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Involvement of an IgE/Mast cell/B cell amplification loop in abdominal aortic aneurysm progression

by Alexia Loste, Marc Clément, Sandrine Delbosc, Kevin Guedj, Jean Sénémaud, Anh-Thu Gaston, Marion Morvan, Guillaume Even, Grégory Gautier, Alexander Eggel, Michel Arock, Emanuele Procopio, Catherine Deschildre, Liliane Louedec, Jean-Baptiste Michel, Lydia Deschamps, Yves Castier, Raphaël Coscas, Jean-Marc Alsac, Pierre Launay, Giuseppina Caligiuri, Antonino Nicoletti, Marie Le Borgne

Aims

IgE type immunoglobulins and their specific effector cells, mast cells (MCs), are associated with abdominal aortic aneurysm (AAA) progression. In parallel, immunoglobulin-producing B cells, organised in tertiary lymphoid organs (TLOs) within the aortic wall, have also been linked to aneurysmal progression. We aimed at investigating the potential role and mechanism linking local MCs, TLO B cells, and IgE production in aneurysmal progression.

Methods and results

Through histological assays conducted on human surgical samples from AAA patients, we uncovered that activated MCs were enriched at sites of unhealed haematomas, due to subclinical aortic wall fissuring, in close proximity to adventitial IgE+ TLO B cells. Remarkably, in vitro the IgEs deriving from these samples enhanced MC production of IL-4, a cytokine which favors IgE class-switching and production by B cells. Finally, the role of MCs in aneurysmal progression was further analysed in vivo in ApoE-/- mice subjected to angiotensin II infusion aneurysm model, through MC-specific depletion after the establishment of dissecting aneurysms. MC-specific depletion improved intramural haematoma healing and reduced aneurysmal progression.

Conclusions

Our data suggest that MC located close to aortic wall fissures are activated by adventitial TLO B cell-produced IgEs and participate to their own activation by providing support for further IgE synthesis through IL-4 production. By preventing prompt repair of aortic subclinical fissures, such a runaway MC activation loop could precipitate aneurysmal progression, suggesting that MC-targeting treatments may represent an interesting adjunctive therapy for reducing AAA progression.

Intravenous immunoglobulin treatment in childhood encephalitis (IgNiTE): a randomised controlled trial

Por: Hill · M. · Iro · M. · Sadarangani · M. · Absoud · M. · Cantrell · L. · Chong · K. · Clark · C. · Easton · A. · Gray · V. · Kneen · R. · Lim · M. · Liu · X. · Pike · M. · Solomon · T. · Vincent · A. · Willis · L. · Yu · L.-M. · Pollard · A. J. · The IgNiTE study team · Pollard · Lim · Solomon
Objective

To investigate whether intravenous immunoglobulin (IVIG) improves neurological outcomes in children with encephalitis when administered early in the illness.

Design

Phase 3b multicentre, double-blind, randomised placebo-controlled trial.

Setting

Twenty-one hospitals in the UK.

Participants

Children aged 6 months to 16 years with a diagnosis of acute or subacute encephalitis, with a planned sample size of 308.

Intervention

Two doses (1 g/kg/dose) of either IVIG or matching placebo given 24–36 hours apart, in addition to standard treatment.

Main outcome measure

The primary outcome was a ‘good recovery’ at 12 months after randomisation, defined as a score of≤2 on the Paediatric Glasgow Outcome Score Extended.

Secondary outcome measures

The secondary outcomes were clinical, neurological, neuroimaging and neuropsychological results, identification of the proportion of children with immune-mediated encephalitis, and IVIG safety data.

Results

18 participants were recruited from 12 hospitals and randomised to receive either IVIG (n=10) or placebo (n=8) between 23 December 2015 and 26 September 2017. The study was terminated early following withdrawal of funding due to slower than anticipated recruitment, and therefore did not reach the predetermined sample size required to achieve the primary study objective; thus, the results are descriptive. At 12 months after randomisation, 9 of the 18 participants (IVIG n=5/10 (50%), placebo n=4/8 (50%)) made a good recovery and 5 participants (IVIG n=3/10 (30%), placebo n=2/8 (25%)) made a poor recovery. Three participants (IVIG n=1/10 (10%), placebo n=2/8 (25%)) had a new diagnosis of epilepsy during the study period. Two participants were found to have specific autoantibodies associated with autoimmune encephalitis. No serious adverse events were reported in participants receiving IVIG.

Conclusions

The IgNiTE (ImmunoglobuliN in the Treatment of Encephalitis) study findings support existing evidence of poor neurological outcomes in children with encephalitis. However, the study was halted prematurely and was therefore underpowered to evaluate the effect of early IVIG treatment compared with placebo in childhood encephalitis.

Trial registration number

Clinical Trials.gov NCT02308982; ICRCTN registry ISRCTN15791925.

The role of psychosocial factors and biological sex on rural Thai adolescents' drinking intention and behaviours: A structural equation model

Abstract

Aims

To examine the contributions of psychosocial factors (attitude towards drinking, perceived drinking norms [PDNs], perceived behavioural control [PBC]), and biological sex on drinking intention and behaviours among rural Thai adolescents.

Design

A cross-sectional study design.

Methods

In 2022, stratified by sex and grade, we randomly selected 474 rural Thai adolescents (M age = 14.5 years; SD = 0.92; 50.6% male) from eight public district schools in Chiang Mai Province, Thailand, to complete a self-administered questionnaire. Structural equation modelling with the weighted least square mean and variance adjusted was used for data analysis.

Results

All adolescents' psychosocial factors contributed significantly to the prediction of drinking intention, which subsequently influenced their drinking onset, current drinking and binge drinking pattern in the past 30 days. PDNs emerged as the strongest psychosocial predictor of drinking intention, followed by PBC. Rural adolescents' drinking intention significantly mediated the relationship between all psychosocial factors and drinking behaviours either fully or partially. The path coefficient between drinking attitude and drinking intention was significantly different between males and females.

Conclusion

Different from previous studies focus on adolescents' drinking attitude, rural Thai adolescents' PDNs play a significant role on their drinking intention and subsequently their drinking onset and patterns. This nuanced understanding supports a paradigm shift to target adolescents' perceived drinking norms as a means to delay their drinking onset and problematic drinking behaviours.

Impact

Higher levels of perceived drinking norms significantly led to the increase in drinking intention among adolescents. Minimizing adolescents' perceptions of favourable drinking norms and promoting their capacity to resist drinking, especially due to peer pressure, are recommended for nursing roles as essential components of health education campaigns and future efforts to prevent underage drinking.

Patient or Public Contribution

In this study, there was no public or patient involvement.

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