Immune cell aberrations in Systemic Lupus Erythematosus: navigating the targeted therapies toward precision management

Abstract

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by multilayered dysregulation of immune cell homeostasis, spanning B cell effector dysfunction, T follicular helper (Tfh) cell hyperactivity, and plasmacytoid dendritic cell (pDC) tolerance breakdown. Advances in high-parameter immunophenotyping, single-cell multiomics profiling, and spatial multiomics have redefined SLE pathogenesis, revealing stage-specific immune network perturbations. These discoveries have propelled mechanism-driven therapeutic strategies, including CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy for B cell depletion, disruption of T-B cell synaptic signaling (CD40L inhibitors), and restoration of pDC tolerance (anti-BDCA2 antibodies). While patient heterogeneity poses challenges for universal therapeutic efficacy, emerging strategies integrating molecular endotyping and cellular biomarkers hold promise for overcoming these limitations. By aligning targeted therapies with the immunophenotypic signatures of individual patients, precision medicine approaches are expected to optimize treatment efficacy, minimize off-target effects, and ultimately enhance long-term clinical outcomes in SLE. This review synthesizes current insights into how immune cell perturbations contribute to SLE pathogenesis, modulate disease flares, and determine therapeutic refractoriness, with a critical synthesis of recent clinical trial outcomes.

Keywords: Immune cells; Immune dysregulation; Precise therapy; Systemic lupus erythematosus; Therapeutic targets.

Fig. 1

Immune network in SLE. Dysregulated immune cell interactions and their pathogenic contributions to systemic lupus erythematosus. The figure was created using Biorender (https://www.biorender.com/). NET, neutrophil extracellular trap; MET, monocyte extracellular traps; IFN, interferon; TACI, transmembrane activator and CAML interactor; BAFF-R, B cell activating factor receptor; IL, interleukin; TCR, T cell receptor; TLR, Toll-like receptor; BAFF, B cell activating factor; NK, natural killer; Th: T helper; Tfh: T follicular helper

Fig. 2

Therapeutic targets in systemic lupus erythematosus. This figure illustrates the interactions among dendritic cells, T cells, and B cells, as well as their associated therapeutic targets. The figure was created using Biorender (https://www.biorender.com/) BAFF, B cell activating factor; BAFFR, BAFF receptor; TACI, transmembrane activator and CAML interactor; BCMA, B cell maturation antigen; BCR, B cell receptor; CD40L, CD40 ligand; ICOS, inducible T cell costimulator; ICOSL, ICOS ligand; IFN-α, interferon alpha; IFN-αR, IFN-α receptor; TCR, T cell receptor; IL-2, interleukin-2; BDCA2, blood dendritic cell antigen 2; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; HLA-DR, human leukocyte antigen—DR isotype

Fig. 3

Mechanisms of bispecific T cell engagers and CAR-T therapies. A The principle of B cell killing mediated by two types of bispecific antibodies. B The therapeutic principles and steps involved in CAR-T cell therapy. Figure was created using Biorender (https://www.biorender.com/). BCMA, B cell maturation antigen; CAR-T, chimeric antigen receptor T cell.

Fig. 4

Regulation of immune cells by intracellular signaling pathways and therapeutic targets. (1) JAK-STAT signaling orchestrates immune cell differentiation through STAT-specific transcriptional regulation: STAT1/STAT4 drive Th1 polarization via T-bet, STAT6 induces Th2 differentiation through GATA3, STAT3 controls Th17/Tfh lineages via RORγt/Bcl-6, and STAT5A/B synergizes with Foxp3 for Treg development. (2) Antigen-bound BCR triggers Lyn-mediated ITAM phosphorylation, recruiting Syk to initiate BTK-PLCγ2 signaling. PLCγ2 hydrolyzes PIP2 into IP3 (inducing Ca²⁺ release) and DAG (activating MAPK/NF-κB), collectively driving B cell proliferation and activation. 3. TLR7-MyD88 activates TRAF6-IKKα-IRF7 for IFN-I production, while TLR8-MyD88 engages TAK1-IKKβ-IRF5 for IFN-II synthesis; both pathways converge on NF-κB to amplify B cell expansion. Figure was created using Biorender (https://www.biorender.com/). JAK, Janus kinase; STAT, signal transducer and activator of transcription; BCL, B cell lymphoma; IKZF1, Ikaros family zinc finger 1; BTK, Bruton’s tyrosine kinase; BCR, B cell receptor; PLC, phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; MEK, mitogen-activated protein; ERK, extracellular signal-regulated kinase; MYC, myelocytomatosis viral oncogene; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NFAT, nuclear factor of activated T cells; TLR, toll-like receptor; TAK, transforming growth factor beta-activated kinase; TRAF, TNF receptor associated factor; IRF, interferon regulatory factor; IFN, interferon; IP3, inositol trisphosphate; PIP2, phosphatidylinositol 4,5-bisphosphate; MAPK, mitogen-activated protein kinase; MyD88, myeloid differentiation primary response 88