Overview

Beyond activated type I IFN signalling, IIMs are also characterized by chronic infiltration of activated T cells and, to a lesser extent, B cells in muscle tissue of patients. A perivascular distribution of CD4⁺ T cells and B cells is typical for DM, while PM shows direct attack by activated CD8⁺ T cells against muscle fibres [1]. Proinflammatory cytokines released from inflammatory cells facilitate the migration of those cells from circulation through cellular adhesion molecules on the endothelial cells in an autoamplificatory mechanism [1]. Type I IFN plays a central role in the dysregulated cytokine and chemokine network involved in myositis pathophysiology. Multiple type I IFN-induced proteins are markedly overexpressed in serum and muscle fibres of DM patients , and the recruitment of Th1 cells through IFN-γ-induced protein 10 (IP10) and CXCR3 interaction has been shown to play an important role in DM skin lesions [2].

Trials

Recently a phase 1b trial of an investigational anti-IFN-α monoclonal antibody, sifalimumab, was completed in adult DM or PM patients (NCT00533091). Gene expression experiments from this study demonstrated suppression of a type I IFN gene signature in both blood and muscle tissue by sifalimumab, along with a positive correlative trend between IFN target neutralization and clinical improvement in myositis patients [3].

Post-treatment changes for all 47 dysregulated serum proteins in myositis patients were assessed by paired t-test in one relevant trial. Eleven proteins demonstrated reduced serum levels by sifalimumab, while no protein showed a significant change in placebo-administered patients. Five of these proteins are inducible by type I IFN, including IL-2RA, MCP-1, MCP-2, BAFF and ferritin. A previous report demonstrated a trend of correlation among MMT-8 improvement, blood and muscle type I IFN target neutralization in patients with >20% target neutralization at day 98 [4]. high protein suppression was observed mostly in sifalimumab-administered patients with >20% IFN target neutralization in blood or muscle, but less so in those with a low IFN signature score or <20% IFN target neutralization in blood. Nevertheless, a few IFN-hi patients with >20% target neutralization displayed an increase in those five IFN-inducible proteins. The discordance between mRNA and protein level regulation may reflect the complex post-transcriptional regulation, protein secretion, receptor shedding and negative feedback processes involved in serum proteome regulation.(5)

IL-2RA, IL-18, TNFR2, BAFF, MCP-1 and MCP-2 are involved in T cell regulation and their baseline levels have been shown to correlate with type I IFN status and clinical activities of DM or PM patients. All these proteins demonstrated significantly reduced levels after sifalimumab, but not placebo, administration . Functional enrichment analysis [Database for Annotation, Visualization, and Integrated Discovery (DAVID)] [6] indicated that positive regulation of T cell proliferation and T cell activation are the only overrepresented gene ontology biological process terms among 11 sifalimumab-regulated proteins when using the 47 up-regulated proteins at baseline as the background gene list (P < 0.05).

 

Relevance

The coordinated down-regulation of T cell–associated proteins by sifalimumab suggests the link between blocking type I IFN signaling and suppression of T cell function.

To investigate the effects of sifalimumab on muscle T cell infiltration can be used anti-CD3 antibody to stain muscle biopsies from the patients with the highest median suppression of T cell-associated proteins.

These results demonstrate a robust over-expression of multiple serum proteins in PM patients, especially those with an elevated type I IFN gene signature at baseline. Sifalimumab but not placebo administration resulted in coordinated suppression of multiple cytokines, adhesion molecules and soluble receptors associated with immune cell activation and movement. The link between IL-2RA suppression and favourable MMT-8 alteration suggests the potential of IL-2RA changes from baseline as a responsive and/or predictive marker of changes in disease activity for IFN-targeted therapies in PM patients.

Further studies will be needed to test this hypothesis as well as to more extensively investigate the impact of IFN blockade on immune cell infiltration in the muscle of IIM patients.

Footnotes:

1. Bilgic H, . Interleukin-6 and type I interferon-regulated genes and chemokines mark disease activity in dermatomyositis. Arthritis Rheum 2009;60:3436-46.CrossRefMedlineWeb of ScienceGoogle Scholar
2. Hengstman GJ, . Myositis during long-term interferon-alpha treatment. Neurology 2000;54:2186..CrossRefGoogle Scholar
3. Higgs BW, . A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-alpha monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients. Ann Rheum Dis 2013.Google Scholar
4. ​Xiang G. Suppression of soluble T cell-associated proteins by an anti-interferon-α monoclonal antibody in adult patients with dermatomyositis or polymyositis. Rheumatology (2013) doi: 10.1093/rheumatology/ket413 First published online: December 19, 2013. http://rheumatology.oxfordjournals.org/content/early/2013/12/19/rheumatology.ket413.full
5. Chen X, . Expression of costimulatory TNFR2 induces resistance of CD4+FoxP3− conventional T cells to suppression by CD4+FoxP3+ regulatory T cells. J Immunol 2010;185:174-82.Abstract/FREE Full Text