TIM-3 Genetic Variants Are Associated with Altered Clinical Outcome and Susceptibility to Gram-Positive Infections in Patients with Sepsis

Abstract

Background: Previous studies have reported the fundamental role of immunoregulatory proteins in the clinical phenotype and outcome of sepsis. This study investigated two functional single nucleotide polymorphisms (SNPs) of T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), which has a negative stimulatory function in the T cell immune response. Methods: Patients with sepsis (n = 712) were prospectively enrolled from three intensive care units (ICUs) at the University Medical Center Goettingen since 2012. All patients were genotyped for the TIM-3 SNPs rs1036199 and rs10515746. The primary outcome was 28-day mortality. Disease severity and microbiological findings were secondary endpoints. Results: Kaplan–Meier survival analysis demonstrated a significantly lower 28-day mortality for TIM-3 rs1036199 AA homozygous patients compared to C-allele carriers (18% vs. 27%, p = 0.0099) and TIM-3 rs10515746 CC homozygous patients compared to A-allele carriers (18% vs. 26%, p = 0.0202). The TIM-3 rs1036199 AA genotype and rs10515746 CC genotype remained significant predictors for 28-day mortality in the multivariate Cox regression analysis after adjustment for relevant confounders (adjusted hazard ratios: 0.67 and 0.70). Additionally, patients carrying the rs1036199 AA genotype presented more Gram-positive and Staphylococcus epidermidis infections, and rs10515746 CC homozygotes presented more Staphylococcus epidermidis infections. Conclusion: The studied TIM-3 genetic variants are associated with altered 28-day mortality and susceptibility to Gram-positive infections in sepsis.

Inflammation in alcohol-associated liver disease progression

“…Finally, and in support of the aforementioned delineation of immune effector functions on bacterial infection and systemic inflammation, as therapeutic strategy, preclinical and clinical studies assessing the safety of neutralising checkpoint receptors including PD-1 and TIM3 in sepsis and septic shock have been used and show promising results [26,57,58,59,60]. Taking this promising data plus the knowledge that preventing the detrimental impact of cytokine targeting remains a challenge, acting on immunoregulatory switches that orchestrate immune effector functions may be an alternative, possibly more favourable approach.…”

Effect of the Lymphocyte Activation Gene 3 Polymorphism rs951818 on Mortality and Disease Progression in Patients with Sepsis—A Prospective Genetic Association Study

“…Their function to limit excess inflammation physiologically mediates the balance between host immune competency and immunosuppression. A variety of genetic variants in immune checkpoint genes as well as pattern recognition receptor, cytokine, and other immune-related genes have been reported to significantly correlate to the clinical course or mortality of sepsis in the past years [15,16,21,24,25,43,49,50].…”

“…For the purpose of the present study, we prospectively enrolled 707 consecutive patients with clinically defined sepsis from three surgical intensive care units (ICUs) at the University Medical Center Goettingen, Germany, since 2012. Our cohort of sepsis patients, or significant proportions of it, were previously studied in other published investigations for other clinical and experimental research questions by our study group [14][15][16]21,24,25,43]. Patient screening for sepsis and study recruitment was performed by study physicians on a daily basis using the currently valid international sepsis definitions and guidelines [1,[44][45][46].…”

“…Diagnostic procedures, pathogen characteristics and antibiotic treatment strategies are exogenous factors, for instance [10,11]. Endogenous factors include preexisting conditions and chronic diseases, host immune status, genetic predisposition, age, gender, and many more [12][13][14][15]. The exploration and investigation of the genetic determinants of sepsis as well as inflammatory conditions in general is a popular method, that could be extensively applied in the future [16][17][18][19][20].…”

Decoding the potential role of regulatory T cells in sepsis‐induced immunosuppression

“…During sepsis‐induced acute lung injury, TIM‐3 + Tregs can upregulate the expression of IL‐4 and IL‐10 in a STAT‐3‐dependent manner [52]. Interestingly, it was found that due to a single nucleotide polymorphism, Tim‐3 may exert a differential influence on the clinical outcome of septic patients [53].…”