Type I Interferons in Systemic Lupus Erythematosus: A Journey from Bench to Bedside

Abstract

Dysregulation of type I interferons (IFNs) has been implicated in the pathogenesis of systemic lupus erythematosus (SLE) since the late 1970s. The majority of SLE patients demonstrate evidence of type I IFN pathway activation; however, studies attempting to address the relationship between type I IFN signature and SLE disease activity have yielded conflicting results. In addition to type I IFNs, type II and III IFNs may overlap and also contribute to the IFN signature. Different genetic backgrounds lead to overproduction of type I IFNs in SLE and contribute to the breakdown of peripheral tolerance by activation of antigen-presenting myeloid dendritic cells, thus triggering the expansion and differentiation of autoreactive lymphocytes. The consequence of the continuous stimulation of the immune system is manifested in different organ systems typical of SLE (e.g., mucocutaneous and cardiovascular involvement). After the discovery of the type I IFN signature, a number of different strategies have been developed to downregulate the IFN system in SLE patients, finally leading to the successful trial of anifrolumab, the second biologic to be approved for the treatment of SLE in 10 years. In this review, we will discuss the bench to bedside translation of the type I IFN pathway and put forward some issues that remain unresolved when selecting SLE patients for treatment with biologics targeting type I IFNs.

Vitamin D3 mitigates autoimmune inflammation caused by activation of myeloid dendritic cells in SLE

“…DCs are key regulators of the innate immune system, which have dual roles in immune activation and immune tolerance 9,10 . Abundant IFN‐α in SLE serum produced by pDCs can promote mDC differentiation and maturation, and then active autoreactive T and B lymphocytes to produce uploaded autoantibodies and form autologous ICs 8,29,30 . To date, whether SLE autologous DNA‐ICs can activate mDCs is still unknown.…”

“…9,10 Abundant IFNα in SLE serum produced by pDCs can promote mDC differentiation and maturation, and then active autoreactive T and B lymphocytes to produce uploaded autoantibodies and form autologous ICs. 8,29,30 To date, whether SLE autologous DNA-ICs can activate mDCs is still unknown. In our present study, we successfully isolated The maturation of mDCs plays a key role in immune responses and regulation.…”

Systemic lupus erythematosus: latest insight into etiopathogenesis

“…It has been shown that monocytes from healthy individuals may be differentiated into myeloid dendritic cells (mDCs) in the presence of serum from a lupus patient [ 15 ]. These mDCs can also have the ability to phagocytize nuclear material and present antigens to naive CD4 + T cells, which can later activate the cytotoxic activity of CD8 + T cells and thus support the proliferation and differentiation of B cells [ 16 ]. Autoreactive IgE, such as anti-dsDNA IgE, was found to be elevated in SLE patients and can also elicit an increase in IFNα production by binding the Fc epsilon RI (FcεRI) of plasmacytoid dendritic cells (pDCs) [ 17 ].…”

Insights into the role of neutrophils in neuropsychiatric systemic lupus erythematosus: Current understanding and future directions

“…LDNs are also reported to express higher levels of TNF-α than high-density neutrophils ( 25 ). Dysregulation of type I IFN signature is well-characterized in SLE ( 33 ) and was previously attributed to increased type I IFN secretion by plasmacytoid dendritic cells (pDC) ( 34 ). Recent work have shown that neutrophils have the capacity to secrete type I IFN upon specific types of stimulation including granulocyte-colony stimulation factor and polyinosinic:polycytidylic acid ( 35 , 36 ).…”