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Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins1,2. Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear3. Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

Regulatory T cells (Treg) are CD4+ T cells with immune-suppressive function, which is defined by Foxp3 expression. However, the molecular determinants defining the suppressive population of T cells have yet to be discovered. Here we report that the cell surface protein Lrig1 is enriched in suppressive T cells and controls their suppressive behaviors. Within CD4+ T cells, Treg cells express the highest levels of Lrig1, and the expression level is further increasing with activation. The Lrig1+ subpopulation from T helper (Th) 17 cells showed higher suppressive activity than the Lrig1- subpopulation. Lrig1-deficiency impairs the suppressive function of Treg cells, while Lrig1-deficient naïve T cells normally differentiate into other T cell subsets. Adoptive transfer of CD4+Lrig1+ T cells alleviates autoimmune symptoms in colitis and lupus nephritis mouse models. A monoclonal anti-Lrig1 antibody significantly improves the symptoms of experimental autoimmune encephalomyelitis. In conclusion, Lrig1 is an important regulator of suppressive T cell function and an exploitable target for treating autoimmune conditions. Regulatory T cells, and to certain extent other T cell subsets, limit the immune response to avoid harmful inflammation and tissue damage. Here authors identify a surface molecule, Lrig1, that is directly responsible for the suppressive function in regulatory T cells and in Il-17-producing helper T cells. [ABSTRACT FROM AUTHOR]

The immune mechanisms that mediate synovitis and joint destruction in rheumatoid arthritis (RA) remain poorly defined. Although increased levels of CD8+ T cells have been described in RA, their function in pathogenesis remains unclear. Here we perform single cell transcriptome and T cell receptor (TCR) sequencing of CD8+ T cells derived from anti-citrullinated protein antibodies (ACPA)+ RA blood. We identify GZMB+CD8+ subpopulations containing large clonal lineage expansions that express cytotoxic and tissue homing transcriptional programs, while a GZMK+CD8+ memory subpopulation comprises smaller clonal expansions that express effector T cell transcriptional programs. We demonstrate RA citrullinated autoantigens presented by MHC class I activate RA blood-derived GZMB+CD8+ T cells to expand, express cytotoxic mediators, and mediate killing of target cells. We also demonstrate that these clonally expanded GZMB+CD8+ cells are present in RA synovium. These findings suggest that cytotoxic CD8+ T cells targeting citrullinated antigens contribute to synovitis and joint tissue destruction in ACPA+ RA. The immune mechanisms underlying synovitis and joint tissue destruction in rheumatoid arthritis (RA) remain incompletely defined. Here, the authors demonstrate that ACPA+ RA patients have activated clonally expanded cytotoxic GZMB+ CD8+ T cells in blood and synovium that target and are activated by citrullinated antigens to mediate cell killing. [ABSTRACT FROM AUTHOR]

Hypoxia-inducible factor-1 alpha ( HIF1A) is an important transcription factor for angiogenesis. Recent studies have used the protein transduction domain (PTD) to deliver genes, but the PTD has not been used to induce the expression of HIF1A. This study aimed at using a novel PTD (Hph-1-GAL4; ARVRRRGPRR) to overexpress the HIF1A and identify the effects on angiogenesis in vitro and in vivo. Overexpression of HIF1A was induced using Hph-1-GAL4 in human umbilical vein/vascular endothelium cells (HUVEC). The expression levels of genes were analyzed by the quantitative real-time polymerase chain reaction (qPCR) after 2 and 4 days, respectively. An in vitro tube formation was performed using Diff-Quik staining. HIF1A and Hph-1-GAL4 were injected subcutaneously into the ventral area of each 5-week-old mouse. All of the plugs were retrieved after 1 week, and the gene expression levels were evaluated by qPCR. Each Matrigel plug was evaluated using the hemoglobin assay and hematoxylin and eosin (HE) staining. The expression levels of HIF1A and HIF1A target genes were significantly higher in HIF1A-transfected HUVEC than in control HUVEC in vitro. In the in vivo Matrigel plug assay, the amount of hemoglobin was significantly higher in the HIF1A-treatment group than in the PBS-treatment group. Blood vessels were identified in the HIF1A-treatment group. The expression levels of HIF1A, vascular endothelial growth factor ( Vegf), and Cd31 were significantly higher in the HIF1A-treatment group than in the PBS-treatment group. These findings suggest that using Hph-1-G4D to overexpress HIF1A might be useful for transferring genes and regenerating tissues. [ABSTRACT FROM AUTHOR]

To determine the importance of career management behavior (CMB) for organizational outcomes, this study investigated the impact of CMB and organizational support for career development (OSCD) on subjective career success (SCS) and eventually on organizational commitment. Based on survey data from 355 employees of large Korean manufacturing firms, we found that both CMB and OSCD were positively associated with SCS. The results show that SCS positively affects organizational commitment and positively mediates both the relationship between CMB and organizational commitment and the relationship between OSCD and organizational commitment. Our findings imply that employee career success, which is affected by individual and organizational efforts, contributes to the outcomes of the organization in which employees are embedded. [ABSTRACT FROM AUTHOR]

Although the T helper 2 (Th2) subset is a critical player in the humoral immune response to extracellular parasites and suppression of Th1-mediated inflammation, Th2 cells have been implicated in allergic inflammatory diseases such as asthma, allergic rhinitis, and atopic dermatitis. GATA binding protein 3 (GATA3) is a primary transcription factor that mediates Th2 differentiation and secretion of Th2 cytokines, including IL-4, IL-5, and IL-13. Here, a nucleus-deliverable form of GATA3-transcription modulation domain (TMD) (ndG3-TMD) was generated using Hph-1 human protein transduction domain (PTD) to modulate the transcriptional function of endogenous GATA3 without genetic manipulation. ndG3-TMD was shown to be efficiently delivered into the cell nucleus quickly without affecting cell viability or intracellular signaling events for T cell activation. ndG3-TMD exhibited a specific inhibitory function for the endogenous GATA3-mediated transcription, such as Th2 cell differentiation and Th2-type cytokine production. Intranasal administration of ndG3-TMD significantly alleviated airway hyperresponsiveness, infiltration of immune cells, and serum IgE level in an OVA-induced mouse model of asthma. Also, Th2 cytokine secretion by the splenocytes isolated from the ndG3-TMD-treated mice substantially decreased. Our results suggest that ndG3-TMD can be a new therapeutic reagent to suppress Th2-mediated allergic diseases through intranasal delivery. • ndG3-TMD is a fusion protein between GATA3-TMD and human-origin Hph-1-PTD. • ndG3-TMD can be transduced into the nucleus of the cells effectively and stably. • ndG3-TMD functions as a competitive inhibitor for GATA3-mediated transcription. • ndG3-TMD inhibits transcription of Th2-type cytokines and Th2 cell differentiation. • Intranasal delivery of ndG3D relieves asthma symptoms in an asthma mouse model. [ABSTRACT FROM AUTHOR]