Disorder of the sympathetic nervous system (SNS) is closely related to the pathogenesis of various autoimmune diseases (ADs). Catecholamine triggered beta2-adrenergic receptor (β2-AR) signaling is important in creating a bidirectional response in the progression of ADs due to factors including diverse expression patterns, single nucleotide polymorphisms (SNPs), biased signals, and desensitization of β2-AR, as well as different subtypes of Gα binding to β2-AR. In this review, we summarize the actions of β2-AR signaling in regulating the functions of immunocytes and in the pathogenesis of ADs, and the application of β2-AR agonists or antagonists in treating major types of ADs is also discussed. We suggest that restoring the immune balance via a soft regulation of the expression or activation of β2-AR is one of the promising therapeutic strategies for systematic ADs.

B-cell activating factor from the tumor necrosis factor family (BAFF) has revealed its critical role in B cell proliferation and survival, as well as the pathogenesis of T-cell mediated autoimmune disease. However, the effect and molecular mechanisms of BAFF on T cell physiological function have not been fully elucidated. In this study it was seen that BAFF can promote the vitality of purified T cells, increase the proportion of CD3⁺CD4⁺, CD4⁺CD25⁺, CD4⁺CD154⁺, and CD4⁺CD69⁺ subgroups and reduce the proportion of CD4⁺CD62L⁺ subgroups. Negating BAFF activity with Atacicept (TACI-Fc) reverses vitality and activation of T cells. Furthermore, immunofluorescence detection revealed that BAFF promotes the expression of BAFF receptor (BAFF-R) and transmembrane activator and CAML interactor (TACI) in T cells. Flow cytometry displayed that BAFF/BAFF-R activates the PI3K-Akt signaling pathway while the application of PI3K inhibitor (wortmannin) illuminated that BAFF induces T cell vitality and activation through the PI3K-Akt signaling pathway. We conclude that BAFF is involved in not only the physiology of B cells, but also that of T cells. BAFF affects physiological T-cell activation through BAFF-R-mediated activation of the PI3K-Akt signaling pathway which mirrors one of the pathological mechanisms of T cell-mediated autoimmune diseases.

To investigate the anti-arthritis and immunomodulatory activities of ginsenoside compound K (C-K) in mice with collagen-induced arthritis (CIA). DBA/1 mice with CIA were treated with C-K (28, 56 or 112 mg·kg(-1)·d(-1), ig) or the positive control methotrexate (2 mg/kg, ig, every 3 d) for 34 d. Splenic T and B lymphocytes were positively isolated using anti-CD3-coated magnetic beads or a pan B cell isolation kit. T lymphocyte subsets, and CD28, T cell receptor (TCR), cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) and programmed death-1 (PD-1) expression in purified splenic T lymphocytes were analyzed using flow cytometry, Western blotting and laser confocal microscopy. C-K treatment significantly ameliorated the pathologic manifestations of CIA mice, remarkably inhibited T lymphocyte proliferation, and marginally inhibited the proliferation of B lymphocytes. C-K treatment significantly suppressed TNF-α and anti-CII antibody levels, and increased IFN-γ level in the joints of CIA mice, but did not alter IL-4 production. Treatment of CIA mice with C-K significantly decreased the percentages of activated T cells, co-stimulatory molecule-expressing T cells and effector memory T cells, and increased the frequencies of naive T cells and regulatory T cells. Furthermore, C-K treatment significantly decreased the expression of CD28 and TCR, whereas it increased the expression of CTLA-4 and PD-1 on T lymphocytes of CIA mice. Methotrexate treatment exerted comparable effects in all these experiments. C-K suppresses the progression of CIA through regulating TCR, CD28, CTLA-4 and PD-1 expression, thus inhibiting the abnormal activation and differentiation of T lymphocytes.

T cell infiltration to synovial tissue is an early pathogenic mechanism of rheumatoid arthritis (RA). In the present work, we reveal that G protein coupled receptor kinase 2 (GRK2) is abundantly expressed in T cells of collagen-induced arthritis (CIA). A GRK2 inhibitor, paroxetine protects the joints from inflammation and destruction, primarily through inhibition of both CD4⁺ helper T (Th) cell and CD8⁺ cytotoxic T (Tc) cell migration to synovial tissue. Meanwhile, paroxetine restores the balance of Th/Tc, effector Th (Theff)/ naïve Th (Thnaive) and effector Tc (Tceff)/ naïve Tc (Tcnaive) to equilibrium by elevating the frequency of Thnaive, Tcnaive and regulatory Th cells; reducing the increased Theff, activated Th and Tceff, having a similar effect as methotrexate (MTX). In addition, both serum and synovial IL-1β, TNF-α and CX3CL1 expression was effectively inhibited in treated rats. In vitro assay confirmed that paroxetine inhibits CX3CL1-induced T cell migration through blocking the activity of GRK2. Among three MAPK families, paroxetine was found to be able to decrease the phosphorylation of ERK. This study elucidates that paroxetine attenuates the symptoms of CIA rats due to its inhibitory effect on T cell activation and infiltration to synovial tissue via suppression of ERK pathway.

G protein-coupled receptors (GPCRs), as the largest family of receptors in the human body, are involved in the pathological mechanisms of many diseases. Heterotrimeric G proteins represent the main molecular switch and receive cell surface signals from activated GPCRs. Growing evidence suggests that Gα₁₂ subfamily (Gα_12/13)-mediated signaling plays a crucial role in cellular function and various pathological processes. The current research on the physiological and pathological function of Gα_12/13 is constantly expanding, Changes in the expression levels of Gα_12/13 have been found in a wide range of human diseases. However, the mechanistic research on Gα_12/13 is scattered. This review briefly describes the structural sequences of the Gα_12/13 isoforms and introduces the coupling of GPCRs and non-GPCRs to Gα_12/13. The effects of Gα_12/13 on RhoA and other signaling pathways and their roles in cell proliferation, migration, and immune cell function, are discussed. Finally, we focus on the pathological impacts of Gα_12/13 in cancer, inflammation, metabolic diseases, fibrotic diseases, and circulatory disorders are brought to focus.