The role of self-reactivity in regulatory T cell development and acquisition of diverse regulatory activities

The importance of regulatory T cells (Tregs) in maintaining lymphocyte homeostasis is best appreciated in mice and humans lacking these cells. FoxP3 KO (scurfy) mice and patients with immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome suffer from excessive lymphocyte activation, lymphocytic infiltration into peripheral organs, and colitis leading to death at an early age. In healthy mice and humans, Tregs control homeostatic proliferation of conventional T and B cells and prevent colitis. Tregs have been classified based on their activation status, expression of surface markers and their ability to migrate to certain tissues. In humans, the proportion of activated and resting Tregs vary with age and the presence immunological disorders. While Tregs have been shown to express self-reactive and foreign-antigen reactive T cell receptors (TCRs), it’s not clear how their antigen specificity determines their regulatory function. In this study, we identified two Treg cell populations, which are differentially selected, based on their affinity for self-antigens; we further investigate their self- reactivity in vitro and assessed their different regulatory properties using three disease models in vivo

Junctional adhesion molecule (JAM)-C deficient C57BL/6 mice develop a severe hydrocephalus

The junctional adhesion molecule (JAM)-C is a widely expressed adhesion molecule regulating cell adhesion, cell polarity and inflammation. JAM-C expression and function in the central nervous system (CNS) has been poorly characterized to date. Here we show that JAM-C−/− mice backcrossed onto the C57BL/6 genetic background developed a severe hydrocephalus. An in depth immunohistochemical study revealed specific immunostaining for JAM-C in vascular endothelial cells in the CNS parenchyma, the meninges and in the choroid plexus of healthy C57BL/6 mice. Additional JAM-C immunostaining was detected on ependymal cells lining the ventricles and on choroid plexus epithelial cells. Despite the presence of hemorrhages in the brains of JAM-C−/− mice, our study demonstrates that development of the hydrocephalus was not due to a vascular function of JAM-C as endothelial re-expression of JAM-C failed to rescue the hydrocephalus phenotype of JAM-C−/− C57BL/6 mice. Evaluation of cerebrospinal fluid (CSF) circulation within the ventricular system of JAM-C−/− mice excluded occlusion of the cerebral aqueduct as the cause of hydrocephalus development but showed the acquisition of a block or reduction of CSF drainage from the lateral to the 3rd ventricle in JAM-C−/− C57BL/6 mice. Taken together, our study suggests that JAM-C−/− C57BL/6 mice model the important role for JAM-C in brain development and CSF homeostasis as recently observed in humans with a loss-of-function mutation in JAM-C

Affinity for self antigen selects T_reg cells with distinct functional properties

The manner in which regulatory T cells (Treg cells) control lymphocyte homeostasis is not fully understood. We identified two Treg cell populations with differing degrees of self-reactivity and distinct regulatory functions. We found that GITR(hi)PD-1(hi)CD25(hi) (Triple(hi)) Treg cells were highly self-reactive and controlled lympho-proliferation in peripheral lymph nodes. GITR(lo)PD-1(lo)CD25(lo) (Triple(lo)) Treg cells were less self-reactive and limited the development of colitis by promoting the conversion of CD4(+) Tconv cells into induced Treg cells (iTreg cells). Although Foxp3-deficient (Scurfy) mice lacked Treg cells, they contained Triple(hi)-like and Triple(lo)-like CD4(+) T cells zsuper< T cells infiltrated the skin, whereas Scurfy Triple(lo)CD4(+) T cells induced colitis and wasting disease. These findings indicate that the affinity of the T cell antigen receptor for self antigen drives the differentiation of Treg cells into distinct subsets with non-overlapping regulatory activities

Relationship between molecular pathogen detection and clinical disease in febrile children across Europe: a multicentre, prospective observational study

BackgroundThe PERFORM study aimed to understand causes of febrile childhood illness by comparing molecular pathogen detection with current clinical practice.MethodsFebrile children and controls were recruited on presentation to hospital in 9 European countries 2016-2020. Each child was assigned a standardized diagnostic category based on retrospective review of local clinical and microbiological data. Subsequently, centralised molecular tests (CMTs) for 19 respiratory and 27 blood pathogens were performed.FindingsOf 4611 febrile children, 643 (14%) were classified as definite bacterial infection (DB), 491 (11%) as definite viral infection (DV), and 3477 (75%) had uncertain aetiology. 1061 controls without infection were recruited. CMTs detected blood bacteria more frequently in DB than DV cases for N. meningitidis (OR: 3.37, 95% CI: 1.92-5.99), S. pneumoniae (OR: 3.89, 95% CI: 2.07-7.59), Group A streptococcus (OR 2.73, 95% CI 1.13-6.09) and E. coli (OR 2.7, 95% CI 1.02-6.71). Respiratory viruses were more common in febrile children than controls, but only influenza A (OR 0.24, 95% CI 0.11-0.46), influenza B (OR 0.12, 95% CI 0.02-0.37) and RSV (OR 0.16, 95% CI: 0.06-0.36) were less common in DB than DV cases. Of 16 blood viruses, enterovirus (OR 0.43, 95% CI 0.23-0.72) and EBV (OR 0.71, 95% CI 0.56-0.90) were detected less often in DB than DV cases. Combined local diagnostics and CMTs respectively detected blood viruses and respiratory viruses in 360 (56%) and 161 (25%) of DB cases, and virus detection ruled-out bacterial infection poorly, with predictive values of 0.64 and 0.68 respectively.InterpretationMost febrile children cannot be conclusively defined as having bacterial or viral infection when molecular tests supplement conventional approaches. Viruses are detected in most patients with bacterial infections, and the clinical value of individual pathogen detection in determining treatment is low. New approaches are needed to help determine which febrile children require antibiotics.FundingEU Horizon 2020 grant 668303

