Citations

Key PointsA total of 47% of patients who achieved CR on brentuximab vedotin remain progression-free after being followed a median of 53 months. Younger age, less functional impairment, and lower disease burden at baseline were associated with CR and prognostic for longer survival.

Abstract Recent thymic emigrants (RTEs) must undergo phenotypic and functional maturation to become long-lived mature naive T cells. In CD4-cre NKAP conditional knockout mice, NKAP-deficient RTEs fail to complete T cell maturation. In this study, we demonstrate that NKAP-deficient immature RTEs do not undergo apoptosis, but are eliminated by complement. C3, C4, and C1q are bound to NKAP-deficient peripheral T cells, demonstrating activation of the classical arm of the complement pathway. As thymocytes mature and exit to the periphery, they increase sialic acid incorporation into cell surface glycans. This is essential to peripheral lymphocyte survival, as stripping sialic acid with neuraminidase leads to the binding of natural IgM and complement fixation. NKAP-deficient T cells have a defect in sialylation on cell surface glycans, leading to IgM recruitment. We demonstrate that the defect in sialylation is due to aberrant α2,8-linked sialylation, and the expression of three genes (ST8sia1, ST8sia4, and ST8sia6) that mediate α2,8 sialylation are downregulated in NKAP-defcient RTEs. The maturation of peripheral NKAP-deficient T cells is partially rescued in a C3-deficient environment. Thus, sialylation during T cell maturation is critical to protect immature RTEs from complement in the periphery.

Abstract Phosphaturic mesenchymal tumours ( PMTs ) are uncommon soft tissue and bone tumours that typically cause hypophosphataemia and tumour‐induced osteomalacia ( TIO ) through secretion of phosphatonins including fibroblast growth factor 23 ( FGF23 ). PMT has recently been accepted by the World Health Organization as a formal tumour entity. The genetic basis and oncogenic pathways underlying its tumourigenesis remain obscure. In this study, we identified a novel FN1–FGFR1 fusion gene in three out of four PMTs by next‐generation RNA sequencing. The fusion transcripts and proteins were subsequently confirmed with RT‐PCR and western blotting. Fluorescence in situ hybridization analysis showed six cases with FN1–FGFR1 fusion out of an additional 11 PMTs . Overall, nine out of 15 PMTs (60%) harboured this fusion. The FN1 gene possibly provides its constitutively active promoter and the encoded protein's oligomerization domains to overexpress and facilitate the activation of the FGFR1 kinase domain. Interestingly, unlike the prototypical leukaemia‐inducing FGFR1 fusion genes, which are ligand‐independent, the FN1–FGFR1 chimeric protein was predicted to preserve its ligand‐binding domains, suggesting an advantage of the presence of its ligands (such as FGF23 secreted at high levels by the tumour) in the activation of the chimeric receptor tyrosine kinase, thus effecting an autocrine or a paracrine mechanism of tumourigenesis. Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

BACKGROUND: The mechanism between ventilator-induced lung injury (VILI) and multiple organ injury is unclear. The aim of our study was to investigate the mechanisms of VILI-induced distal organ injury. METHODS: VILI was induced in rat lungs with high tidal volume (V T ) ventilation of 40 mL/kg for 6 h. Rats with low V T ventilation of 6 mL/kg served as controls. Inflammatory and apoptotic indices in lung and distal organs were assessed. RESULTS: VILI increased lung weight, airway pressure, inflammation, and apoptotic pathologic changes without hemodynamic changes. The white blood cell count and the levels of H 2 O 2 , interleukin-1β (IL-1β), tumor necrosis factor alpha, and macrophage inflammatory protein-2 in bronchoalveolar lavage fluid were higher in the VILI group compared with the control group. H 2 O 2 , IL-1β, and tumor necrosis factor alpha in blood from the left ventricle were up-regulated. H 2 O 2 , IL-1β, tumor necrosis factor alpha, macrophage inflammatory protein-2, c-Jun N-terminal kinase, p38, nuclear factor kappa B, and caspase-3 in lung, heart, liver, and kidney tissues in the VILI group were up-regulated. Furthermore, the apoptotic score for the kidneys was higher than those for other distal organs in the VILI group. CONCLUSIONS: High V T ventilation induces VILI and is associated with inflammation and apoptosis in distal organs. Up-regulation of reactive oxygen species and cytokines in VILI is associated with systemic inflammatory responses. Kidney tissue appears to be more vulnerable than heart and liver tissues following VILI.

Abstract We recently described a novel H2E class II-transgenic model (A−E+) of experimental autoimmune thyroiditis (EAT) that permits disease induction with heterologous thyroglobulin (Tg), but unlike conventional susceptible strains, precludes self-reactivity to autologous mouse Tg. In transgenic E+B10 (A+E+) mice, the presence of endogenous H2A genes is protective against H2E-mediated thyroiditis, inhibiting EAT development. The suppressive effect of H2A genes on H2E-mediated thyroiditis mirrors previous reports of H2E suppression on H2A-mediated autoimmune diseases, including EAT. The mechanism of the reciprocal-suppressive effect between class II genes is unclear, although the involvement of regulatory T cells has been proposed. We have recently reported that CD4+CD25+ regulatory T cells mediate peripheral tolerance induced with mouse Tg in CBA mice. To determine whether these cells play a role in our E+-transgenic model, we first confirmed the existence of CD4+CD25+ T cells regulating thyroiditis in E+B10.Ab0 (A−E+) and B10 (A+E−) mice by i.v. administration of CD25 mAb before EAT induction. The depletion of CD4+CD25+ T cells enhanced thyroiditis induction in the context of either H2E or H2A. Moreover, reconstitution of CD4+CD25+ T cells from naive B10 mice restored resistance to EAT. E+B10 (A+E+) mice were also depleted of CD4+CD25+ T cells before the challenge to determine their role in thyroiditis in the presence of both H2A and H2E genes. Depletion of CD4+CD25+ regulatory T cells offset the suppression of H2E-mediated thyroiditis by H2A. Thus, these regulatory T cells may be involved in the reciprocal-suppressive effect between class II genes.

