Recent evidence suggests that a substantial portion of complex disease risk alleles modify gene expression in a cell-specific manner. To identify candidate causal genes and biological pathways of immune-related complex diseases, we conducted expression quantitative trait loci (eQTL) analysis on five subsets of immune cells (CD4 T cells, CD8 T cells, B cells, natural killer (NK) cells and monocytes) and unfractionated peripheral blood from 105 healthy Japanese volunteers. We developed a three-step analytical pipeline comprising (i) prediction of individual gene expression using our eQTL database and public epigenomic data, (ii) gene-level association analysis and (iii) prediction of cell-specific pathway activity by integrating the direction of eQTL effects. By applying this pipeline to rheumatoid arthritis data sets, we identified candidate causal genes and a cytokine pathway (upregulation of tumor necrosis factor (TNF) in CD4 T cells). Our approach is an efficient way to characterize the polygenic contributions and potential biological mechanisms of complex diseases.

In the resistive-shell tokamak, JIPP T-II , a control of the current density profile has been attempted by programming both gas puffing and plasma current waveform. A stable high-density plasma has been obtained with the following parameters: the maximum line-average electron density is n̄e = 8.5 × 1013cm−3, the minimum q(a)-value is 2.2, and the relative amplitude of the m/n = 2/l mode is suppressed to an extent less than 10−3. A derivation of the current density profile by solving the magnetic-diffusion equation on the basis of the experimental data shows that the current density profile favourable to the stability of low-m kink and tearing modes is realized by combining the effects of cooling through an increase in density and of heating by a current rise in the outer plasma region. The results of kink and tearing modes analysis agree well with the experimental observations. The criterion that the current density profile is successfully controlled by this method is derived as a function of the ratio of plasma current to electron density in the current-rise phase, i.e. 20 × 10−13 ⪅ Ip/n̄e ⪅ 30 × 10−13 kA·cm3. The major disruption due to the density increase is completely suppressed by the method proposed in this paper. The major disruption due to a reduction of q(a) to less than 2.2 has, however, not yet been suppressed. In future, the current density profile should be maintained more precisely at its optimum shape by using a feedback-control technique and a control of the plasma boundary with titanium gettering, etc.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that leads to destructive arthritis. Although the HLA class II locus is the strongest genetic risk factor for rheumatoid arthritis, the relationship between HLA class II alleles and lymphocyte activation remains unclear. We performed immunophenotyping of peripheral blood mononuclear cells on 91 HLA-DRB1-genotyped RA patients and 110 healthy donors. The frequency of memory CXCR4+CD4+ T cells, and not Th1 and Th17 cells, was significantly associated with disease severity by multiple linear regression analysis. RA patients with one or more susceptible HLA-DR haplotypes (shared epitope: SE) displayed a significantly higher frequency of memory CXCR4+CD4+ T cells. Moreover, the frequency of memory CXCR4+CD4+ T cells significantly correlated with the expression level of HLA-DR on B cells, which was elevated in RA patients with SE. In vitro analysis and transcriptomic pathway analysis suggested that the interaction between HLA-DR and T cell receptors is an important regulator of memory CXCR4+CD4+ T cells. Clinically, a higher frequency of memory CXCR4+CD4+ T cells predicted a better response to CTLA4-Ig. Memory CXCR4+CD4+ T cells may serve as a powerful biomarker for unraveling the linkage between HLA-DRB1 genotype and disease activity in RA.

Objective The balance between effector and regulatory CD4+ T cells plays a key role in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to examine whether the RA autoantigen BiP has epitopes for both effector and regulatory immunities. Methods The proliferation and cytokine secretion of peripheral blood mononuclear cells (PBMCs) from HLA–DR4–positive RA patients in response to BiP‐derived peptides were examined by 3H‐thymidine uptake and enzyme‐linked immunosorbent assay. As a mouse therapeutic model, a BiP‐derived peptide was administered orally to mice with collagen‐induced arthritis (CIA). Results Among the peptides examined, BiP336–355 induced the strongest proliferation of PBMCs from RA patients, but not from healthy donors. The proliferation of PBMCs in response to BiP336–355 showed a correlation with clinical RA activity and serum anti‐BiP/citrullinated BiP antibodies. In contrast, BiP456–475 induced interleukin‐10 (IL‐10) secretion from CD25‐positive PBMCs obtained from RA patients and healthy donors without inducing cell proliferation, and it actively suppressed the BiP336–355–induced proliferation and proinflammatory cytokine secretion by PBMCs. Oral administration of BiP456–475 to mice with CIA reduced the severity of arthritis and T cell proliferation and increased the secretion of IL‐10 from T cells as well as the number of CD4+CD25+FoxP3+ regulatory T cells. Conclusion Effector and regulatory T cells recognized different BiP epitopes. The deviated balance toward BiP‐specific effector T cells in RA may be associated with disease activity; therefore, BiP‐specific effector or regulatory T cells could be a target of new RA therapies.

BackgroundRegulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4+CD25−LAG3+ T cells (LAG3+ Tregs) and their association with rheumatoid arthritis (RA).MethodsLAG3+ Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3+ Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4+ T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays.ResultsLAG3+ Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25+ Tregs. Cell-to-cell contact was required for the suppressive function of LAG3+ Tregs. The frequency of LAG3+ Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3+ Tregs significantly increased after 6 months of abatacept treatment, whereas CD25+ Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4+ T cells, and abatacept-treated CD4+ T cells exhibited suppressive activity.ConclusionsIL-10-producing LAG3+ Tregs are associated with the immunopathology and therapeutic response in RA. LAG3+ Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-017-1309-x) contains supplementary material, which is available to authorized users.