T-cell and B-cell signaling biomarkers and treatment targets in lupus

Abstract

Purpose of review: Systemic lupus erythematosus is characterized by the production of antinuclear autoantibodies and dysfunction of T-cells, B-cells, and dendritic cells. Here, we review newly recognized genetic factors and mechanisms that underlie abnormal intracellular signal processing and intercellular communication within the immune system in systemic lupus erythematosus.

Recent findings: Activation of the mammalian target of rapamycin plays a pivotal role in abnormal activation of T and B-cells in systemic lupus erythematosus. In T-cells, increased production of nitric oxide and mitochondrial hyperpolarization were identified as metabolic checkpoints upstream of mammalian target of rapamycin activation. Mammalian target of rapamycin controls the expression T-cell receptor-associated signaling proteins CD4 and CD3zeta through increased expression of the endosome recycling regulator HRES-1/Rab4 gene, mediates enhanced Ca2+ fluxing and skews the expression of tyrosine kinases both in T and B-cells, and blocks the expression of Foxp3 and the expansion of regulatory T-cells. Mitochondrial hyperpolarization and the resultant ATP depletion predispose T-cells to necrosis, thus promoting the dendritic cell activation, antinuclear autoantibody production, and inflammation.

Summary: Mitochondrial hyperpolarization, increased activity of mammalian target of rapamycin and Syk kinases, enhanced receptor recycling and Ca2+ flux have emerged as common T and B-cell biomarkers and targets for treatment in systemic lupus erythematosus.

Figure 1. Schematic outline of mTOR activation and its role in the recycling of surface receptors such as CD4 and TFR and signaling and adaptor proteins such as TCRζ and CD2AP

mTOR senses the Δψ_m and regulates IP3R-mediated Ca²⁺ release [42]. Activation of mTOR controls the expression of TCRζ and Lck, mediates their lysosomal degradation by activating HRES-1/Rab4 which in turn results in the substitution of TCRζ by FcεRIγ and the recruitment of Syk. The intracellular rapamycin receptor FKBP12 directly binds the RyR. The small GTPase HRES-1/Rab4 regulates endocytic recycling of surface receptors such as CD4 and adaptors such as TCRζ and their traffic to lysosomes. Ca²⁺ controls the activation of calcineurin, a phosphatase that dephosphorylates the transcription factor NFAT and allows it to translocate into the nucleus. Ca²⁺ release from the endoplasmic reticulum also initiates opening of the CRAC channel through activation of Stim1 and Orai1. mTOR, mammalian target of rapamycin; TFR, transferrin receptor.

Figure 2. Schematic diagram of B-cell activation

In resting B-cells, the BCR is excluded from lipid rafts. The rafts concentrate GPI-linked proteins and myristylated proteins, such as LYN and phosphoprotein associated with glycosphingolipid-enriched microdomains (PAG). After antigen engagement, the BCR relocates within rafts. The phosphoinositide3-kinases (PI3Ks) are recruited to the BCR through BCR and SYK-dependent phosphorylation of CD19 and BCAP, which contains a tyrosine-X-X-methionine activation motif. BCAP and Vav contribute to the activation of PI3K. BTK contributes to BCR-stimulated calcium signaling by phosphorylating and activating PLCγ2 [77]. The subsequent recruitment of PKCβ leads to the phosphorylation of S180 of the TEC-homology domain and inactivation of BTK. FcγRIIB, an inhibitory receptor for the Fc of immunoglobulin G, contains one immunoreceptor tyrosine-based inhibitory motif (ITIM) in its cytoplasmic domain. When FcγRIIB is cross-linked along with the BCR, the SH2-domain-containing inositol 5-phosphatase (SHIP) is recruited, leading to the abrogation of BCR signaling by the hydrolysis of phosphatidylinositol-3,4,5-triphosphate (PIP3). B-cell activation is also downregulated by LYN that phosphorylates a tyrosine of PAG which then recruits c-SRC tyrosine kinase (Csk) to the rafts. Csk phosphorylates and decreases the enzymatic activity of LYN. The accumulation of PIP3 activates the Akt/mTOR axis [78] and stimulation of the IP3 receptor and the RyR on the endoplasmic reticulum. The subsequent release of Ca²⁺ from the endoplasmic reticulum turns on the CRAC channel, which also operates in B-cells [79]. Elevated Ca²⁺ levels activate NFAT [80,81] and NFAT-dependent B-cell stimulators such as Blys [82]. Rab4 regulates IgG internalization-dependent antigen processing [83]. BCAP, B-cell PI3K adaptor protein; BCR, B-cell receptor; GPI, glycosylphosphatidylinositol; IgH, immunoglobulin heavy chain; IgL, immunoglobulin light chain; P, phosphate; PIP2, phosphatidylinositol-4,5-bisphosphate or phosphatidylinositol-3,4-bisphosphate.