Abstract
Evaluation of sepsis-induced immunoparalysis has highlighted how decreased lymphocyte number/function contribute to worsened infection/cancer. Yet, an interesting contrast exists with autoimmune disease development, wherein diminishing pathogenic effectors may benefit the post-septic host. Within this framework, the impact of cecal ligation and puncture (CLP)-induced sepsis on the development of experimental autoimmune encephalomyelitis (EAE) was explored. Notably, CLP mice have delayed onset and reduced disease severity, relative to sham mice. Reduction in disease severity was associated with reduced number, but not function, of autoantigen (MOG)-specific pathogenic CD4 T cells in the CNS during disease and draining lymph node during priming. Numerical deficits of CD4 T cell effectors are associated with the loss of MOG-specific naive precursors. Critically, transfer of MOG-TCR transgenic (2D2) CD4 T cells after, but not before, CLP led to EAE disease equivalent to sham mice. Thus, broad impairment of antigenic responses, including autoantigens, is a hallmark of sepsis-induced immunoparalysis.
Highlights
Sepsis poses both a significant health concern, affecting 1.7 million and killing 270,000 Americans yearly, and economic burden (> $20 billion annually) (CDC, 2020)
cecal ligation and puncture (CLP) effectively mimics the pathophysiology of acute peritonitis and corresponding septic inflammation, with the capacity to modulate disease severity through adjustment of surgical parameters (Dejager et al, 2011; Sjaastad et al, 2020a)
The sepsis-induced cytokine storm remains a life-threatening condition, it has become apparent that the aftermath of the septic event leads to significant changes in the immune systems of individuals who survive
Summary
Sepsis poses both a significant health concern, affecting 1.7 million and killing 270,000 Americans yearly, and economic burden (> $20 billion annually) (CDC, 2020). Emphasis has been strongly shifted toward determining the mechanisms by which sepsis impairs the immune response to subsequent infection or cancer (Chen et al, 2019; Condotta et al, 2015; Condotta et al, 2013; Danahy et al, 2019a; Jensen et al, 2018b). Sepsis can impair antigen-specific T cell responses through various cell extrinsic factors, including diminished number/function of dendritic cells (DCs) and diminished capacity of endothelial cells to promote chemotaxis (Danahy et al, 2017; Strother et al, 2016) These findings suggest that, while detrimental to control of pathogens/cancer, sepsis may alternately diminish a host’s capacity to develop autoimmunity. These data further define how the sepsis-induced immunoparalysis reduces host capacity to generate antigen-specific responses, regardless of whether it is a foreign antigen or an endogenous autoantigen
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