Biology subjects

Bruestle, A.

Publications and source records attributed to Bruestle, A..

3 recordsLinked to original sources

bioRxiv2025

Selective alteration to CD4 T cell differentiation by heterozygous IRF4L116R protects against neuroinflammation

The decision of naive T cells to differentiate into a specific Th cell subset after antigen encounter is a critical pivot point of the immune response and, when out of balance, can lead to autoimmunity, allergy or immunodeficiency. Th subset differentiation is determined by the expression of transcription factors including IRF4. We here describe a point mutation (IRF4L116R) in the DNA-binding domain of IRF4 leading to a dysregulation of CD4-T cell subsets and their functions. This point mutation does not alter overall protein expression. In sharp contrast to IRF4-null mice, neither the CD4/CD8 ratio nor T cell activation and memory is altered in naive mice carrying the point mutation. However, IRF4L116R T cells are reduced in their capability to differentiate into Th1, Th17 and Treg cells in a dose-dependent manner, contrasting with the findings in IRF4KO T cells. Particularly striking is the loss of Th1-differentiation in T cells from homozygous Irf4L116R/L116R mice while T cells completely lacking IRF4 show no reduction in Th1 differentiation. Furthermore, despite maintained ability to generate Th17 cells, expression of the IRF4L116R variant protects mice against disease development in the Th17 cell-dependent EAE mouse model of neuroinflammation. This contrasts with IRF4 knock-out mice, where expression of one wild-type allele of IRF4 is sufficient for full disease development. Together our results show that the L116R point mutation in IRF4 can selectively alter the differentiation and function of some CD4 T cell subsets and suggest that the L116R mutation is not a classical loss- or gain-of-function variant.

immunology↗

bioRxiv2025

Characterisation of CD4 Th subsets as well as dietary, exercise and lifestyle factors in an established Rheumatoid Arthritis cohort; pilot study.

BackgroundSex disparities in the incidence and severity of Rheumatoid Arthritis (RA) are well-documented, with females experiencing more aggressive disease and different responses to treatment. While underlying mechanisms remain elusive, immune factors and lifestyle components, such as diet and physical activity, could play a role in shaping disease outcomes. Since Th cells are key drivers of RA, this study characterised CD4 Th subset frequencies, including Th1, Th2, Th17 and Th1/17 cells, in a cohort of males and females with established RA. Considering the role of diet and lifestyle in RA development, we also evaluated participant diet and lifestyle patterns. MethodsAn observational cross-sectional cohort study profiling 39 individuals (19 RA and 20 age and sex matched controls) with no major co-morbidities was conducted. Percentages of Th1, Th2, Th17 and Th1/17 cells from peripheral blood were determined by flow cytometry as well as serum levels of RF and cytokines IL17, IFN-{gamma}, TNF-, GM-CSF, TGF-{beta}, IL-6, and CRP by ELISA. Dietary intake was assessed by Food Frequency Questionnaire (FFQ), the Dietary inflammatory Index (DII) calculated from nutrient intake. Physical activity levels were evaluated by Global Physical Activity Questionnaire (GPAQ). ResultsSex-specific differences of Th17, Th1 an Th2 cells were observed in RA groups. Males had lower levels of Th1 cells and higher levels of Th17 cells than control subjects, while females had lower levels of Th2 cells than controls. Female RA subjects had higher ratio of Th1:Th2 cells than controls, while male RA subjects had higher Th17:Th1 ratio than controls. Interestingly, circulating CD4 Th subset levels were predictive of RA in this cohort. No changes in cytokine levels were observed. The male RA group consumed 30% less carbohydrate (RA = 156g +/-57g, Control = 253g +/-59g; p=0.003), 37% less sugar (RA = 74.1g +/-29g, Control = 118g +/-33g; p=0.004) and 30% less dietary fibre (R = 33g +/-8g, Control = 48g +/-13 g; p=0.008) than the male control group. The female RA group had the lowest consumption of alcohol in comparison to female control group (RA = 0.31g, Control = 8.97g; p=0.047). Male subjects had a 4x higher DII than females (p=0.012). ConclusionsOur findings highlight potential sex-specific differences in CD4+ Th cell subsets in individuals with established RA, indicating that sex may influence immune cell composition in this disease. Furthermore, dietary components showed sex-specific consumption patterns, underscoring the potential role of tailored lifestyle interventions in modulating immune responses in RA. Evaluating immunological sex differences and dietary and lifestyle factors may be important for enhancing management strategies in RA.

immunology↗

bioRxiv2024

Alpha Synuclein Induced Immune Response Triggers Parkinson's Disease Like Symptoms

Increasing evidence suggests that Parkinsons disease is an autoimmune disorder, with findings of elevated peripheral blood mononuclear cell in patients, and antigenic properties of -synuclein driving both the innate and adaptive immunity. Yet, how the interaction of -synuclein and a specific immune response participates to Parkinsons disease ontogenesis has remained unanswered. Here, we reveal that autoimmune response to an -synuclein antigen underlies Parkinsons disease. We demonstrate that autoimmunity mediated by CD4+T cell activation with -synuclein -syn61-75 antigen is required to lead to immune cell infiltration and localized inflammation in the substantia nigra, triggering dopaminergic cell neurodegeneration and deficits in locomotion and gait kinematics. This study offers the first immune-induced mouse model that recapitulates all features of Parkinsons disease to study the mechanisms triggering disease onset. It provides the basis for temporally tracking symptom development, exploring preventive strategies and prodromal therapeutic interventions in Parkinsons Disease. In briefPeripheral -synuclein immunization causes Parkinsons disease-like symptoms in mice. Highlights- Both CD4+ T cells and -synuclein are essential for Parkinsons disease ontogenesis. - Peripheral injection of -syn61-75 induces significant CD4+ T cell infiltration in the mouse brain. - -syn61-75 immunization is associated with inflammation, -synuclein aggregation and dopaminergic cell loss in the substantia nigra pars compacta. - Levodopa-sensitive motor symptoms are detected 8 weeks following -syn61-75 immunization in mice. - This study offers a novel autoimmune -synuclein induced mouse model of Parkinsons disease.

neuroscience↗