CD40 is constitutively expressed on platelets and provides a novel mechanism for platelet activation

CD40 is a 48-kDa phosphorylated transmembrane glycoprotein belonging to the TNF receptor superfamily. CD40 has been demonstrated on a range of cell types, and it has an important role in adaptive immunity and inflammation. CD40 has recently been described on platelets but platelet activation by CD40 has not been described. In the present study, we use flow cytometry and immunoblotting to confirm that platelets constitutively express surface CD40. CD40 mRNA was undetectable, suggesting that the protein is synthesized early in platelet differentiation by megakaryocytes. Ligation of platelet CD40 with recombinant soluble CD40L trimer (sCD40LT) caused increased platelet CD62P expression, -granule and dense granule release, and the classical morphological changes associated with platelet activation. CD40 ligation also caused ß3 integrin activation, although this was not accompanied by platelet aggregation. These actions were abrogated by the CD40L blocking antibody TRAP-1 and the CD40 blocking antibodies M2 and M3, showing that activation was mediated by CD40L binding to platelet CD40. ß3 integrin blockade with eptifibatide had no effect, indicating that outside-in signaling via IIbß3 was not contributing to these CD40-mediated effects. CD40 ligation led to enhanced platelet-leukocyte adhesion, which is important in the recruitment of leukocytes to sites of thrombosis or inflammation. Our results support a role for CD40-mediated platelet activation in thrombosis, inflammation, and atherosclerosis

T-lymphocyte activation in steroid-sensitive nephrotic syndrome in childhood

We undertook a sequential study in 29 children with steroid-sensitive nephrotic syndrome (SSNS) off treatment to seek evidence for T-cell activation in relapse. T-cell subsets and activation markers were analysed using two-colour flow cytometry. Soluble IL2 receptor (sIL2R) was measured in serum and urine by enzyme-linked immunosorbent assay (ELISA). Fifteen children were examined in remission and subsequent relapse (group A) and fourteen remained in remission (group B). In group A the proportion of CD4+ cells expressing the activation marker CD25 (alpha-chain of the IL2 receptor) increased significantly from remission to relapse: CD4+25+ cells rose from 5.6 to 7.0% of total lymphocytes, and from 15.8 to 19.1% of CD4+ lymphocytes (paired t test: P<0.0005 and <0.001 respectively). No correlations were found between CD4+25+ cells and plasma albumin or cholesterol concentrations. SIL2R concentration in serum did not change in relapse, but increased significantly in urine from 272 to 592 U/mg creatinine (P<0.01). No significant difference was found in remission between groups A and B. We conclude that early relapse in SSNS is associated with activation of CD4+ (T-helper) cells which is not secondary due to the nephrotic state itsel

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury