Interleukin 15 Primes Natural Killer Cells to Kill via NKG2D and cPLA2 and This Pathway Is Active in Psoriatic Arthritis

NK cells are large granular lymphocytes that form a critical component of the innate immune system, whose functions include the killing of cells expressing stress-induced molecules. It is increasingly accepted that despite being considered prototypical effector cells, NK cells require signals to reach their full cytotoxic potential. We previously showed that IL-15 is capable of arming CD8 effector T cells to kill independently of their TCR via NKG2D in a cPLA2-dependent process. As NK cells also express NKG2D, we wanted to investigate whether this pathway functioned in an analogous manner and if resting NK cells could be primed to the effector phase by IL-15. Furthermore, to establish relevance to human disease we studied a possible role for this pathway in the pathogenesis of psoriatic arthritis, since there are aspects of this disease that suggest a potential effector role for the innate immune system. We found that PsA patients had upregulated IL-15 and MIC in their affected synovial tissues, and that this unique inflammatory environment enabled NK cell activation and killing via NKG2D and cPLA2. Moreover, we were able to reproduce the phenotype of joint NK cells from blood NK cells by incubating them with IL-15. Altogether, these findings suggest a destructive role for NK cells when activated by environmental stress signals during the pathogenesis of PsA and demonstrate that IL-15 is capable of priming resting NK cells in tissues to the effector phase.</p

Interleukin 15 Primes Natural Killer Cells to Kill via NKG2D and cPLA2 and This Pathway Is Active in Psoriatic Arthritis

NK cells are large granular lymphocytes that form a critical component of the innate immune system, whose functions include the killing of cells expressing stress-induced molecules. It is increasingly accepted that despite being considered prototypical effector cells, NK cells require signals to reach their full cytotoxic potential. We previously showed that IL-15 is capable of arming CD8 effector T cells to kill independently of their TCR via NKG2D in a cPLA2-dependent process. As NK cells also express NKG2D, we wanted to investigate whether this pathway functioned in an analogous manner and if resting NK cells could be primed to the effector phase by IL-15. Furthermore, to establish relevance to human disease we studied a possible role for this pathway in the pathogenesis of psoriatic arthritis, since there are aspects of this disease that suggest a potential effector role for the innate immune system. We found that PsA patients had upregulated IL-15 and MIC in their affected synovial tissues, and that this unique inflammatory environment enabled NK cell activation and killing via NKG2D and cPLA2. Moreover, we were able to reproduce the phenotype of joint NK cells from blood NK cells by incubating them with IL-15. Altogether, these findings suggest a destructive role for NK cells when activated by environmental stress signals during the pathogenesis of PsA and demonstrate that IL-15 is capable of priming resting NK cells in tissues to the effector phase

Lidocaine bolus may facilitate computed tomographic coronary angiography in patients with frequent premature ventricular contractions

INTRODUCTION: Heart rate irregularities are the major limitations of computed tomographic coronary angiography (CTCA) due to severe motion artifacts. AIM: To evaluate the safety and efficacy of a lidocaine intravenous bolus in preserving good image quality by the transient suppression of premature ventricular contractions (PVC) during the CTCA scan. MATERIAL AND METHODS: The study group comprised 67 consecutive patients with sinus rhythm and numerous PVC scheduled for CTCA. Intravenous boluses of 25–50 mg lidocaine were given after calcium score assessment and immediately before CTCA. The control group comprised 67 patients with sinus rhythm without PVC matched according to the body mass index (BMI), age, sex, and calcium score. All coronary vessel segments were assessed for image quality and presence of significant stenosis. RESULTS: As compared with calcium score assessment, after administration of lidocaine and during the CTCA scan PVC were completely suppressed in 22 (40%), reduced in 10 (18%), unchanged in 18 (32%), and intensified in 5 (10%) patients. Overall, there were 32 (58%) patients with sinus rhythm during CTCA as compared with only 11 (20%) patients free from PVC during calcium score assessment (p < 0.001). Image quality in 871 coronary segments including both the study group and control patients was worse in patients with PVC (p < 0.0001). However, there was no statistically significant difference in the number of patients with at least one segment of non-diagnostic quality (6% vs. 12%, p = 0.36; respectively). CONCLUSIONS: Single lidocaine bolus given prior to CTCA is safe, may temporarily eliminate or reduce the intensity of arrhythmia, and hence results in improved quality of CTCA in patients with numerous PVC

Relation between coronary plaque calcium deposits as described by computed tomography coronary angiography and acute results of stent deployment as assessed by intravascular ultrasound

