The Pathogenesis, Molecular Mechanisms, and Therapeutic Potential of the Interferon Pathway in Systemic Lupus Erythematosus and Other Autoimmune Diseases

Abstract

Therapeutic success in treating patients with systemic lupus erythematosus (SLE) is limited by the multivariate disease etiology, multi-organ presentation, systemic involvement, and complex immunopathogenesis. Agents targeting B-cell differentiation and survival are not efficacious for all patients, indicating a need to target other inflammatory mediators. One such target is the type I interferon pathway. Type I interferons upregulate interferon gene signatures and mediate critical antiviral responses. Dysregulated type I interferon signaling is detectable in many patients with SLE and other autoimmune diseases, and the extent of this dysregulation is associated with disease severity, making type I interferons therapeutically tangible targets. The recent approval of the type I interferon-blocking antibody, anifrolumab, by the US Food and Drug Administration for the treatment of patients with SLE demonstrates the value of targeting this pathway. Nevertheless, the interferon pathway has pleiotropic biology, with multiple cellular targets and signaling components that are incompletely understood. Deconvoluting the complexity of the type I interferon pathway and its intersection with lupus disease pathology will be valuable for further development of targeted SLE therapeutics. This review summarizes the immune mediators of the interferon pathway, its association with disease pathogenesis, and therapeutic modalities targeting the dysregulated interferon pathway.

Keywords: autoimmunity; interferon; systemic lupus erythematosus.

Figure 1

Activation of type I interferon response by viral nucleic acids and pattern recognition signaling pathways. Pattern recognition receptors located in the endosome (e.g., TLR3/7/8/9), the cell membrane (e.g., TLR4), or the cytoplasm (e.g., cGAS, RIG-I, MDA-5) detect viral nucleic acids to trigger a signaling pathway that results in type I interferon production from pDCs, macrophages, epithelial cells, and fibroblasts. cGAS, cGAMP synthase; ds, double-stranded; IFN, interferon; IKK, inhibitor of kappa B kinase; IRAK, interleukin 1 receptor-associated kinase; IRF, interferon regulatory factor; MAVS, mitochondrial antiviral-signaling protein; MDA-5, melanoma differentiation-associated protein 5; MyD88, myeloid-differentiation primary response protein 88; NF, nuclear factor; pDC, plasmacytoid dendritic cell; PRR, pattern recognition receptor; RIG-1, retinoic acid inducible gene-I; ss, single-stranded; STING, stimulator of interferon genes; TLR, Toll-like receptor; TBK1, TRAF family associated NF-κB activator (TANK)-binding kinase-1; TRAF, tumor necrosis factor receptor-associated factor; TRIF, TIR domain-containing adaptor inducing interferon-β.

Figure 2

Type I interferons and immune complex formation contributes to organ damage in the cycle of SLE pathophysiology. BAFF, B-cell activating factor; IFN, interferon; IL, interleukin; mDC, myeloid dendritic cell; NK, natural killer; pDC, plasmacytoid dendritic cell; SLE, systemic lupus erythematosus; TNFα, tumor necrosis factor alpha.

Figure 3

Timeline showing multiple lines of evidence that support the role of type I interferon in SLE and autoimmune pathogenesis. IFN, interferon; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

Figure 4

Representative heat map visualizing genes differentially expressed in whole blood from patients with SLE relative to healthy controls. The heatmap includes 110 upregulated interferon-α/β-inducible transcripts, measured in whole blood samples from patients with SLE (―; n = 41) and compared with whole blood samples from healthy controls (―; n = 24). Figure reproduced from Yao et al. Hum Genomics Proteomics 2009, 374312 [54]. IFN, interferon; SLE, systemic lupus erythematosus.

Figure 5

Elevated type I interferon gene signature expression in tissues of patients with SLE, SSc, DM, PM, and RA relative to healthy controls. The type I interferon gene signature score was calculated by measuring the expression of 5 type I IFN-inducible genes in disease target tissue and expressed as a fold-change relative to healthy controls. Horizontal bars represent the median values for each group and the gray dashed line indicates the threshold for signature positive or negative status. Lesional skin samples from patients with SLE (n = 16) and SSc (n = 16) had significantly greater IFNGS expression than samples from healthy controls (n = 25) (p < 0.05 for both). Muscle biopsy samples from patients with DM (n = 37) and PM (n=36) had significantly greater IFNGS expression than those from healthy controls (n = 14) (p < 0.0001 and p < 0.01, respectively). No statistical test was performed to compare the IFNGS expression in synovium tissues from patients with RA versus healthy controls, owing to the small sample size (n = 2 vs. n = 20). Figure reproduced from Higgs, B.W. et al. Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway. Ann Rheum Dis 2011, 70, (11), 2029-36. 2021 [30], with permission from BMJ Publishing Group Ltd. DM, dermatomyositis; IFN, interferon; PM, polymyositis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.

Figure 6

Median percentage of baseline IFNGS score throughout the treatment period in IFNGS-high patients with SLE in a phase 3 trial of anifrolumab versus placebo alongside background standard therapy. IFNGS was measured using the expression of 21 IFN-α/β inducible genes and expressed as a median percentage of baseline score. Error bars represent median absolute deviation. All patients received background therapy with oral glucocorticoids and/or immunosuppressants. Figure reproduced from Morand, E.F. et al. Trial of anifrolumab in active systemic lupus erythematosus. New Engl J Med 2020, 382, (3), 211–221 [50]. 2021 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. IFN, interferon; IFNGS, interferon gene signature; SLE, systemic lupus erythematosus.

Figure 7

Timeline showing dates of publication of clinical trial data for interferon-targeting biologics in patients with autoimmune disease. CLE, cutaneous lupus erythematosus; DM, dermatomyositis; IFN, interferon; IFN-K, interferon kinoid; LN, lupus nephritis; PM, polymyositis; SSc, systemic sclerosis; SLE, systemic lupus erythematosus.