IL-6 can mediate proinflammatory effects, and IL-6 receptor (IL-6R) blockade as a treatment for inflammatory diseases has entered clinical practice. However, opposing effects of IL-6 have been ...observed in models of GN. Although IL-6 is proinflammatory in murine lupus nephritis, protective effects have been observed for IL-6 in the nephrotoxic nephritis (NTN) model of acute crescentic GN. In light of the potential dangers of IL-6-directed treatment, we studied the mechanisms underlying the contradictory findings in GN. IL-6 can signal through the membrane-bound IL-6R, which is expressed only on hepatocytes and certain leukocytes (classic), or through the soluble IL-6R, which binds the ubiquitously expressed gp130 (alternative). Preemptive treatment of mice with anti-IL-6R or anti-IL-6 worsened NTN, whereas selective blockade of alternative IL-6 signaling by the fusion protein sgp130Fc did not. FACS analysis of mouse spleen cells revealed proinflammatory macrophages express the highest levels of IL-6Rα, and in vitro treatment with IL-6 blocked macrophage proliferation. Furthermore, proinflammatory macrophages were expanded during inflammation in IL-6(-/-) mice. Late application of anti-IL-6 after establishment of adaptive nephritogenic immunity was sufficient to aggravate NTN within 2.5 days, a period when macrophages are active. Finally, NTN was aggravated in mice with macrophage-specific impairment of IL-6 classic signaling, coincident with enhanced macrophage proliferation and accumulation in the kidney. Our data thus reveal a novel mechanism in which IL-6-mediated dampening of macrophage activation protects tissues from overshooting immune responses. This finding has important implications for potential IL-6-directed therapies and supports the careful choice of recipient patients and timing.
Systemic lupus erythematosus (SLE) is a complex and potentially fatal autoimmune disorder. Although Th17 cells are thought to be central mediators of SLE, mechanisms underlying their counter ...regulation remain largely unknown. To help define this, we studied the function of the newly defined Stat3-dependent Th17-specific regulatory T cells (Treg17). Treg-specific deletion of Stat3 was achieved by generating Foxp3Cre × Stat3fl/fl mice and SLE was induced by intraperitoneal injection of pristane. Lack of Treg17 cells in these mice caused selectively enhanced peritoneal Th17 inflammation. Importantly, Treg17 deficiency also resulted in aggravated pulmonary vasculitis with increased percentages of Th17 cells and significantly higher mortality. Similarly, 4 and 9 months after pristane injection, analysis of renal and systemic immunity showed overshooting Th17 responses in the absence of Treg17 cells, associated with the aggravation of lupus nephritis. Expression of the Th17 characteristic trafficking receptor CCR6 was strikingly reduced on Tregs of Foxp3Cre × Stat3fl/fl mice, resulting in impaired renal Treg infiltration. Thus, Stat3-induced Treg17 cells are novel antiinflammatory mediators of SLE. One mechanism enabling Treg17 cells to target pathogenic Th17 responses is shared expression of the chemokine receptor CCR6.
Cells expressing both the regulatory T cell (Treg)-inducing transcription factor Foxp3 and the Th17 transcription factor RORγt have been identified (biTregs). It is unclear whether RORγt(+)Foxp3(+) ...biTregs belong to the Th17-specific Treg17 cells, represent intermediates during Treg/Th17 transdifferentiation, or constitute a distinct cell lineage. Because the role of biTregs in inflammatory renal disease is also unknown, we studied these cells in the nephrotoxic nephritis (NTN) model of acute crescentic GN. Induction of NTN resulted in rapid renal and systemic expansion of biTregs. Notably, analyses of the biTreg expression profile revealed production of both anti-inflammatory (IL-10, IL-35) and proinflammatory (IL-17) cytokines. Additionally, biTregs expressed a signature of surface molecules and transcription factors distinct from those of Th17 cells and conventional Tregs (cTregs), and biTregs were identified in Treg17-deficient mice. Finally, fate reporter and cell transfer studies confirmed that biTregs are not Treg/Th17 transdifferentiating cells. Therapeutic transfer of biTregs suppressed the development of nephritis to an extent similar to that observed with transferred cTregs, but in vitro studies indicated different mechanisms of immunosuppression for biTregs and cTregs. Intriguingely, as predicted from their cytokine profile, endogenous biTregs displayed additional proinflammatory functions in NTN that were abrogated by cell-specific deletion of RORγt. In summary, we provide evidence that RORγt(+)Foxp3(+) biTregs are a novel and independent bifunctional regulatory T cell lineage distinct from cTregs, Treg17 cells, and Th17 cells. Furthermore, biTregs appear to contribute to crescentic GN and hence may be novel therapeutic targets.