INTRODUCTION: The findings from intravascular ultrasound studies on the impact of calcium deposits on the results of stent implantation are conflicting. AIM: To evaluate whether calcium deposits as assessed by (CTCA) influence results of stent deployment. MATERIAL AND METHODS: The study population comprised 60 patients (43 male; age 64.2 ±8.6 years) who underwent CTCA before stent implantation. Lesion calcium score, total calcium length, and maximal area and maximal thickness of calcium deposits within the lesion segment were assessed. Plaques were divided into those with calcium score ≥ median (group 1), calcium score < median (group 2), and without calcium (group 3). Intravascular ultrasound (IVUS) was performed after attainment of optimal angiographic results of the stent procedure. Focal and diffuse stent expansion was defined as either minimum stent area (MSA) or mean stent area over the length of the stent divided by reference lumen area. RESULTS: The proximal reference segments of lesions with higher calcium score contained a larger plaque burden (47 ±12% vs. 41 ±9% vs. 34 ±18%, p = 0.02) – respectively for groups 1, 2, and 3. Positive correlation was observed between lesion calcium score and frequency of post-dilation (R = 0.28, p = 0.03). There was no difference in focal stent expansion (71 ±14% vs. 65 ±15% vs.71 ±15%, p = 0.3) or diffuse stent expansion (92 ±30% vs. 85 ±30% vs. 93 ±38%, p = 0.7) comparing groups 1, 2, and 3. Lesion calcium score, total length of calcium, and maximum area and thickness of calcium deposits did not correlate with focal or diffuse stent expansion. CONCLUSIONS: Lesions with a higher CTCA calcium score had larger reference plaque burden after stent implantation and more likely required post-dilation, but final stent expansion as assessed by IVUS was not affected by the amount of CTCA calcium provided an angiographically optimal result was achieved

Reprogramming of CTLs into natural killer–like cells in celiac disease

Celiac disease is an intestinal inflammatory disorder induced by dietary gluten in genetically susceptible individuals. The mechanisms underlying the massive expansion of interferon γ–producing intraepithelial cytotoxic T lymphocytes (CTLs) and the destruction of the epithelial cells lining the small intestine of celiac patients have remained elusive. We report massive oligoclonal expansions of intraepithelial CTLs that exhibit a profound genetic reprogramming of natural killer (NK) functions. These CTLs aberrantly expressed cytolytic NK lineage receptors, such as NKG2C, NKp44, and NKp46, which associate with adaptor molecules bearing immunoreceptor tyrosine-based activation motifs and induce ZAP-70 phosphorylation, cytokine secretion, and proliferation independently of T cell receptor signaling. This NK transformation of CTLs may underlie both the self-perpetuating, gluten-independent tissue damage and the uncontrolled CTL expansion leading to malignant lymphomas in severe forms of celiac disease. Because similar changes were detected in a subset of CTLs from cytomegalovirus-seropositive patients, we suggest that a stepwise transformation of CTLs into NK-like cells may underlie immunopathology in various chronic infectious and inflammatory diseases

Antigen-driven colonic inflammation is associated with development of dysplasia in primary sclerosing cholangitis

© The Author(s). Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.Primary sclerosing cholangitis (PSC) is an immune-mediated disease of the bile ducts that co-occurs with inflammatory bowel disease (IBD) in almost 90% of cases. Colorectal cancer is a major complication of patients with PSC and IBD, and these patients are at a much greater risk compared to patients with IBD without concomitant PSC. Combining flow cytometry, bulk and single-cell transcriptomics, and T and B cell receptor repertoire analysis of right colon tissue from 65 patients with PSC, 108 patients with IBD and 48 healthy individuals we identified a unique adaptive inflammatory transcriptional signature associated with greater risk and shorter time to dysplasia in patients with PSC. This inflammatory signature is characterized by antigen-driven interleukin-17A (IL-17A)+ forkhead box P3 (FOXP3)+ CD4 T cells that express a pathogenic IL-17 signature, as well as an expansion of IgG-secreting plasma cells. These results suggest that the mechanisms that drive the emergence of dysplasia in PSC and IBD are distinct and provide molecular insights that could guide prevention of colorectal cancer in individuals with PSC.This work was supported by the Leona M. and Harry B. Helmsley Charitable trust (SHARE), the Digestive Diseases Research Core Center C-IID P30 DK42086 at the University of Chicago, the PSC Partners Seeking a Cure Canada and the Sczholtz Family Foundation. K.R.M. is supported by grant no. NS124187. S.C.S. is supported by an American Gastroenterological Association Research Scholar Award, Veterans Affairs Career Development Award (no. ICX002027A01) and the San Diego Digestive Diseases Research Center (no. P30 DK120515). C.Q. is supported by the BBSRC Core Strategic Programme Grant (BB/CSP1720/1, BBS/E/T/000PR9818 and BBS/E/T/000PR9817). I.H.J. is supported by a Rosalind Franklin Fellowship from the University of Groningen and a Netherlands Organization for Scientific Research VIDI grant no. 016.171.047. D.G.S. is supported by grant no. F30DK121470.info:eu-repo/semantics/publishedVersio

Cytosolic PLA2 is required for CTL-mediated immunopathology of celiac disease via NKG2D and IL-15

