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Genetic studies have revealed that autoimmune susceptibility variants are over-represented in memory CD4+ T cell regulatory elements1-3. Understanding how genetic variation affects gene expression in different T cell physiological states is essential for deciphering genetic mechanisms of autoimmunity4,5. Here, we characterized the dynamics of genetic regulatory effects at eight time points during memory CD4+ T cell activation with high-depth RNA-seq in healthy individuals. We discovered widespread, dynamic allele-specific expression across the genome, where the balance of alleles changes over time. These genes were enriched fourfold within autoimmune loci. We found pervasive dynamic regulatory effects within six HLA genes. HLA-DQB1 alleles had one of three distinct transcriptional regulatory programs. Using CRISPR-Cas9 genomic editing we demonstrated that a promoter variant is causal for T cell-specific control of HLA-DQB1 expression. Our study shows that genetic variation in cis-regulatory elements affects gene expression in a manner dependent on lymphocyte activation status, contributing to the interindividual complexity of immune responses.

OBJECTIVES:To investigate the efficacy and safety of ixekizumab for up to 52 weeks in two phase 3 studies of patients with active radiographic axial spondyloarthritis (r-axSpA) who were biological disease-modifying antirheumatic drug (bDMARD)-naive (COAST-V) or tumour necrosis factor inhibitor (TNFi)-experienced (COAST-W). METHODS:Adults with active r-axSpA were randomised 1:1:1:1 (n=341) to 80 mg ixekizumab every 2 (IXE Q2W) or 4 weeks (IXE Q4W), placebo (PBO) or 40 mg adalimumab Q2W (ADA) in COAST-V and 1:1:1 (n=316) to IXE Q2W, IXE Q4W or PBO in COAST-W. At week 16, patients receiving ixekizumab continued their assigned treatment; patients receiving PBO or ADA were rerandomised 1:1 to IXE Q2W or IXE Q4W (PBO/IXE, ADA/IXE) through week 52. RESULTS:In COAST-V, Assessment of SpondyloArthritis international Society 40 (ASAS40) responses rates (intent-to-treat population, non-responder imputation) at weeks 16 and 52 were 48% and 53% (IXE Q4W); 52% and 51% (IXE Q2W); 36% and 51% (ADA/IXE); 19% and 47% (PBO/IXE). Corresponding ASAS40 response rates in COAST-W were 25% and 34% (IXE Q4W); 31% and 31% (IXE Q2W); 14% and 39% (PBO/IXE). Both ixekizumab regimens sustained improvements in disease activity, physical function, objective markers of inflammation, QoL, health status and overall function up to 52 weeks. Safety through 52 weeks of ixekizumab was consistent with safety through 16 weeks. CONCLUSION:The significant efficacy demonstrated with ixekizumab at week 16 was sustained for up to 52 weeks in bDMARD-naive and TNFi-experienced patients. bDMARD-naive patients initially treated with ADA demonstrated further numerical improvements after switching to ixekizumab. Safety findings were consistent with the known safety profile of ixekizumab. TRIAL REGISTRATION NUMBER:NCT02696785/NCT02696798.

ObjectiveTo provide evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA).MethodsA core group led the development of the recommendations, starting with the treatment questions. A literature review group conducted systematic literature reviews of studies that addressed 57 specific treatment questions, based on searches conducted in OVID Medline (1946-2014), PubMed (1966-2014), and the Cochrane Library. We assessed the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. A separate voting group reviewed the evidence and voted on recommendations for each question using the GRADE framework.ResultsIn patients with active AS, the strong recommendations included use of nonsteroidal antiinflammatory drugs (NSAIDs), use of tumor necrosis factor inhibitors (TNFi) when activity persists despite NSAID treatment, not to use systemic glucocorticoids, use of physical therapy, and use of hip arthroplasty for patients with advanced hip arthritis. Among the conditional recommendations was that no particular TNFi was preferred except in patients with concomitant inflammatory bowel disease or recurrent iritis, in whom TNFi monoclonal antibodies should be used. In patients with active nonradiographic axial SpA despite treatment with NSAIDs, we conditionally recommend treatment with TNFi. Other recommendations for patients with nonradiographic axial SpA were based on indirect evidence and were the same as for patients with AS.ConclusionThese recommendations provide guidance for the management of common clinical questions in AS and nonradiographic axial SpA. Additional research on optimal medication management over time, disease monitoring, and preventive care is needed to help establish best practices in these areas.

