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Monocyte Human Leukocyte Antigen–DR Transcriptional Downregulation by Cortisol during Septic Shock

Service de Réanimation Médicale et des Maladies Infectieuses, Laboratoire d'Hématologie et de Biologie des Cellules Sanguines UPRES-EA 22-33, Laboratoire de Pharmacologie Clinique et Expérimentale, