T-helper 17 cell cytokines and interferon type I: Partners in crime in systemic lupus erythematosus?

Introduction: A hallmark of systemic autoimmune diseases like systemic lupus erythematosus (SLE) is the increased expression of interferon (IFN) type I inducible genes, so-called IFN type I signature. Recently, T-helper 17 subset (Th17 cells), which produces IL-17A, IL-17F, IL-21, and IL-22, has been implicated in SLE. As CCR6 enriches for Th17 cells, we used this approach to investigate whether CCR6+ memory T-helper cells producing IL-17A, IL-17F, IL-21, and/or IL-22 are increased in SLE patients and whether this increase is related to the presence of IFN type I signature.Methods: In total, 25 SLE patients and 15 healthy controls (HCs) were included. SLE patients were divided into IFN type I signature-positive (IFN+) (n = 16) and negative (IFN-) (n = 9) patients, as assessed by mRNA expression of IFN-inducible genes (IFIGs) in monocytes. Expression of IL-17A, IL-17F, IL-21, and IL-22 by CD4+CD45RO+CCR6+ T cells (CCR6+ cells) was measured with flow cytometry and compared between IFN+, IFN- patients and HCs.Results: Increased percentages of IL-17A and IL-17A/IL-17F double-producing CCR6+ cells were observed in IFN+ patients compared with IFN- patients and HCs. IL-17A and IL-17F expression within CCR6+ cells correlated significantly with IFIG expression. In addition, we found significant correlation between B-cell activating factor of the tumor necrosis family (BAFF)-a factor strongly correlating with IFN type I - and IL-21 producing CCR6+ cells.Conclusions: We show for the first time higher percentages of IL-17A and IL-17A/IL-17F double-producing CCR6+ memory T-helper cells in IFN+ SLE patients, supporting the hypothesis that IFN type I co-acts with Th17 cytokines in SLE pathogenesis

Het integriteitsvraagstuk in de moderne sport als ‘learning journey’

Dit artikel bevat een sport-filosofische analyse om te komen tot een alternatieve duiding van de diverse criminaliteits-/ integriteitsvraagstukken in de sport. Vanuit een ethische reflectie op meta-niveau wordt de systemische dimensie van de integriteitscrisis in de sport onthuld. Gevolgd door een antwoord op de vraag, hoe verantwoordelijkheden (niet) belegd zijn in dit publieke domein: de dynamiek tussen landelijke beleidspartners in de sport, sportbonden, de diverse overheidslagen en andere relevante partijen. Het artikel adresseert de terughoudendheid / weerstand in de sport om pro-actief tegen risico’s / problemen in actie te komen, en partijen van buiten daarbij te betrekken. Maar de recente maatschappelijke aandacht voor integriteitsthema’s zorgen toch ook hier voor verschuivingen

Ungrounding Homo Ludens: On Agamben and Modern Sports

In this paper, I argue that the central ontological presupposition in the philosophy of sport is the ‘sport-as-play’ paradigm. In reconstructing its archaeological origins, a normative narrative is uncovered in which ‘play’ represents a creative and ‘lusory’ social practice, governed by game rules. In the philosophy of sports discourse, Homo Ludens is considered as the ideal, virtuous and innocent character, free from repressive, work-related duties or constraints. In the early works of Giorgio Agamben (1942), the conceptual pair play—ritual offers a contemporary frame of reference, rigorously different from our Homo Ludens ideal. In Agamben’s later works, the provocative Homo Sacer concept can hardly be more opposite to the utopian Homo Ludens paradigm. As Agamben states, political power in late modernity is based on a so-called ‘state-of-exception’, in which ‘bare life’ (as expressed in Homo Sacer) at first is excluded from society, but then again reincluded as an exception, in order to realize law and order. In this paper, I introduce philosophical archaeology as a promising new method in the philosophy of sport, debunking our prevailing Homo Ludens discourse. I argue that modern sports in our times—inadvertently—more and more seem to function as a ‘state-of-exception’, strengthening bio-political power

Hands, Feet, Eyes, and the Object a: A Lacanian Anatomy of Football

In this paper, we present a Lacanian perspective on football, while notably fathoming its normative dimension. Starting with a defining imperative, the prohibition against ‘handling’ or touching the ball with your hands, diverging football historically from rugby, we will subsequently focus our attention on the role of the foot, the eye (notably the eyes of the audience) and the ‘object a’ (in the context of gender). Against this backdrop, we will address pressing issues such as the troubled position of the referee (as an ‘impossible profession’), the commercialisation of football, and the rising tides of violence, match—fixing and other instances of systemic deviance. As we will argue, football exemplifies modern sport as an arena defined by prohibitions and desire, by inclusion and exclusion, by purity and abuse, culminating in recent challenges involved in gender trouble. Symbolical practices, like modern football, are based on in- and exclusion. Instead of more regulations and dichotomies, we advocate careful attention to the delicate art of handling desire in practice