A pathogenic role for Th17 cells in inflammatory renal disease is well established. The mechanisms underlying their counter-regulation are, however, largely unknown. Recently, Th17 lineage-specific ...regulatory T cells (Treg17) that depend on activation of the transcription factor Stat3 were identified. We studied the function of Treg17 in the nephrotoxic nephritis (NTN) model of crescentic GN. The absence of Treg17 cells in Foxp3(Cre)×Stat3(fl/fl) mice resulted in the aggravation of NTN and skewing of renal and systemic immune responses toward Th17. Detailed analysis of Stat3-deficient Tregs revealed that the survival, activation, proliferation, and suppressive function of these cells remained intact. However, Tregs from Foxp3(Cre)×Stat3(fl/fl) mice lacked surface expression of the chemokine receptor CCR6, which resulted in impaired renal trafficking. Furthermore, aggravation of NTN was reversible in the absence of Th17 responses, as shown in CD4(Cre)×Stat3(fl/fl) mice lacking both Treg17 and Th17 cells, suggesting that Th17 cells are indeed the major target of Treg17 cells. Notably, immunohistochemistry revealed CCR6-bearing Treg17 cells in kidney biopsy specimens of patients with GN. CCR6 expression on human Treg17 cells also appears dependent on STAT3, as shown by analysis of Tregs from patients with dominant-negative STAT3 mutations. Our data indicate the presence and involvement of Stat3/STAT3-dependent Treg17 cells that specifically target Th17 cells in murine and human crescentic GN, and suggest the kidney-specific action of these Treg17 cells is regulated by CCR6-directed migration into areas of Th17 inflammation.
IL‐10‐secreting regulatory B cells have been postulated as negative mediators of inflammation. However, their impact on immune‐mediated diseases requires further investigation. We recently found that ...IL‐10‐secreting B cells infiltrate the kidney during crescentic glomerulonephritis (GN). We therefore studied the function of B‐cell‐derived IL‐10 in light of the potential risks associated with increasingly used B‐cell depleting therapies. Lack of IL‐10 production by B cells, however, did not influence acute or adaptively mediated progressive renal injury in terms of renal function and histological damage in the nephrotoxic nephritis model of GN. Renal leukocyte infiltration and cytokine expression were similar apart from increased macrophages in mice lacking B‐cell‐derived IL‐10. Systemic immune responses as assessed by cytokine production, leukocyte composition, proliferation, and activation were indistinguishable, while production and renal deposition of Ag‐specific IgG were mildly impaired in the absence of B‐cell‐produced IL‐10. Importantly, detailed analysis of systemic and renal regulatory T cells did not show any differences between nephritic mice bearing IL‐10‐deficient B cells and WT controls. Finally, studies in reporter mice revealed that B cells are only a minor source of systemic IL‐10. In summary, our data reveal that endogenous B‐cell‐derived IL‐10 does not play a major role in the nephrotoxic nephritis model of crescentic GN.
Purpose
Team handball is associated with a high risk of severe knee injury that needs to be reduced, particularly at the youth level. The purpose of this study was to show how an injury-prevention ...programme effectively reduces severe knee injury in adolescent team handball players.
