Therapeutic effect of omega-3 fatty acids on T cell-mediated autoimmune diseases

The present study was to demonstrate that the G protein coupled receptors serve as targets for the treatment of autoimmune disease such as rheumatoid arthritis and multiple sclerosis. Rats received pristane at the base of the tail. Affected joints were counted daily. The T cell mediated autoimmune diseases such as pristine-induced arthritis (PIA) and autoimmune encephalomyelitis (EAE) in a rat model were profoundly ameliorated by treatment with the specific G protein couple receptors 120 (GPR120) stimuli omega-3 fatty acids (ω-3 FAs). Our study further revealed that the activation of GPR120 by ω-3 FAs can result in a decrease of phosphorylated transforming growth factor-β activated kinase 1 (TAK1), and further inhibit the downstream IKKβ/I-κB pathway and the terminal NF-κB activation which serves as a mediator of T cell activation. ω-3 Fatty acids exhibited an inhibitory effect on TAK1 by enhancing the association of β-arrestin2 and TAK1 binding protein 1 (TAB1), thus the disassociation of TAB1 from the TAB1/TAK1 complex renders a limited effect on β-arrestin2 signaling as an innate immunity regulation. GPR120 is a functional receptor of ω-3 fatty acids in T cell-mediated autoimmune disease compared with its effect on innate immunity.     

Special AT‐rich sequence binding protein 1 is required for maintenance of T cell receptor responsiveness and development of experimental autoimmune encephalomyelitis

The genome organizer special AT‐rich sequence binding protein 1 (SATB1) regulates specific functions through chromatin remodeling in T helper cells. It was recently reported by our team that T cells from SATB1 conditional knockout (SATB1cKO) mice, in which the Satb1 gene is deleted from hematopoietic cells, impair phosphorylation of signaling molecules in response to T cell receptor (TCR) crosslinking. However, in vivo T cell responses upon antigen presentation in the absence of SATB1 remain unclear. In the current study, it was shown that SATB1 modulates T cell antigen responses during the induction and effector phases. Expression of SATB1 was upregulated in response to TCR stimulation, suggesting that SATB1 is important for this antigen response. The role of SATB1 in TCR responses and induced experimental autoimmune encephalomyelitis (EAE) was therefore examined using the myelin oligodendrocyte glycoprotein peptide 35‐55 (MOG35‐55) and pertussis toxin. SATB1cKO mice were found to be resistant to EAE and had defects in IL‐17‐ and IFN‐γ‐producing pathogenic T cells. Thus, SATB1 expression appears necessary for T cell function in the induction phase. To examine SATB1 function during the effector phase, a tamoxifen‐inducible SATB1 deletion system, SATB1cKO‐ER‐Cre mice, was used. Encephalitogenic T cells from MOG35‐55‐immunized SATB1cKO‐ER‐Cre mice were transferred into healthy mice. Mice that received tamoxifen before the onset of paralysis were resistant to EAE. Furthermore, no disease progression occurred in recipient mice treated with tamoxifen after the onset of EAE. Thus, SATB1 is essential for maintaining TCR responsiveness during the induction and effector phases and may provide a novel therapeutic target for T cell‐mediated autoimmune diseases.     

Structural mechanisms of GABAA receptor autoimmune encephalitis

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Application of CAR-T cell technology in autoimmune diseases and human immunodeficiency virus infection treatment

Chimeric antigen receptor (CAR) T-cell therapy is an immunotherapy approach that has played a tremendous role in the battle against cancer for years. Since the CAR T lymphocytes are unrestricted-major histocompatibility complex T lymphocytes, they could identify more targets than natural T cells, resulting in practical and widespread functions. The good prospects of CAR T-cell therapy in oncology can be additionally applied to treat other diseases such as autoimmune and infectious diseases. CAR-T cell-derived immunotherapy for autoimmune disorders can be allocated to CAR-Tregs and chimeric autoantibody receptor T cells. Other generations of CARs target human immunodeficiency virus (HIV) proteins. In this review, we summarize CAR-T cell therapies in autoimmune disorders and HIV infection.     

The mitochondrial fission factor dynamin-related protein 1 modulates T-cell receptor signalling at the immune synapse

During antigen-specific T-cell activation, mitochondria mobilize towards the vicinity of the immune synapse. We show here that the mitochondrial fission factor dynamin-related protein 1 (Drp1) docks at mitochondria, regulating their positioning and activity near the actin-rich ring of the peripheral supramolecular activation cluster (pSMAC) of the immune synapse. Mitochondrial redistribution in response to T-cell receptor engagement was abolished by Drp1 silencing, expression of the phosphomimetic mutant Drp1S637D and the Drp1-specific inhibitor mdivi-1. Moreover, Drp1 knockdown enhanced mitochondrial depolarization and T-cell receptor signal strength, but decreased myosin phosphorylation, ATP production and T-cell receptor assembly at the central supramolecular activation cluster (cSMAC). Our results indicate that Drp1-dependent mitochondrial positioning and activity controls T-cell activation by fuelling central supramolecular activation cluster assembly at the immune synapse.     

HLA-G与自身免疫病相关性研究进展

非经典人类白细胞抗原G（human leukocyte antigen-G,HLA-G）是机体内一类重要的免疫调节分子,包括膜结合型HLA—G（mHLA—G）及可溶性HLA—G（sHLA—G）两种分子表达形式。HLA-G分子可通过与受体结合直接抑制多种免疫活性细胞的生物学功能,或通过诱导产生免疫调节细胞间接抑制机体的免疫应答。研究显示,HLA—G基因多态性及分子表达在母胎免疫、感染、自身免疫病及肿瘤的发生发展中均有重要意义。对HLA—G在自身免疫病中的作用作一综述。     

Autophagy in immunity: Implications in etiology of autoimmune/autoinflammatory diseases

Autophagy is now emerging as a spotlight in trafficking events that activate innate and adaptive immunity. It facilitates innate pathogen detection and antigen presentation, as well as pathogen clearance and lymphocyte homeostasis. In this review, we first summarize new insights into its functions in immunity, which underlie its associations with autoimmunity. As some lines of evidence are emerging to support its role in autoimmune and autoinflammatory diseases, we further discuss whether and how it affects autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus and multiple sclerosis, as well as autoinflammatory diseases, such as Crohn disease and vitiligo.     

Emerging role of bystander T cell activation in autoimmune diseases

Autoimmune disease is known to be caused by unregulated self-antigen-specific T cells, causing tissue damage. Although antigen specificity is an important mechanism of the adaptive immune system, antigen non-related T cells have been found in the inflamed tissues in various conditions. Bystander T cell activation refers to the activation of T cells without antigen recognition. During an immune response to a pathogen, bystander activation of self-reactive T cells via inflammatory mediators such as cytokines can trigger autoimmune diseases. Other antigen-specific T cells can also be bystander-activated to induce innate immune response resulting in autoimmune disease pathogenesis along with self-antigen-specific T cells. In this review, we summarize previous studies investigating bystander activation of various T cell types (NKT, γδ T cells, MAIT cells, conventional CD4⁺, and CD8⁺ T cells) and discuss the role of innate-like T cell response in autoimmune diseases. In addition, we also review previous findings of bystander T cell function in infection and cancer. A better understanding of bystander-activated T cells versus antigen-stimulated T cells provides a novel insight to control autoimmune disease pathogenesis.     

Flip-flops of natural killer cells in autoimmune diseases versus cancers: Immunologic axis

Natural killer (NK) cells play an essential role in the immune response to infections, inflammations, and malignancies. Recent studies suggest that NK cell surface receptors and cytokines are the key points of the disease development and protection. We hypothesized that the interactions between NK cell receptors and targeted cells construct an eventual niche, and this niche has an eventual profile in various autoimmune diseases and cancers. The NK cells preactivated with cytokines, such as interleukin-2 (IL-2), IL-12, IL-15, and IL-18 can have higher cytotoxicity; however, the toxic side effect of IL-2 should be considered. The vicissitudes of NK cell profile and its receptors obey the environmental communications and cell interactions. Our vision around the NK cells as an immune axis remained dual, and we still cannot judge the immune responses based on the NK cell flip-flop. A design of eventual niche to monitor the NK cell and targeted cell interaction is needed to strengthen our ability in diagnosis and treatment approaches based on the NK cells. Here, we have reviewed the shifts in the NK cells and their surface receptors in autoimmune diseases, solid tumors, and leukemia, and also discussed the effective chemokines that affect NK cell activation and proliferation. The main aim of this review is to present a broader vision of the NK cell changes in autoimmune disease and cancers.     

T-cell receptor Vbeta gene usage in CSF lymphocytes in X-linked adrenoleukodystrophy

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder with impaired very-long-chain fatty acid (VLCFA) metabolism that produces a neurological disease with significant variability of clinical phenotypes even within kindred. The two most common forms are the cerebral form (CALD) with an important inflammatory reaction at the active edge of demyelinating lesions, resembling some aspects of multiple sclerosis pathology, and adrenomyeloneuropathy (AMN), which involves the spinal cord and in which the inflammatory reaction is mild or absent. One hypothesis is that the phenotypic variability is related to T cell-mediated immune mechanisms playing a primary role in the demyelinating pathogenic process of CALD. The present study aims to test the hypothesis that CSF of patients with the CALD form contains highly restricted T cell populations. The variable regions of the T cell receptor beta chains (TCR Vbeta) were studied in CSF from 29 ALD patients with different phenotypes. RNA was extracted and cDNA synthesized from CSF lymphocytes; TCR Vbeta gene segments were amplified from the cDNA by polymerase chain reaction (PCR) using 20 family-specific primers. PCR products were analyzed by Southern blot. Some amplified Vbeta products were sequenced. The majority of ALD patients (21/29), whatever their phenotype, exhibited oligoclonal T cell expansion. However the overexpression of some TCR Vbeta families was heterogeneous among the different patients without any preponderance of specific Vbeta families or any clustering according to clinical phenotype. In particular a dominant TCR Vbeta utilization was not found in patients with CALD.     

