Read on Twitter
reading more into dynamics of 'sepsis' - which do vary a little by source and organism, but generally a period of intense aggression is followed by immune paresis - predisposing to nosocomial infections. In some quarters, people feel this is a natural brake on
the immune response - i.e. part of a balancing act. Immune tolerance is the phrase often coined. From a cell biology point of view, various innate cells reduce expression of HLA-DR (a naughty contender in auto immune diseases), and attacking T cells very much start to disappear
in favour of T reg cells and memory cells. Similarly, other lymphocytes like B cells may start to calm down. One of the most striking changes in the 'immune paresis' stage post septic shock is the upregulation of a protein called PD-1 (programmed death receptor 1 natch)
which asks all the T cells to calm down/die. But what I find most interesting is that the cell biology motifs seen in the normal course of sepsis/immune paresis stage, are closely matched by the phenotype of the ageing immune system
indeed, anti PD-1 is a modulator therapy for improving microbial clearance and survival from septic shock in animals. In humans, there is an age-determined response to anti PD1 (we are saying the elderly have too much PD1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324578/
Some references for above https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4056426/
Furthermore what I like, is that clearly there are upstream regulators of PD-1, which demonstrate the susceptibility of certain individuals to sepsis - for example, an intact cell clock (BMAL-1) - not the pineal gland - reduces PD-1 activation
whilst glycolysis and lactate enhance it....interestingly the fundamental importance of what seems an unhelpful molecule (PD-1) is demonstrated in the fact that when inhibited it predisposes to auto immune disease
such as destruction of beta cells = type 1 diabetes. I have started to come round to the idea we need the immunosuppression following hyper inflamm in sepsis and trauma, and will just have to deal with the nosocomial infections!
how can we mimic immune tolerance as a part of a healthy immune system? The usual - exercise (which releases Il-6/TNFa btw! ... and a PD-1 ligand) https://www.sciencedirect.com/science/article/pii/S2666354620300144
Obviously we do it all the time with steroids AND BY THE WAY NOT ALL STEROIDS HAVE THE SAME T CELL EFFECT!!!!!!!!!!! dex is v v epigenetic https://link.springer.com/article/10.1007/s00262-020-02555-2
how do we keep bmal 1 (cell clock) intact? Exercise, fasting, proper sleep in sync with sunlight, and not feeding people round the clock. 
