Autoimmunity Increases Susceptibility to and Mortality from Sepsis

Abstract

We recently demonstrated how sepsis influences the subsequent development of experimental autoimmune encephalomyelitis (EAE) presented a conceptual advance in understanding the postsepsis chronic immunoparalysis state. However, the reverse scenario (autoimmunity prior to sepsis) defines a high-risk patient population whose susceptibility to sepsis remains poorly defined. In this study, we present a retrospective analysis of University of Iowa Hospital and Clinics patients demonstrating increased sepsis prevalence among multiple sclerosis (MS), relative to non-MS, patients. To interrogate how autoimmune disease influences host susceptibility to sepsis, well-established murine models of MS and sepsis and EAE and cecal ligation and puncture, respectively, were used. EAE, relative to non-EAE, mice were highly susceptible to sepsis-induced mortality with elevated cytokine storms. These results were further recapitulated in LPS and Streptococcus pneumoniae sepsis models. This work highlights both the relevance of identifying highly susceptible patient populations and expands the growing body of literature that host immune status at the time of septic insult is a potent mortality determinant. ImmunoHorizons, 2021, 5: 844-854.

Causal associations between autoimmune disease and sepsis: a two-sample Mendelian randomization study

“…[6, 7, 11] However, recent studies have yielded divergent and even contradictory ndings across different types of AID. [5,6,8,12,25] Not to mention con rming the causal relationship between AID and sepsis, which could have been achieved through MR.…”

“…MS is a central nervous system disorder involving autoimmune demyelination, which is mediated by various in ammatory cells. [5,39] The association between sepsis and MS is intricate. On one hand, sepsis has been postulated to signi cantly contribute to the development of MS, as demonstrated by a recent retrospective cohort study conducted in Taiwan, which reported a nearly threefold increased likelihood of MS development among patients with sepsis.…”

“…However, the effectiveness of treatments targeting this response has been shown to be unsuccessful in human trials. [5][6][7] In a septic condition, inadequate clearance of pathogens and toxins may lead to the escalation of a localized infection into systemic in ammation. Therefore, accurate identi cation of pathogens is crucial for the host to mount an e cient immune response against the insult.…”

“…[10] Actually, AID has been reported by several researchers to lead to worse clinical outcomes among sepsis patients as a result of the modulated immune response associated with AID and their treatment. [5][6][7]11] However, the available experimental evidences substantiating a causal relationship between AID and sepsis are limited and occasionally contradictory. Notably, a recent study conducted by Sheth et al at a single medical center suggested that AID may be linked to a reduced risk-adjusted short-term mortality in individuals with sepsis (OR: 0.73; 95% CI: 0.57-0.93).…”

Inflammation Controls Susceptibility of Immune-Experienced Mice to Sepsis

“…Moreover, heightened basal inflammation is not only observed after sequential infection (or acute infections) but also during autoimmune settings, such as experimental autoimmune encephalomyelitis (EAE; murine model of multiple sclerosis). Importantly, Jensen et al (53) show that EAE mice have increased mortality to CLP when EAE-induced inflammation is elevated; however, the cell type contributing to the elevated steady-state inflammation was not interrogated.…”