The CD3ζ forms part of the T cell receptor (TCR) where it plays an important role in coupling antigen recognition to several intracellular signal-transduction pathways leading to T cell effector functions. Down regulation of CD3ζ leads to impairment of immune responses including reduced cell proliferation and cytokine production. In experimental models, helminth parasites have been shown to modulate immune responses directed against them and unrelated antigens, so called bystander antigens, but there is a lack of studies validating these observations in humans. This study investigated the relationship between expression levels of the TCR CD3ζ chain with lymphocyte cell proliferation during human infection with the helminth parasite, Schistosoma haematobium, which causes uro-genital schistosomiasis. Using flow cytometry, peripheral blood mononuclear cells (PBMCs) from individuals naturally exposed to S. haematobium in rural Zimbabwe were phenotyped, and expression levels of CD3ζ on T cells were related to intensity of infection. In this population, parasite infection intensity was inversely related to CD3ζ expression levels (p < 0.05), consistent with downregulation of CD3ζ expression during helminth infection. Furthermore, PBMC proliferation was positively related to expression levels of CD3ζ (p < 0.05) after allowing for confounding variables (host age, sex, and infection level). CD3ζ expression levels had a differing relationship between immune correlates of susceptibility and immunity, measured by antibody responses, indicating a complex relationship between immune activation status and immunity. The relationships between the CD3ζ chain of the TCR and schistosome infection, PBMC proliferation and schistosome-specific antibody responses have not previously been reported, and these results may indicate a mechanism for the impaired T cell proliferative responses observed during human schistosome infection.
Vancomycin remains a useful agent in the infection doctor’s toolkit, particularly for Staphylococcus aureus and MRSA infections. Therapeutic drug monitoring (TDM) is essential to maintain efficacy and avoid toxicity. Until recently, trough-based dosing has been the recommended method but in recent years the reliability of this has been questioned. The 2020 Infectious Diseases Society of America (IDSA) vancomycin guideline update has sent a clear message that trough-based dosing is not to be relied on, instead recommending dosing via 24 h AUC/MIC. The UK, however, has yet to follow suit in this, despite the wealth of evidence showing that trough-based dosing puts patients at higher risk of nephrotoxicity. Clearly, it is time to incorporate AUC/MIC-based dosing to utilize this effective antibiotic safely.
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