B cell activation occurs largely through B cell receptors (BCRs), B cell activating factor receptors (BAFF-Rs) and Toll-like receptors (TLRs). BCR can recognize foreign antigens, and upon ligand-binding a cross-linking and oligomerization of the receptor occur (19). The ligand binding receptor unit makes a complex with the CD79A/CD79B chains, which carry immunoreceptor tyrosine-based activation motifs (ITAMs) that get phosphorylated by Src kinases, like Lyn, and recruit downstream kinases like the Syk and the Bruton’s tyrosine kinase (BTK) (20). During the diverse phosphorylation cascade, the activation of phospholipase Cγ2 (PLCγ2) results in Ca²⁺-release – which enables the functions of Ca²⁺-dependent enzymes like calcineurin – and the translocation of nuclear factor kappa B (NF-κB), meanwhile the phosphorylation of phosphoinositide 3-kinase (PI3K) activates the protein kinase B (AKT) pathway thereby contributing to cell survival (Figure 1) (20). Altogether, signaling through BCR is essential for survival, proliferation and many effector cell responses (19).

BTK is becoming an appealing therapeutic target in several autoimmune diseases, and it has an important role in the downstream signaling of the BCR-mediated pathway. Orelabrutinib seemed to be effective in SLE patients: higher proportion of patients achieved the SLE responder index (SRI)-4 response at week 12 in the orelabrutinib groups compared to placebo (21). The effect was even more robust in patients with a higher disease activity in this phase 1/2 clinical study (NCT04305197) (21). Orelabrutinib also had a favorable effect on the remission rate of arthritis, effectively reduced anti-dsDNA titers and increased complement levels (21). In addition, it was a well-tolerated therapy: lymphocyte count reduction, anemia, petechia and upper respiratory tract infections occurred slightly more frequently in orelabrutinib-treated patients than in the placebo group (21). What makes orelabrutinib a promising choice over previously tested BTK-inhibitors (that were found to be non effective in SLE studies) is its very high potency, near 100% target occupancy and maybe its selectivity (22). It is an irreversible BTK inhibitor (as a result of its covalent binding) and its inhibitory effect persists for 24 hours after administration (22). Newer BTK inhibitors like zanubrutinib is currently undergoing a phase 2 clinical trial in patients with lupus nephritis (NCT04643470), while BI-BTK-1 showed promising preclinical results in a murine model of lupus nephritis (23–25).

Duvelisib is a PI3K-inhibitor, which decreased the autoantibody-levels in a murine lupus model, while having a beneficial effect on IgG deposition in the kidney and the degree of glomerulonephritis in mice (26).

Ikaros (IKZF1) and Aiolos (IKZF3) belong to the Kruppel transcription factor family. Ikaros has an important role in the development of lymphoid cells (27). Both Ikaros and Aiolos showed to be risk factors in SLE (28). Iberdomide is an orally available cereblon modulator that promotes the degradation of the transcription factors Ikaros and Aiolos. At a dose of 0.45 mg, iberdomide-treated SLE patients had a higher SRI-4 response rate than the placebo group (29). Adverse events – most commonly urinary and upper respiratory tract infections or neutropenia – occurred more frequently in the iberdomide-treated patients (29). However, longer clinical trials are needed to provide a more accurate answer to the question of safety (29).

The T cell receptor (TCR) is capable of recognizing antigens associated with the major histocompatibility complex (MHC) (30). TCR is a heterodimeric receptor consisting of TCRα and TCRβ chains in αβ T cells, and it is assembled with the CD3 complex proteins (CD3γ, δ, ϵ, and ζ chains), where ITAM regions can be found. The ITAM gets phosphorylated by the Src kinase Lck and ZAP-70 (the T cell-equivalent of Syk) is recruited (30). ZAP-70 phosphorylates the linker for activation of T cells (LAT) and other molecules, which mediate downstream signaling: leading to the activation of transcription factors like the nuclear factor of activated T cells (NFAT) through calcineurin, NF-κB and AP-1 (Figure 1) (31). Atorvastatin modifies the compositions of lipid rafts resulting in the disruption of colocalization of Lck and CD45 in the lipid raft, leading to the reduction of active Lck. In SLE patients, atorvastatin reduced the IL-10, IL-6 and T cell levels (32).

The novel oral calcineurin-inhibitor voclosporin prevents the formation of the calcineurin-calmodulin complex, thereby inhibiting the effect of the calcineurin signaling pathway in T cells (33). Following successful clinical trials, voclosporin was approved for the treatment of lupus nephritis. T cells are major sources of important cytokines during autoimmune inflammation, where the G protein–coupled receptor kinase-2 (GRK2)-dependent development of the TCR-CXCR4 complex is important (34). The pharmacological inhibition of GRK2 using CP-25 ameliorated the development of pristane-induced lupus, resulting in decreased antibody-production and an improved histopathological phenotype (35).

The above mentioned Aiolos and Ikaros inhibitor iberdomide potentially also acts on T cell receptor signaling in SLE patients (29).

