MONITORING OF SEPSIS-INDUCED IMMUNOPARALYSIS BY MEASURING MONOCYTIC HLA-DR IN PATIENTS WITH SEPTIC SHOCK

Identification of reliable biomarkers is key to guide targeted therapies in septic patients. Expression monitoring of monocyte HLA-DR and neutrophil CD64 could fulfill the above need. However, it is unknown whether their expression on circulating cells reflects the status of tissue resident cells. We compared expressions of HLA-DR and CD64 markers in the circulation and airways of septic shock patients and evaluated their outcome prognostic value. The expression of CD64 on neutrophils and HLA-DR on monocytes was analyzed in the peripheral blood and mini-bronchoalveolar lavage fluid cells by flow cytometry. Twenty-seven patients with septic shock were enrolled into the study. The fluorescence intensity of HLA-DR on circulating monocytes was 3.5-fold lower than on the pulmonary monocytes (p=0.01). The expression of CD64 on circulating and airway neutrophils was similar (p=0.47). Only the expression of CD64 on circulating neutrophils was higher in nonsurvivors versus survivors (2.8-fold;p=0.031). Pulmonary monocytes display a higher level of HLA-DR activation compared to peripheral blood monocytes but the expression of neutrophil CD64 is similar on lung and circulating cells. Death in septic patients was effectively predicted by neutrophil CD64 but not monocytic HLA-DR. Prognostic value of cellular activation markers in septic shock appears to strongly depend on their level of compartmentalization.

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Effects of stress-dose hydrocortisone therapy in septic shock (part III): monocyte HLA-DR expression and blood interferon-? concentration. Preliminary results of a double blinded, randomized, placebo-controlled cross-over study

Critical Care ◽

10.1186/cc480 ◽

1999 ◽

Vol 3 (Suppl 1) ◽

pp. P106

Author(s):

T Böhnke ◽

C Schulz ◽

D Keh ◽

M Pettersson ◽

S Weber-Carstens ◽

...

Keyword(s):

Septic Shock ◽

Preliminary Results ◽

Hla Dr ◽

Effects Of Stress ◽

Double Blinded ◽

Stress Dose

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Decreased expression of HLA-DR antigen-associated invariant chain mRNA predicts mortality after septic shock

Critical Care ◽

10.1186/cc11698 ◽

2012 ◽

Vol 16 (S3) ◽

Author(s):

M-A Cazalis ◽

L Cavé ◽

J Demaret ◽

V Barbalat ◽

E Cerrato ◽

...

Keyword(s):

Septic Shock ◽

Invariant Chain ◽

Hla Dr

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Characterization of Circulating IL-10-Producing Cells in Septic Shock Patients: A Proof of Concept Study

Frontiers in Immunology ◽

10.3389/fimmu.2020.615009 ◽

2021 ◽

Vol 11 ◽

Author(s):

Astrid Fabri ◽

Khalil Kandara ◽

Rémy Coudereau ◽

Morgane Gossez ◽

Paul Abraham ◽

...

Keyword(s):