Hyper‐reactive cloned mice generated by direct nuclear transfer of antigen‐specific CD4+ T cells

T‐cell receptor (TCR)‐transgenic mice have been employed for evaluating antigen‐response mechanisms, but their non‐endogenous TCR might induce immune response differently than the physiologically expressed TCR. Nuclear transfer cloning produces animals that retain the donor genotype in all tissues including germline and immune systems. Taking advantage of this feature, we generated cloned mice that carry endogenously rearranged TCR genes from antigen‐specific CD4⁺ T cells. We show that T cells of the cloned mice display distinct developmental pattern and antigen reactivity because of their endogenously pre‐rearranged TCRα (rTα) and TCRβ (rTβ) alleles. These alleles were transmitted to the offspring, allowing us to establish a set of mouse lines that show chronic‐type allergic phenotypes, that is, bronchial and nasal inflammation, upon local administrations of the corresponding antigens. Intriguingly, the existence of either rTα or rTβ is sufficient to induce in vivo hypersensitivity. These cloned mice expressing intrinsic promoter‐regulated antigen‐specific TCR are a unique animal model with allergic predisposition for investigating CD4⁺ T‐cell‐mediated pathogenesis and cellular commitment in immune diseases.     

Kinetic and conformational properties of a novel T-cell antigen receptor transmembrane peptide in model membranes

Core peptide (CP; GLRILLLKV) is a 9-amino acid peptide derived from the transmembrane sequence of the T-cell antigen receptor (TCR) alpha-subunit. CP inhibits T-cell activation both in vitro and in vivo by disruption of the TCR at the membrane level. To elucidate CP interactions with lipids, surface plasmon resonance (SPR) and circular dichroism (CD) were used to examine CP binding and secondary structure in the presence of either the anionic dimyristoyl-L-alpha-phosphatidyl-DL-glycerol (DMPG), or the zwitterionic dimyristoyl-L-alpha-phoshatidyl choline (DMPC).Using lipid monolayers and bilayers, SPR experiments demonstrated that irreversible peptide-lipid binding required the hydrophobic interior provided by a membrane bilayer. The importance of electrostatic interactions between CP and phospholipids was highlighted on lipid monolayers as CP bound reversibly to anionic DMPG monolayers, with no detectable binding observed on neutral DMPC monolayers.CD revealed a dose-dependent conformational change of CP from a dominantly random coil structure to that of beta-structure as the concentration of lipid increased relative to CP. This occurred only in the presence of the anionic DMPG at a lipid : peptide molar ratio of 1.6:1 as no conformational change was observed when the zwitterionic DMPC was tested up to a lipid : peptide ratio of 8.4 : 1.     

Caspases as regulators of apoptosis and other cell functions

This review covers current knowledge on the involvement in apoptosis of a new family of endopeptidases denoted as caspases. Their structure, specific substrates, and inhibitors are considered. The recent classification of cysteine proteases of the caspase family based on their structural and functional features is presented. The biological significance of caspases not related to their proapoptotic effect is discussed.     

Exacerbation of experimental autoimmune encephalomyelitis in mice deficient for DCIR,an inhibitory C-type lectin receptor

Dendritic cell immunoreceptor (DCIR) is a C-type lectin receptor containing a carbohydrate recognition domain in its extracellular portion and an immunoreceptor tyrosine–based inhibitory motif, which transduces negative signals into cells, in its cytoplasmic portion. Previously, we showed that Dcir^–/– mice spontaneously develop autoimmune diseases such as enthesitis and sialadenitis due to excess expansion of dendritic cells (DCs), suggesting that DCIR is critically important for the homeostasis of the immune system. In this report, we analyzed the role of DCIR in the development of experimental autoimmune encephalomyelitis (EAE), an autoimmune disease model for multiple sclerosis. We found that EAE was exacerbated in Dcir^–/– mice associated with severe demyelination of the spinal cords. The number of infiltrated CD11c⁺ DCs and CD4⁺ T cells into spinal cords was increased in Dcir^–/– mice. Recall proliferative response of lymph node cells was higher in Dcir^–/– mice compared with wild-type mice. These observations suggest that DCIR is an important negative regulator of the immune system, and Dcir^–/– mice should be useful for analyzing the roles of DCIR in an array of autoimmune diseases.