The signal transduction of Fc receptors shows many similarities to the signaling of the other two immunoreceptors, namely the B cell and the T cell receptor. When the autoantigen-autoantibody immune complex binds to an activating Fcγ receptor, the ITAM region gets phosphorylated by Src-family kinases (36). These proteins recruit and phosphorylate Syk, which directly or indirectly activates several downstream molecules, including the MAP kinases and NF-κB leading to transcriptional changes, the PI3K or the Bruton’s tyrosine kinase (Figure 1) (36). As we mentioned above, Fc receptor signaling overlaps with the signal transduction of the other two immunoreceptors at several aspects, therefore some of the therapies mentioned above (e.g. BTK inhibitors) may also contribute to the improvement of SLE symptoms through the inhibition of Fc receptor signaling.

Toll-like receptors (TLRs) – as pattern recognition receptors (PRRs) – get activated by specific pathogen-associated molecular patterns (PAMPs) and lead to first-line host defense cell responses (15). Some of these receptors induce cell activation against extracellular microbial agents, while others are located intracellularly and sense RNA or DNA fragments (15). As circulating nucleic acid-containing complexes can stimulate plasmacytoid dendritic cells (pDCs) in systemic lupus erythematosus, some intracellular Toll-like receptors (like TLR3, TLR7, TLR8, TLR9) and their signaling pathways could be potential therapeutic targets (37). Downstream from the receptor-ligand interaction, several intracellular proteins get activated, like MyD88 or IL-1R-associated kinases (IRAKs) (Figure 1) (15). Interestingly, patients with MyD88- and IRAK-deficiency are protected against autoreactive autoantibody production (38). One of the major consequences of TLR signaling is the increased type 1 interferon (IFN)-production through transcriptional upregulation of IFN-related genes (38). The inhibition of signal transduction of Toll-like receptors can be approached in two main ways: 1) preventing the binding of TLR to its ligand (by hydroxi-chloroquine, oligonucleotide-based antagonists, small molecules or monoclonal antibodies) or blocking the downstream cascade (by small molecules inhibiting IRAKs, molecules stimulating IRAK degradation or molecules targeting adaptor proteins) (39). The small molecule TLR7/8 inhibitor, enpatoran reached significant improvements in the disease activity of cutaneous lupus erythematosus (CLE) patients compared to placebo in a phase 2 clinical trial with an acceptable safety profile (NCT05162586) (40). E6742, a dual TLR7/8 antagonist resulted in a suppression of the interferon gene signature responses, while showing promising preliminary efficacy signals in SLE patients in a phase 1/2 study (NCT05278663) (41). Meanwhile, E6742 seemed to be well-tolerated, since the incidence of adverse events was 58.5% in the E6742-treated groups in contrast to 66.7% in connection with the placebo (41). In contrast to the central role of MyD88 in the signaling process, only promising in vitro results are available for the MyD88 inhibitor, TJ-M2010-5, which was able to reduce the activation of lupus-like B cells by preventing proliferation and antibody production (42). In several experimental lupus models, the inhibition of IRAK4 with a highly selective inhibitor (by BMS-986126) resulted in a reduction in skin and kidney manifestations in a dose-dependent manner (43). Several inhibitors of the IRAK enzymes – like zimlovisertib, edecesertib or R835 – have now completed successful phase 1 trials, where mainly their acceptable safety profiles were determined, but a few efficiency-related effects were also included, such as inhibition of cytokine release in the case of R835 treatment (39). There is already an ongoing phase 2 trial with edecesertib in cutaneous lupus erythematosus patients (NCT05629208).

Type 1 interferons (IFNs) specifically bind to their heterodimeric receptor, which contains a high affinity (IFNAR2) and a low affinity (IFNAR1) receptor chain (44). The binding of type 1 IFNs to their receptors induces the intracellular signaling through Janus-kinases (JAKs). IFNAR2 is associated with JAK1, while IFNAR1 leads to the activation of another JAK, namely Tyrosine kinase 2 (TYK2) (44). Activated JAKs go through autophosphorylation, then phosphorylate the IFN receptor and recruit Signal transducer and activator of transcription proteins (STATs). This leads to the nuclear translocation of STATs, which triggers the activation of interferon-stimulated genes (Figure 1) (44). The JAK1 inhibitor upadacitinib showed significant improvements in the disease activity in SLE patients: 54.8% of upadacitinib-treated patients achieved SRI-4 response rate and were able to reduce the daily glucocorticoid dose to a maximum of 10 mg by week 24 compared to the 37.5% in the placebo group. Upadacitinib also reduced the frequency of flares, while novel safety concerns were not detected in the upadacitinib group in this phase 2 clinical trial (NCT03978520) (45). Upadacitinib is currently undergoing a phase 3 trial, where it is administered orally once daily (NCT05843643). In another phase 2 clinical study, the TYK2-inhibitor deucravacitinib brought promising results: significantly higher proportion of the treated groups achieved the primary endpoint compared to the placebo (NCT03252587); while the incidence of serious adverse events was comparable between the treated and placebo groups (46). Two currently ongoing phase 3 trials will help to more accurately determine the effect of deucravacitinib in SLE patients (NCT05617677, NCT05620407) (47). Moreover, in the MRL/lpr lupus model, the JAK1/JAK3 inhibitor tofacitinib ameliorated renal manifestations, while decreasing plasma anti-dsDNA levels and proteinuria (48). Tofacitinib also demonstrated significant therapeutic potential in SLE patients with arthritis in a retrospective cohort study, where tofacitinib resulted in a reduction in serum Il-6 levels and T cell activation (49). While there was a higher incidence of infections in connection with tofacitinib therapy, no severe adverse event was detected (49).