Septic Shock ◽

T Cells ◽

T Lymphocytes ◽

T Lymphocyte ◽

Whole Blood ◽

Cd4 T Cells ◽

Interleukin 10 ◽

Risk Of Death ◽

Hla Dr ◽

Increased Risk

Sepsis is a worldwide health priority characterized by the occurrence of severe immunosuppression associated with increased risk of death and secondary infections. Interleukin 10 (IL-10) is a potent immunosuppressive cytokine which plasma concentration is increased in septic patients in association with deleterious outcomes. Despite studies evaluating IL-10 production in specific subpopulations of purified cells, the concomitant description of IL-10 production in monocytes and lymphocytes in septic patients’ whole blood has never been performed. In this pilot study, we characterized IL-10 producing leukocytes in septic shock patients through whole blood intracellular staining by flow cytometry. Twelve adult septic shock patients and 9 healthy volunteers were included. Intracellular tumor necrosis factor-α (TNFα) and IL-10 productions after lipopolysaccharide stimulation by monocytes and IL-10 production after PMA/Ionomycine stimulation by lymphocytes were evaluated. Standard immunomonitoring (HLA-DR expression on monocytes, CD4+ T lymphocyte count) of patients was also performed. TNFα expression by stimulated monocytes was reduced in patients compared with controls while IL-10 production was increased. This was correlated with a reduced monocyte HLA-DR expression. B cells, CD4+, and CD4- T lymphocytes were the three circulating IL-10 producing lymphocyte subsets in both patients and controls. No difference in IL-10 production between patients and controls was observed for B and CD4- T cells. However, IL-10 production by CD4+ T lymphocytes significantly increased in patients in parallel with reduced CD4+ T cells number. Parameters reflecting altered monocyte (increased IL-10 production, decreased HLA-DR expression and decreased TNFα synthesis) and CD4+ T lymphocyte (increased IL-10 production, decreased circulating number) responses were correlated. Using a novel technique for intracellular cytokine measurement in whole blood, our results identify monocytes and CD4+ T cells as the main IL-10 producers in septic patients’ whole blood and illustrate the development of a global immunosuppressive profile in septic shock. Overall, these preliminary results add to our understanding of the global increase in IL-10 production induced by septic shock. Further research is mandatory to determine the pathophysiological mechanisms leading to such increased IL-10 production in monocytes and CD4+ T cells.

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CIITA G-286A promoter polymorphism impairs monocytes HLA-DR expression in septic shock and is rescued by interferon-γ

10.1101/2021.02.19.21252097 ◽

2021 ◽

Author(s):

Jordi Miatello ◽

Anne-Claire Lukaszewicz ◽

Valérie Faivre ◽

Stéphane Hua ◽

Kim Zita Martinet ◽

...

Keyword(s):

Septic Shock ◽

Mhc Class Ii ◽

Promoter Activity ◽

Class Ii ◽

Interferon Γ ◽

Site Directed Mutagenesis ◽

Proximal Promoter ◽

List Type ◽

Hla Dr ◽

Ifn Γ

ABSTRACTMonocyte HLA-DR is an increasingly recognized markers of sepsis-induced immunodepression, but its regulatory mechanisms remain poorly understood in sepsis. Several evidence for positive selection on the 5’ promoter region of HLA class II transactivator (CIITA) gene, the master regulator of MHC class II, have been gathered in the European population, and its role in sepsis has never been demonstrated, whilst suggested in autoimmune disease. We aim to describe the effect of rs3087456 polymorphism, localized on CIITA promoter III (pIII), on mortality of patients with septic shock, and investigate the mechanisms regulating HLA-DR expression. Genotyping of 203 patients with septic shock showed that, in A dominant model, GG genotype was associated with 28-day mortality (OR 2.29; 95%CI: 1.01 to 5.22; P = 0.043). Monocyte HLA-DR remained low in patients with GG genotype whereas it increases as early as at the end of the first week in intensive care in patients with AA or AG genotype. Using site-directed mutagenesis, in vitro reporter gene promoter activity of the pIII was decreased in GG genotype in monocyte cell line. Interferon-γ (IFN-γ) restored pIII activity in GG genotype as well as restore, in ex vivo experiment in healthy volunteers, CIITA pIII expression of GG genotype. Hereby, we demonstrated that rs3087456, a positively selected polymorphism of CIITA proximal promoter, significantly impact monocyte HLA-DR expression in patients with septic shock through CIITA promoter activity, that can be rescued using IFN-γ, offering a new perspective in genetic susceptibility to sepsis and targeted immunomodulatory therapy.KeypointsCIITA G-286A polymorphism reduces promotor activity and significantly impact monocyte HLA-DR expression and mortality in septic shockDownregulatory effects of CIITA G-286A polymorphism on monocyte HLA-DR expression can be reverse by IFN-γ in patients with septic shock

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