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In psoriatic arthritis (PsA), predisposing class I HLA alleles, the presence of synovial clonally proliferated CD8 + T cells and autoantibodies all point towards the loss of immune tolerance. However, the key mechanisms that lead to immune dysregulation are not fully understood. In other types of inflammatory arthritis, T regulatory cell (Treg) dysfunction and plasticity at sites of inflammation were suggested to negatively affect peripheral tolerance. We here addressed if Treg variances associate with psoriatic disease. We collected clinical data, sera and peripheral blood mononuclear cells from 13 healthy controls, 21 psoriasis and 21 PsA patients. In addition, we obtained synovial fluid mononuclear cells from 6 PsA patients. We studied characteristics of CD4 + CD25 + CD127loFoxp3 + Tregs by flow cytometry and used ELISA to quantify antibodies against ADAMTSL5, a recently discovered autoantigen in psoriatic disease. In comparison with their circulating counterparts, Tregs from inflamed joints express increased levels of ICOS, CTLA-4 and TIGIT. Furthermore, synovial fluid-derived Tregs have a distinct phenotype, characterized by IL-17A production and upregulation of CD161 and RORγt. We identified a subset of Tregs with intermediate Foxp3 expression as the major cytokine producer. Furthermore, ICOS + Tregs associate with PsA disease activity as measured by PASDAS. Lastly, we observed that presence of the Foxp3int Tregs associates with an increased abundance of anti-ADAMTSL5 autoantibodies. Tregs derived from the inflammatory environment of inflamed PsA joints exhibit a distinct phenotype, which associates with loss of peripheral immune tolerance in psoriatic disease. [ABSTRACT FROM AUTHOR]

Summary: Autoimmune rheumatic diseases (AIRD) are categorized seropositive or seronegative, dependent upon the presence or absence of specific autoreactive antibodies, including rheumatoid factor and anti‐citrullinated protein antibodies. Autoantibody‐based diagnostics have proved helpful in patient care, not only for diagnosis but also for monitoring of disease activity and prediction of therapy responsiveness. Recent work demonstrates that AIRD patients develop autoantibodies beyond those contained in the original categorization. In this study we discuss key mechanisms that underlie autoantibody development in AIRD: defects in early B cell development, genetic variants involved in regulating B cell and T cell tolerance, environmental triggers and antigen modification. We describe how autoantibodies can directly contribute to AIRD pathogenesis through innate and adaptive immune mechanisms, eventually culminating in systemic inflammation and localized tissue damage. We conclude by discussing recent insights that suggest distinct AIRD have incorrectly been denominated seronegative. [ABSTRACT FROM AUTHOR]

Aim Nodal status is the most important prognostic factor in colorectal cancer ( CRC). Small occult metastases may remain undetected on conventional histopathological examination, potentially resulting in undertreatment. Ex vivo sentinel lymph node mapping ( SLNM) can be used to improve the accuracy of nodal staging, but the currently used tracers suffer from drawbacks, which hamper implementation of the technique in routine clinical practice. Magnetic tracers are the optimal size for sentinel lymph node ( SLN) retention and allow objective quantitative selection of SLNs; they therefore have great potential for SLNM in CRC. The study evaluates the feasibility of ex vivo magnetic SLNM and compares the performance of this technique with blue dye SLNM. Method Twenty-eight ex vivo SLNM procedures were performed in 27 histological node-negative patients with CRC using a magnetic tracer and blue dye. A magnetometer was used to select magnetic SLNs after formalin fixation of the CRC specimen. Both magnetic and blue SLNs were subjected to serial sectioning and immunohistochemical staining to reveal occult metastases. Results At least one SLN was successfully identified in 27/28 (96%) and 25/28 (89%) of the cases with the magnetic technique and blue dye. Isolated tumour cells were detected in 10 patients. This was predicted with 100% sensitivity and accuracy using the magnetic technique, and with 91% sensitivity and 96% accuracy using the blue dye technique. Conclusion This study demonstrates that ex vivo magnetic SLNM is a feasible technique for use in routine clinical practice, improving nodal staging accuracy of CRC patients. [ABSTRACT FROM AUTHOR]