Abstract Decoy receptor 3 (DcR3), a soluble receptor belonging to the TNFR superfamily, is a receptor for both Fas ligand (FasL) and LIGHT. It has been demonstrated that DcR3 is up-regulated in lung and colon cancers, thus promoting tumor growth by neutralizing the cytotoxic effects of FasL and LIGHT. In this study, we found that DcR3.Fc profoundly modulated dendritic cell differentiation and maturation from CD14+ monocytes, including the up-regulation of CD86/B7.2, and the down-regulation of CD40, CD54/ICAM-1, CD80/B7.1, CD1a, and HLA-DR. Moreover, DcR3-treated dendritic cells suppressed CD4+ T cell proliferation in an allogeneic MLR and up-regulated IL-4 secretion of CD4+CD45RA+ T cells. This suggests that DcR3.Fc may act not only as a decoy receptor to FasL and LIGHT, but also as an effector molecule to skew T cell response to the Th2 phenotype.

Abstract Biliary epithelial cells (cholangiocytes) respond to proinflammatory cytokines such as IFN-γ and actively participate in the regulation of biliary inflammatory response in the liver. B7-H1 (also known as CD274 or PD-L1) is a member of the B7 costimulatory molecules and plays a critical immunoregulatory role in cell-mediated immune responses. In this study, we show that resting human cholangiocytes in culture express B7-H1 mRNA, but not B7-H1 protein. IFN-γ induces B7-H1 protein expression and alters the microRNA (miRNA) expression profile in cholangiocytes. Of those IFN-γ-down-regulated miRNAs, we identified microRNA-513 (miR-513) with complementarity to the 3′-untranslated region of B7-H1 mRNA. Targeting of the B7-H1 3′-untranslated region by miR-513 results in translational repression. Transfection of cholangiocytes with an antisense oligonucleotide to miR-513 induces B7-H1 protein expression. Additionally, transfection of miR-513 precursor decreases IFN-γ-induced B7-H1 protein expression and consequently influences B7-H1-associated apoptotic cell death in cocultured Jurkat cells. Thus, miR-513 regulates B7-H1 translation and is involved in IFN-γ-induced B7-H1 expression in human cholangiocytes, suggesting a role for miRNA-mediated gene silencing in the regulation of cholangiocyte response to IFN-γ.

Abstract Susceptibility and resistance to experimental autoimmune thyroiditis is encoded by MHC H2A genes. We reported that traditionally resistant B10 (H2b) mice permit thyroiditis induction with mouse thyroglobulin (mTg) after depleting regulatory T cells (Tregs), supporting Ab presentation to thyroiditogenic T cells. Yet, Eak transgenic mice, expressing Ab and normally absent Eb molecules (E+B10 mice), are susceptible to thyroiditis induction without Treg depletion. To explore the effect of Eb expression on mTg presentation by Ab, seven putative Ab-binding, 15–16-mer peptides were synthesized. Five were immunogenic for both B10 and E+B10 mice. The effect of Eb expression was tested by competition with an Eα52-68 peptide, because Eα52-68 occupies ∼15% of Ab molecules in E+B10 mice, binding with high affinity. Eα52-68 competitively reduced the proliferative response to mTg, mTg1677, and mTg2342 of lymph node cells primed to each Ag. Moreover, mTg1677 induced mild thyroiditis in Treg-depleted B10 mice, and in E+B10 mice without the need for Treg depletion. Eα52-68 competition with mTg-derived peptides may impede clonal deletion of pathogenic, mTg-specific T cells in the thymus.

Background Cardiovascular implantable electronic device (CIED) pocket infections are often related to recent CIED placement or manipulation, but these infections are not well characterized. The clinical presentation of CIED pocket infection, based on temporal onset related to last CIED procedure, deserves further study. Methods The MEDIC (Multicenter Electrophysiologic Device Infection Cohort) prospectively enrolled subjects with CIED infection. Subjects were stratified into those whose infection occurred <12 months (early) or ≥12 months (late) since their last CIED‐related procedure. Results There were 132 subjects in the early group and 106 in the late group. There were more females (P = 0.009) and anticoagulation use (P = 0.039) in the early group. Subjects with early infections were more likely to have had a generator change or lead addition as their last procedure (P = 0.03) and had more prior CIED procedures (P = 0.023). Early infections were more likely to present with pocket erythema (P < 0.001), swelling (P < 0.001), and pain (P = 0.007). Late infections were more likely to have pocket erosion (P = 0.005) and valvular vegetations (P = 0.009). In bacteremic subjects, early infections were more likely healthcare‐associated (P < 0.001). In‐hospital and 6‐month mortality were equivalent. Conclusion A total of 45% of patients with CIED pocket infection presented >12 months following their last CIED‐related procedure. Patients with early infection were more likely to be female, on anticoagulation, and present with localized inflammation, whereas those with late infection were more likely to have CIED erosion or valvular endocarditis.