B cells biology in sepsis

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Sepsis is common, with an extrapolated critical care treated incidence of 103 per 100,000 population in 2014 in England. As critical care incidence represents a small proportion of sepsis cases treated within a health care system, making it more common than some cancers, with an estimated global case load of 16 million cases per year. The improving in hospital mortality generates more sepsis survivors, with longer-term sequelae such as increased health care use and greater risk of death compared to general population.
Immunologically, the transition from infection to sepsis represents an inflection point in the race between the human immune system devised to detect danger signals and overwhelm pathogens, ideally without causing a non-homeostatic systemic activation of immune cells. The consequence of such non-homeostatic immune system activation, characterised using whole blood leukocyte transcriptome, highlight changes in major canonical signalling pathways of cellular function, metabolism, in both innate and adaptive immune systems. Either a consequence or primary manifestation of this allostatic overload is accelerated lymphocyte apoptosis, contributing to lymphopenia seen in sepsis patients.
In contrast to T cell biology in sepsis, B cell biology is poorly characterised, despite the likely inevitability of B cell changes when there are T cell changes such as loss of helper T cells and impaired ability of T cells to respond to new antigen challenge. We measured key aspects of B cell biology in community acquired sepsis, in adults without any documented immune co-morbidity, prior to critical care admission. In this cohort, B cells are lower than normal at critical care admission, despite normal levels of B cell survival factors (BAFF and APRIL). As a proportion of total B cells, the transitional and naïve B cell subsets were similar, whilst plasmablasts and memory B cells were significantly lower, compared to age-matched health controls. The greater loss of memory loss was secondary to higher apoptosis and the apoptotic cells had greater phosphosrylated-erk mean fluorescent intensity (MFI). In addition, there was reciprocal lower MFI for CD22 without concomitant higher MFI for Bruton’s tyrosine kinase (BTK) and spleen tyrosine kinase (SYK). Using micro-array on negatively selected CD19 positive B cells, the apoptosis networks highlighted by the Ingenuity pathways analysis involved intrinsic pathway with higher expression of CASP2, CASP6, pro-apoptotic BCL2 proteins (APAF1, HTRA2, HIP1 and BOK) and death Receptor pathway with higher expression of plasma membrane death receptor (DR) genes (FAS, TNFRSF25, TNFRSF10B, TNFRSF10A, DR4, DR5 and Trail-R), DR adaptor proteins (CRADD, PIDD1 and FADD), CFLAR, CASP8 and CASP10. Thus, in sepsis, there are major alternations in B cell biology. These findings highlight potential interventions for improving both acute and for longer-term sequalae to sepsis such re-infections related to immunosuppression.