Sport and Politics in the Twenty-First Century

In this article, we address the aporia(s) of the Olympic discourse produced by the troubled split between sport and politics. To start our argument, we will show that sporting governing bodies continuously insist that they are still on the other side of any kind of politics. Guided by Aristotle, who presented the reciprocity of ethics and politics, we will unveil the fallacy of this discourse. In a short genealogy of the relationship between sport, ethics, and politics, we will highlight the Munich Olympics 1936 and Mexico Olympics 1968, where political engagement of sport was exposed clearly. At the same time, the supposed political neutrality of sport manifested an aristocratic preference for radical right regimes. After that, we will analyse the contemporary relation between sport, ethics, and politics in the light of recent developments, including sport’s ambiguous reaction on the Ukraine war. Further argument will be that sport’s in- and external politics, supported by sport ethics and the inherited mantra of the split between sport and politics, is more than just a hypocrisy. At the start, modern sport claims autonomy of governance to keep away from state domination, yet this very autonomy also freezes sport’s ethical core, forbidding athletes, coaches and others active in sport, to express any political engagement, other than passive acceptance of the regulation by governing sport bodies, as the only politics to be respected without deliberation. In the final part an alternative understanding of the dynamics between politics, the political and sport’s ethical core, will be presented to be included in the philosophy of sport and fully developed in following articles

T-helper 17 cell cytokines and interferon type I: Partners in crime in systemic lupus erythematosus?

Introduction: A hallmark of systemic autoimmune diseases like systemic lupus erythematosus (SLE) is the increased expression of interferon (IFN) type I inducible genes, so-called IFN type I signature. Recently, T-helper 17 subset (Th17 cells), which produces IL-17A, IL-17F, IL-21, and IL-22, has been implicated in SLE. As CCR6 enriches for Th17 cells, we used this approach to investigate whether CCR6+ memory T-helper cells producing IL-17A, IL-17F, IL-21, and/or IL-22 are increased in SLE patients and whether this increase is related to the presence of IFN type I signature.Methods: In total, 25 SLE patients and 15 healthy controls (HCs) were included. SLE patients were divided into IFN type I signature-positive (IFN+) (n = 16) and negative (IFN-) (n = 9) patients, as assessed by mRNA expression of IFN-inducible genes (IFIGs) in monocytes. Expression of IL-17A, IL-17F, IL-21, and IL-22 by CD4+CD45RO+CCR6+ T cells (CCR6+ cells) was measured with flow cytometry and compared between IFN+, IFN- patients and HCs.Results: Increased percentages of IL-17A and IL-17A/IL-17F double-producing CCR6+ cells were observed in IFN+ patients compared with IFN- patients and HCs. IL-17A and IL-17F expression within CCR6+ cells correlated significantly with IFIG expression. In addition, we found significant correlation between B-cell activating factor of the tumor necrosis family (BAFF)-a factor strongly correlating with IFN type I - and IL-21 producing CCR6+ cells.Conclusions: We show for the first time higher percentages of IL-17A and IL-17A/IL-17F double-producing CCR6+ memory T-helper cells in IFN+ SLE patients, supporting the hypothesis that IFN type I co-acts with Th17 cytokines in SLE pathogenesis

Increased Tregs associated with elevated Indoleamine-2,3-dioxygenase activity and an imbalanced Kynurenine pathway in IFNpositive primary Sjögren's syndrome

Introduction Indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme converting tryptophan (TRP) to kynurenine (KYN), is driven in part by type I/II IFNs. Naïve T cells are polarized into FoxP3+ regulatory T cells (Tregs) upon exposure to either IDO+ cells or KYN. Recent studies suggest the KYN pathway to reflect a crucial interface between the immune and nervous system. Here we hypothesized an increase in Tregs, in conjunction with increased IDO activity, in IFN signature positive primary Sjögren's syndrome (pSS) patients and investigated the downstream KYN pathway. Methods Serum of 71 Healthy controls (HC), 58 IFNnegative (IFNneg) and 66 IFNpositive (IFNpos) pSS patients was analyzed using HPLC, for TRP and KYN levels. CD14+ monocyte mRNA-expression of IDO and downstream enzymes in the KYN pathway were assessed using real-time quantitative PCR. CD4+CD45RO+T helper (Th) memory cell populations were analyzed by flow cytometry. Results IDO activity (KYN/TRP-ratio; p=0.0054) and percentage of CD25hiFoxP3+Tregs (p=0.039) were significantly increased in IFNpos pSS, and correlated significantly (p=0.002;r=0.509). Circulating IFNpos pSS monocytes upregulated IDO1-expression (p<0.0001), which correlated with the IFNscore (p<0.0001;r=0.816). Interestingly, the pro-apoptotic and neurotoxic downstream enzyme KMO (p=0.0057) was upregulated, whereas KATI (p=0.0003), KATIII (p=0.016) and KATIV (p=0.04) were downregulated in IFNpos pSS compared to HC. Conclusion Here we find enhanced IDO activity in conjunction with increased CD25hiFoxP3+Tregs, and identify an imbalanced KYN pathway with evidence for a shift towards potentially more pro-apoptotic and neurotoxic metabolites in IFNpos pSS patients. Intervening in these IFN and IDO-induced imbalances offers a new array of possibilities for therapeutic interventions in pSS. This article is protected by copyright. All rights reserved