This study evaluated the safety and tolerability of anifrolumab, a monoclonal antibody targeting the type I interferon (IFN) receptor, in Japanese patients with moderate-to-severe systemic lupus erythematosus (SLE).
Thus, the current study provides a direct link between type I IFN pathway overactivation and the abnormally high frequency and proinflammatory properties of transitional B cells in active SLE patients, which contributes to the understanding of the roles of type I IFNs and B cells in the pathogenesis of SLE.
Given that diseases associated with anti-SSA/Ro autoantibodies, such as systemic lupus erythematosus and Sjögren syndrome, are linked with an upregulation of IFN and type I IFN-stimulated genes, including sialic acid-binding Ig-like lectin 1 (Siglec-1), a receptor on monocytes/macrophages, recent attention has focused on a potential role for IFN and IFN-stimulated genes in the pathogenesis of congenital heart block (CHB).
Previous reports have described the appearance of systemic lupus erythematosus (SLE) cases following interferon-α (IFN-α) therapy, IFN-regulated gene expression is significantly increased in SLE, and an association between SLE and gene variants belonging to IFN downstream pathways has been shown.
High type I IFN activity correlated with levels of IFN-γ and IFN-α and associated with active SLE in most domains: weight loss, fatigue, fever, rash, lymphadenopathy, arthritis, nephritis and haematological manifestations.
However, these results suggest that closing the door on targeting the type 1 IFN pathway in SLE may be premature and highlight the emerging question of whether an organ-specific approach toward lupus trials and treatment should be the wave of the future.
Sensing self-nucleic acids through toll-like receptors in plasmacytoid dendritic cells (pDCs), and the dysregulated type I IFN production, represent pathogenic events in the development of the autoimmune responses in systemic lupus erythematosus (SLE).
Thus, sole upregulation of IFN-α is sufficient to induce SLE, and the double-negative T cells expanded by IFN-α are directly responsible for the organ manifestations, such as lupus skin disease or nephritis.
Neutrophil extracellular traps (NETs) are considered a potential source of antigenic trigger in SLE that can lead to type I IFN gene induction, as well as increased autoantibody production.
Immunologically, anti-CD40 treatment disrupted multiple processes that contribute to the pathogenesis of systemic lupus erythematosus (SLE), including autoreactive B cell activation, T effector cell function in target tissues, and type I IFN production.
BIIB059 administration in patients with SLE decreased expression of IFN response genes in blood, normalized MxA expression, reduced immune infiltrates in skin lesions, and decreased CLASI-A score.
Here, we show that conventional dendritic cells (cDCs) from predisease lupus-prone B6.NZM Sle1/Sle2/Sle3 triple congenic (TCSle) mice produce more IL-10 than wild-type congenic cDCs upon TLR stimulation, and this overproduction is prevented by blocking the type I IFN receptor (IFNAR) with specific Abs.
10-week old female lupus-prone (NZM2328), wild-type (BALB/c) and iNZM mice (lack a functional type I IFN receptor on NZM2328 background) were treated on their dorsal skin with 100 mJ/cm<sup>2</sup> of UVB for 5 consecutive days.
IFN-γ<sup>+</sup> cells in the CD4<sup>+</sup>CD25<sup>+</sup>T subset fresh-isolated from SLE patients increased slightly, but IFN-γ-producing response to stimulation in CD4<sup>+</sup>CD25<sup>+</sup>T subset of SLE decreased.
Pathogenesis of ASIA-MO is not clear, but is characterized by chronic granulomatous inflammation, like the pristane model in mice, with increase of proinflammatory cytokines: type I interferons (IFNα and IFNß), systemic lupus erythematosus (SLE), and erosive arthritis.
Significant advances in the understanding of the molecular basis of innate immunity have led to the identification of interferons (IFNs), particularly IFN-α, as central mediators in the pathogenesis of Systemic Lupus Erythematosus.
IFN-α gene expression was measured by real-time polymerase chain reaction (PCR) assay in 123 Egyptian female patients with SLE and in 100 females as a healthy control group.