IL-15 and NKG2D promote autoimmunity and celiac disease by arming cytotoxic T lymphocytes (CTLs) to cause tissue destruction. However, the downstream signaling events underlying these functional properties remain unclear. Here, we identify cytosolic phospholipase A2 (cPLA2) as a central molecule in NKG2D-mediated cytolysis in CTLs. Furthermore, we report that NKG2D induces, upon recognition of MIC+ target cells, the release of arachidonic acid (AA) by CTLs to promote tissue inflammation in association with target killing. Interestingly, IL-15, which licenses NKG2D-mediated lymphokine killer activity in CTLs, cooperates with NKG2D to induce cPLA2 activation and AA release. Finally, cPLA2 activation in intraepithelial CTLs of celiac patients provides an in vivo pathophysiological dimension to cPLA2 activation in CTLs. These results reveal an unrecognized link between NKG2D and tissue inflammation, which may underlie the emerging role of NKG2D in various immunopathological conditions and define new therapeutic targets

Chronic inflammation permanently reshapes tissue-resident immunity in celiac disease

Tissue-resident lymphocytes play a key role in immune surveillance, but it remains unclear how these inherently stable cell populations respond to chronic inflammation. In the setting of celiac disease (CeD), where exposure to dietary antigen can be controlled, gluten-induced inflammation triggered a profound depletion of naturally occurring Vγ4+/Vδ1+ intraepithelial lymphocytes (IELs) with innate cytolytic properties and specificity for the butyrophilin-like (BTNL) molecules BTNL3/BTNL8. Creation of a new niche with reduced expression of BTNL8 and loss of Vγ4+/Vδ1+ IELs was accompanied by the expansion of gluten-sensitive, interferon-γ-producing Vδ1+ IELs bearing T cell receptors (TCRs) with a shared non-germline-encoded motif that failed to recognize BTNL3/BTNL8. Exclusion of dietary gluten restored BTNL8 expression but was insufficient to reconstitute the physiological Vγ4+/Vδ1+ subset among TCRγδ+ IELs. Collectively, these data show that chronic inflammation permanently reconfigures the tissue-resident TCRγδ+ IEL compartment in CeD

Original paperEndothelium-dependent acetylcholine-induced vasodilatory response of saphenous vein grafts

Introduction: It has been suggested that endothelial dysfunction is critical to saphenous vein graft (SVG) occlusion. Aim: To evaluate in vivo endothelium-mediated vasoreactivity in angiographically non-stenotic SVG. Methods: The group consisted of 31 patients (pts), aged 58.7&#177;8.7 years, 54&#177;38 months after coronary bypass surgery. In each patient one angiographically normal SVG was selected for the study. Endothelium-dependent vasoreactivity was investigated with acetylcholine (Ach) 50 &#181;g intragraft infusion. Graft diameter changes were measured by quantitative computer angiography (QCA). Results: In 17 (54.8%) pts there was a significant reduction in graft diameter following Ach infusion, from 3.8&#177;0.7 to 3.2&#177;0.7 mm (p=0.0001), whereas in 4 (12.9%) pts there were no diameter changes (3.2&#177;0.7 mm). In the 10 remaining pts (32.3%) we found graft dilatation from 3.5&#177;0.5 mm to 3.9&#177;0.5 mm (p=0.0002). In multivariate linear regression analysis, SVG dilatation positively correlated with a low ratio of graft/artery diameter (pWstęp: Dotychczas opublikowano niewiele prac oceniających funkcję śródbłonka żylnych pomostów aortalno-wieńcowych (SVG), chociaż powszechnie uznaje się, że ma ona decydujący wpływ na czas ich funkcjonowania. Cel: Ocena in vivo odległej, zależnej od środbłonka wazoreaktywności angiograficznie prawidłowych SVG. Metoda: Badaną grupę stanowiło 31 chorych w wieku średnio 58,7&#177;8,7 lat, skierowanych na badania hemodynamiczne z powodu nawrotu dolegliwości wieńcowych średnio 54&#177;38 mies. po operacji tętnic wieńcowych. U każdego chorego badaniu poddano jeden SVG. Zależną od śródbłonka wazoreaktywnoś&#230; pomostu badano za pomocą oceny, metodą angiografii ilościowej, zmiany średnicy SVG po bezpośrednim podaniu do pomostu 50 &#181;g acetylocholiny (Ach) w bolusie. Wyniki: U 17 chorych (54,8%) po podaniu Ach stwierdzono zwężenie światła SVG ze średnio 3,8&#177;0,7 mm do 3,2&#177;0,7 mm (p=0,0001), a u 4 chorych (12,9%) średnica SVG nie uległa zmianie (3,2&#177;0,7 mm). U 10 chorych (32,3%) pod wpływem Ach doszło do istotnego poszerzenia światła pomostu z 3,5&#177;0,5 mm do 3,9&#177;0,5 mm, (p=0,0002). W analizie wieloczynnikowej regresji liniowej poszerzenie się SVG pod wpływem Ach było skorelowane z mniejszą dysproporcją pomiędzy średnicą SVG a średnicą pomostowanej tętnicy (