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Objective: Syk is a cytoplasmic protein tyrosine kinase that plays a role in signaling via B cell and Fc receptors (FcR). FcR engagement and signaling via Syk is thought to be important in antineutrophil cytoplasm antibody (ANCA) IgG–mediated neutrophil activation. This study was undertaken to investigate the role of Syk in ANCA‐induced myeloid cell activation and vasculitis pathogenesis. Methods: Phosphorylation of Syk in myeloid cells from healthy controls and ANCA‐associated vasculitis (AAV) patients was analyzed using flow cytometry. The effect of Syk inhibition on myeloperoxidase (MPO)–ANCA IgG activation of cells was investigated using functional assays (interleukin‐8 and reactive oxygen species production) and targeted gene analysis with NanoString. Total and phosphorylated Syk at sites of tissue inflammation in patients with AAV was assessed using immunohistochemistry and RNAscope in situ hybridization. Results: We identified increased phosphorylated Syk at critical activatory tyrosine residues in blood neutrophils and monocytes from patients with active AAV compared to patients with disease in remission or healthy controls. Syk was phosphorylated in vitro following MPO‐ANCA IgG stimulation, and Syk inhibition was able to prevent ANCA‐mediated cellular responses. Using targeted gene expression analysis, we identified up‐regulation of FcR‐ and Syk‐dependent signaling pathways following MPO‐ANCA IgG stimulation. Finally, we showed that Syk is expressed and phosphorylated in tissue leukocytes at sites of organ inflammation in AAV. Conclusion: These findings indicate that Syk plays a critical role in MPO‐ANCA IgG–induced myeloid cell responses and that Syk is activated in circulating immune cells and tissue immune cells in AAV; therefore, Syk inhibition may be a potential therapeutic option. [ABSTRACT FROM AUTHOR]

Background The diagnosis of antibody-mediated rejection (AMR) is reached using the Banff Classification for Allograft Pathology, which now includes gene expression analysis. In this study, we investigate the application of 'increased expression of thoroughly validated gene transcripts/classifiers strongly associated with AMR' as diagnostic criteria. Method We used quantitative real-time polymerase chain reaction for 10 genes associated with AMR in a retrospective cohort of 297 transplant biopsies, including biopsies that met the full diagnostic criteria for AMR, even without molecular data (AMR, n = 27), biopsies that showed features of AMR, but that would only meet criteria for AMR with increased transcripts [suspicious for AMR (AMRsusp), n = 49] and biopsies that would never meet criteria for AMR (No-AMR, n = 221). Results A 10-gene AMR score trained by a receiver-operating characteristic to identify AMR found 16 cases with a high score among the AMRsusp cases (AMRsusp-high) that had significantly worse graft survival than those with a low score (AMRsusp-low; n = 33). In both univariate and multivariate Cox regression analysis, the AMR 10-gene score was significantly associated with an increased hazard ratio (HR) for graft loss (GL) in the AMRsusp group (HR = 1.109, P = 0.004 and HR = 1.138, P = 0.012, respectively), but not in the whole cohort. Net reclassification index and integrated discrimination improvement analyses demonstrated improved risk classification and superior discrimination, respectively, for GL when considering the gene score in addition to histological and serological data, but only in the AMRsusp group, not the whole cohort. Conclusions This study provides evidence that a gene score strongly associated with AMR helps identify cases at higher risk of GL in biopsies that are suspicious for AMR but do not meet full criteria. [ABSTRACT FROM AUTHOR]

In many settings, adults with active or latent tuberculosis will also be coinfected with helminths. Our study aimed to investigate how anthelmintic treatment modulates antimycobacterial immunity, in a setting where helminth reinfection should not occur. We investigated the potential impact of helminth infection on immune responses to Mycobacterium tuberculosis (Mtb) in patients with latent Mtb infection with or without helminth infection ( Strongyloides or Schistosoma), and tested T-cell responses before and after anthelmintic treatment. The study was performed in migrants resident in the United Kingdom, where reexposure and reinfection following anthelmintic treatment would not occur. The frequency of CD4+IFN-γ+ T cells was measured following stimulation with Mtb Purified Protein Derivative or ESAT-6/CFP-10 antigen, and concentrations of IFN-γ in culture supernatants measured by ELISA and multiplex bead array. Helminth infection was associated with a lower frequency of CD4+IFN-γ+ T cells, which increased following treatment. Patients with helminth infection showed a significant increase in CD4+FoxP3+ T cells (Treg) compared to those without helminth infection. There was a decrease in the frequency of Treg cells, and an associated increase in CD4+IFN-γ+ T cells after the anthelmintic treatment. Here, we show a potential role of Treg cells in reducing the frequency and function of antimycobacterial CD4+IFN-γ+ T cells, and that these effects are reversed after anthelmintic treatment. [ABSTRACT FROM AUTHOR]

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL). It has been postulated that ATLL cells might act as regulatory T cells (T [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTLs) play a central role in the protective immune response to human T-lymphotropic virus 1 (HTLV-1). Here we consider two questions. First, what determines the strength of an individual's HTLV-1-specific CTL response? Second, what controls the rate of expression of HTLV-1 in vivo, which is greater in patients with HAM/TSP than in asymptomatic carriers with the same proviral load? Recent evidence shows that FoxP3+CD4+ T cells are abnormally frequent in HTLV-1 infection, and the frequency of these cells is inversely correlated with the rate of CTL lysis of HTLV-1-infected cells, suggesting that FoxP3+CD4+ cell frequency is an important determinant of the outcome of HTLV-1 infection. There is also new evidence that the rate of expression of HTLV-1 in vivo is associated with the transcriptional activity of the flanking host genome. We suggest that the frequencies of HTLV-1-infected T cell clones in vivo are determined by a dynamic balance between positive and negative selection forces that differ among the clones.