Study design. Retrospective. Objective. We aimed to describe a magnetic resonance imaging (MRI)-based grading system of inflammatory features of the lumbar facet joints using an atlas and assess its reliability. Summary of Background Data. Chronic low back pain is often caused by facet joint arthropathy. Inflammatory features are often evident on MRI. While several grading systems of facet arthropathy have been described, there is scant data on the reliability of these systems, and none focus exclusively on inflammatory features. Materials and Methods. We describe a grading system that assesses facet joint effusion, bone marrow edema, and soft tissue edema. Each feature was graded from 0 to 3 (facet edema) or 0 to 2 (bone marrow edema intensity and extent, soft tissue edema intensity and extent). Four spine experts graded MRIs of 50 subjects at the bilateral L3/4, L4/5, and L5/S1 levels. All subjects had symptomatic facet arthropathy and received therapeutic facet joint injections. We assessed the intra-reader and inter-reader reliability of each feature at each joint and summarized across all six joints. Results. The mean age of subjects was 56 years (SD = 17), and 48% were female. The injections occurred at the L3/4 level in 12% of cases, at L4/5 in 88%, and at L5/S1 in 80% of cases. The intra- reader reliability kappa's for each feature ranged from 0.42 to 0.81. In contrast, the inter-reader reliability kappa values for each feature ranged from 0.37 to 0.54. Conclusion. MRI inflammatory features of the lumbar facet joints are often noted in patients with low back pain. The proposed grading system is reliable and could serve as a research tool for studies assessing the clinical relevance and prognostic value of these features. [ABSTRACT FROM AUTHOR]

We have developed a multiplexed reverse phase protein (RPP) microarray platform for simultaneous monitoring of site-specific phosphorylation of numerous signaling proteins using nanogram amounts of lysates derived from stimulated living cells. We first show the application of RPP microarrays to the study of signaling kinetics and pathway delineation in Jurkat T lymphocytes. RPP microarrays were used to profile the phosphorylation state of 62 signaling components in Jurkat T cells stimulated through their membrane CD3 and CD28 receptors, identifying a previously unrecognized link between CD3 crosslinking and dephosphorylation of Raf-1 at Ser259. Finally, the potential of this technology to analyze rare primary cell populations is shown in a study of differential STAT protein phosphorylation in interleukin (IL)-2-stimulated CD4[sup.+]CD25[sup.+] regulatory T cells. RPP microarrays, prepared using simple procedures and standard microarray equipment, represent a powerful new tool for the study of signal transduction in both health and disease., Author(s): Steven M Chan [1]; Joerg Ermann [1]; Leon Su [1]; C Garrison Fathman [1]; Paul J Utz (corresponding author) [1] Reversible phosphorylation of proteins by kinases and phosphatases represents [...]

Mature donor T cells cause graft-versus-host disease (GVHD), but they are also the main mediators of the beneficial graft-versus-tumor (GVT) activity of allogeneic bone marrow transplantation. Suppression of GVHD with maintenance of GVT activity is a desirable outcome for clinical transplantation. We have previously shown that donor-derived CD4[sup.+]CD25[sup.+] regulatory T cells inhibit lethal GVHD after allogeneic bone marrow transplantation across major histocompatibility complex (MHC) class I and II barriers in mice. Here we demonstrate that in host mice with leukemia and lymphoma, CD4[sup.+]CD25[sup.+] regulatory T cells suppress the early expansion of alloreactive donor T cells, their interleukin-2-receptor (IL-2R) [alpha]-chain expression and their capacity to induce GVHD without abrogating their GVT effector function, mediated primarily by the perforin lysis pathway. Thus, CD4[sup.+]CD25[sup.+] T cells are potent regulatory cells that can separate GVHD from GVT activity mediated by conventional donor T cells., Author(s): Matthias Edinger [1, 3]; Petra Hoffmann [2, 3]; Joerg Ermann [2]; Kathryn Drago [1]; C Garrison Fathman [2]; Samuel Strober [2]; Robert S Negrin (corresponding author) [1] T cells [...]

Axial spondyloarthritis, which includes ankylosing spondylitis, is a potentially disabling inflammatory arthritis of the spine which usually presents as chronic back pain. It is underrecognized, and there is usually a significant delay in diagnosis. Treatment options have improved recently with the approval of a new class of medication. [ABSTRACT FROM AUTHOR]