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Qualität der Zusammenarbeit zwischen Tandems von PH-Dozierenden und Praxis-Dozierenden?

Kongress der Schweizerischen Gesellschaft für Bildungsforschung (SGBF), Biel, 01. September 2020 (online

Junctional adhesion molecule (JAM)-C deficient C57BL/6 mice develop a severe hydrocephalus

The junctional adhesion molecule (JAM)-C is a widely expressed adhesion molecule regulating cell adhesion, cell polarity and inflammation. JAM-C expression and function in the central nervous system (CNS) has been poorly characterized to date. Here we show that JAM-C(-/-) mice backcrossed onto the C57BL/6 genetic background developed a severe hydrocephalus. An in depth immunohistochemical study revealed specific immunostaining for JAM-C in vascular endothelial cells in the CNS parenchyma, the meninges and in the choroid plexus of healthy C57BL/6 mice. Additional JAM-C immunostaining was detected on ependymal cells lining the ventricles and on choroid plexus epithelial cells. Despite the presence of hemorrhages in the brains of JAM-C(-/-) mice, our study demonstrates that development of the hydrocephalus was not due to a vascular function of JAM-C as endothelial re-expression of JAM-C failed to rescue the hydrocephalus phenotype of JAM-C(-/-) C57BL/6 mice. Evaluation of cerebrospinal fluid (CSF) circulation within the ventricular system of JAM-C(-/-) mice excluded occlusion of the cerebral aqueduct as the cause of hydrocephalus development but showed the acquisition of a block or reduction of CSF drainage from the lateral to the 3(rd) ventricle in JAM-C(-/-) C57BL/6 mice. Taken together, our study suggests that JAM-C(-/-) C57BL/6 mice model the important role for JAM-C in brain development and CSF homeostasis as recently observed in humans with a loss-of-function mutation in JAM-C

Backtracing persistent biomarker shifts to the age of onset: A novel procedure applied to men’s and women’s white blood cell counts in post-traumatic stress disorder

Background: Traumatic experiences tend to be preserved in altered biomarker profiles. These profiles can be traced back from cross-sectional data regarding the age of exposure. Consequently, the change across developmental stages, e.g. from childhood to adulthood, can also be reconstructed. This study introduces a backtrace procedure that is illustrated using white blood cell (WBC) counts in full / partial post-traumatic stress disorder (PTSD). The procedure was applied separately on men's and women's data to provide a replication of the analysis based on different subsamples. Methods: The analysis was carried out with data from the CoLaus|PsyCoLaus study (N = 5111, 2370 men and 2741 women, age range 35–88 years). It was restricted to traumatic experiences that occurred until the age of 35, i.e., the lower age limit of the sample. The WBC counts from up to two assessments were standardized, pooled and assigned to the reported age of trauma exposure. This resulted in age series for each marker, whereas the reference values were based on subjects who did not experience any trauma exposure. The backtrace procedure ascertained the peaks and troughs of the age series and determined the best-fitting critical age range surrounding each peak or trough based on the best p-value from simple t-tests. Results: In CoLaus|PsyCoLaus, 750 participants reported trauma exposure until the age of 35, and 86 (out of 329) men and 187 (out of 421) women thereof were coded with a full or partial PTSD. Full / partial PTSD after trauma exposure in childhood was characterized by increased WBC counts (lymphocytes, eosinophils – in women also neutrophils). This pattern was partly retained during adolescence, in men due to eosinophils counts and in women due to lymphocyte counts. For exposure in young adulthood, the deviations were in the negative direction – in men with decreased basophils, in women with decreased lymphocytes and monocytes. Conclusions: Summarizing, the backtrace approach revealed WBC profiles in PTSD that were specific to particular developmental age stages. The strongest persistent upregulation of the immune system related to trauma exposure was traceable to childhood / early adolescence both in men and in women. Further research will show which biomarkers are similarly suitable for backtracing as WBC counts. As in PTSD, the backtrace approach could also be applied to identifying persistent biomarker profiles in other mental disorders, as well as autoimmune and other chronic diseases