pSS patients as well as systemically.

• Prevalence of type I IFN signature in monocytes of pSS patients is about 55%.

• pSS patients with increased type I IFN activity appear to be a distinct subgroup within Sjögren’s syndrome with higher disease activity, presence of autoantibodies, hypergammaglobulinemia, lower complement and lower lymphocytes and neutrophils.

• In mouse models, it has been shown that type I IFN can directly affect glandular function.

• Type I IFN-producing plasmacytoid dendritic cells have been found increased in salivary glands of pSS patients.

• Next to antiviral and antitumor capacities, type I IFN carries out many immunomodulatory effects such as activation of dendritic cells, B cell activation through induction of BAFF, Th17 activation and upregulation of proapoptotic molecules Fas and Fas ligand and autoantigens.

• The type I IFN system is a possible future therapeutic target for pSS and blockade with biologic agents can be exerted by interfering with different upstream and downstream targets of the type I IFN system.

• Enzyme immune assay for assessment of whole blood MxA levels is an easy and practical assay for identifying systemic type I IFN bioactivity.

Notes