Systemic lupus erythematosus (SLE) is characterized by immune system dysfunction and is clinically heterogeneous, exhibiting renal, dermatological, neuropsychiatric, and cardiovascular symptoms. Clinical and physiological assessment is usually inadequate for diagnosing and assessing pathophysiological processes in SLE. Clinical and immunological biomarkers could play a critical role in improving diagnosis, assessment, and ultimately, control of SLE. This article reviews clinical and immunological biomarkers that could diagnose and monitor disease activity in SLE, with and without organ-specific injury. In addition, novel SLE biomarkers that have been discovered through “omics” research are also reviewed.

Regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and immune homeostasis. IL-10 has an important role in maintaining the normal immune state. Here, we show that IL-10-secreting Tregs can be delineated in normal mice as CD4⁺CD25⁻Foxp3⁻T cells that express lymphocyte activation gene 3 (LAG-3), an MHC-class-II-binding CD4 homolog. Although ≈2% of the CD4⁺CD25⁻T cell population consisted of CD4⁺CD25⁻LAG3⁺T cells in the spleen, CD4⁺CD25⁻LAG3⁺T cells are enriched to ≈8% in the Peyer's patch. They are hypoproliferative upon in vitro antigenic stimulation and suppress in vivo development of colitis. Gene expression analysis reveals that CD4⁺CD25⁻LAG3⁺Tregs characteristically express early growth response gene 2 (Egr-2), a key molecule for anergy induction. Retroviral gene transfer of Egr-2 converts naïve CD4⁺T cells into the IL-10-secreting and LAG-3-expressing phenotype, and Egr-2-transduced CD4⁺T cells exhibit antigen-specific immunosuppressive capacity in vivo. Unlike Foxp3⁺natural Tregs, high-affinity interactions with selecting peptide/MHC ligands expressed in the thymus do not induce the development of CD4⁺CD25⁻LAG3⁺Tregs. In contrast, the number of CD4⁺CD25⁻LAG3⁺Tregs is influenced by the presence of environmental microbiota. Thus, IL-10-secreting Egr-2⁺LAG3⁺CD4⁺Tregs can be exploited for the control of peripheral immunity.

Inhibitory cytokines, such as transforming growth factor-β (TGF-β) and interleukin-10 (IL-10), are humoral factors involved in the suppressive function of regulatory T cells and play critical roles in maintaining immune homeostasis. However, TGF-β and IL-10 also have pleiotropic effects and induce humoral immune responses depending on conditions, and thus their therapeutic application to autoimmune diseases remains limited. Here, we show that a combination of TGF-β and IL-10, but not single cytokine, is required to suppress B cell activation induced by toll-like receptor (TLR) stimulation. In in vivo analyses, the simultaneous presence of TGF-β and IL-10 effectively suppressed TLR-mediated antigen-specific immune responses and ameliorated pathologies in imiquimod (TLR7 agonist)-induced lupus model and lupus-prone MRL/lpr mice. Intriguingly, TGF-β and IL-10 synergistically modulated transcriptional programs and suppressed cellular energetics of both glycolysis and oxidative phosphorylation via inhibition of the mammalian target of rapamycin complex 1 (mTORC1)/S6 kinase 1 (S6K1) pathway in TLR-stimulated B cells. On the other hand, enhancement of mTOR signaling and mitochondrial biosynthesis in TLR-stimulated B cells counteracted the synergistic inhibitory effects. The inhibitory cytokine synergy of TGF-β and IL-10 via suppression of energy metabolism was also observed in human TLR-stimulated B cells. There is increasing evidence supporting the importance of adequate metabolic signals in various immune cells to exert their immune function. In this study, we have shown that a previously unrecognized synergy of inhibitory cytokines regulates systemic humoral immune responses via modulating immunometabolism in B cells. Our findings indicate that inhibition of B cell metabolism mediated by two synergistic cytokines contributes to the induction of immune tolerance and could be a new therapeutic strategy for autoimmune diseases such as systemic lupus erythematosus.

Interleukin (IL)-27, a member of IL-12/IL-23 heterodimeric family of cytokines, has pleiotropic properties that can enhance or limit immune responses. IL-27 acts on various cell types, including T cells, B cells, macrophages, dendritic cells, natural killer (NK) cells and non-hematopoietic cells. Intensive studies have been conducted especially on T cells, revealing that various subsets of T cells respond uniquely to IL-27. IL-27 induces expansion of Th1 cells by activating signal transducer and activator of transcription (STAT) 1-mediated T-bet signaling pathway. On the other hand, IL-27 suppresses immune responses through inhibition of the development of T helper (Th) 17 cells and induction of IL-10 production in a STAT1- and STAT3-dependent manner. IL-27 is a potentially promising cytokine for therapeutic approaches on various human diseases. Here, we provide an overview of the biology of IL-27 related to T cell subsets, its structure, and production mechanism.