Methods
Of 23 adolescent handball teams of both sexes, 13 were randomly allocated into the intervention group (168 players) and 10 into the control group (111 players). Players of the intervention group regularly participated in an injury-prevention programme for one season. Handball exposure and sustained injuries were documented for both groups on a monthly basis. The primary outcome parameter of the injury-prevention programme was the incidence of severe knee injury.
Results
Of the 279 included players, 68 (24%) sustained 82 injuries yielding an overall incidence of 1.85 injuries per 1000 h handball exposure (intervention group: 50 injuries/incidence: 1.90/1000 h; control group: 32 injuries/incidence: 1.78/1000 h). Knee injury was the second most frequent injury in adolescent team handball. The primary outcome parameter, severe knee injury occurred significantly more often in the control group mean age (SD) 15.1 (1.0), injury incidence 0.33/1000 h than in the intervention group mean age (SD) 14.9 (0.9), injury incidence 0.04/1000 h. The odds ratio was 0.11 (95% CI 0.01–0.90),
p
= 0.019. Other injuries to the lower extremities showed no significant difference between the two groups.
Conclusions
Frequent neuromuscular exercises prevent severe knee injury in adolescent team handball players and should thus be included in the practical routine as well as in the education of team coaches.
Purpose
Scientific injury data in men’s professional team handball injuries are rare and even less scientific information exists on injury prevention. In 2011, Germany’s national second team handball ...league was restructured by merging the existing two regional leagues into one league. This study evaluates the injury patterns in professional team handball and compares the injury rates between the first and second league before and after the restructure.
Methods
All players of Germany’s national first and second men’s team handball leagues have mandatory trauma insurance with the same insurance company. This retrospective cohort study analysed the injury data of three consecutive seasons 2010–2013 using standardized injury definitions.
Results
1194 professional team handball players were included in this study. The majority of severe injuries affected the lower extremities, shoulders, and hands. The average injury incidence significantly differed between the first (4.9 injuries per 1000 h) and the second league (3.9 per 1000 h,
p
< 0.01). The injury incidence in the restructured second league had increased from 3.7 to 4.1 per 1000 h (
p
< 0.01) and prevalence from 67.1 to 79.3% (
p
< 0.001), thus almost to the same levels of the first league. The second league showed more time-loss injuries at all severity levels.
Conclusion
This study yielded a high injury incidence after the restructure of the national second team handball league and presents details on prevalence, incidence, and patterns of injury in professional men’s team handball. This study is an important basis for developing injury prevention strategies that should focus on the shoulders, hands, and lower extremities and on reducing the number of matches and travel burden.
Level of evidence
III.
To compare survival rates and age at death among very preterm infants in 10 national and regional neonatal networks.
A cohort study of very preterm infants, born between 24 and 29 weeks' gestation ...and weighing <1500 g, admitted to participating neonatal units between 2007 and 2013 in the International Network for Evaluating Outcomes of Neonates. Survival was compared by using standardized ratios (SRs) comparing survival in each network to the survival estimate of the whole population.
Network populations differed with respect to rates of cesarean birth, exposure to antenatal steroids and birth in nontertiary hospitals. Network SRs for survival were highest in Japan (SR: 1.10; 99% confidence interval: 1.08-1.13) and lowest in Spain (SR: 0.88; 99% confidence interval: 0.85-0.90). The overall survival differed from 78% to 93% among networks, the difference being highest at 24 weeks' gestation (range 35%-84%). Survival rates increased and differences between networks diminished with increasing gestational age (GA) (range 92%-98% at 29 weeks' gestation); yet, relative differences in survival followed a similar pattern at all GAs. The median age at death varied from 4 days to 13 days across networks.
The network ranking of survival rates for very preterm infants remained largely unchanged as GA increased; however, survival rates showed marked variations at lower GAs. The median age at death also varied among networks. These findings warrant further assessment of the representativeness of the study populations, organization of perinatal services, national guidelines, philosophy of care at extreme GAs, and resources used for decision-making.
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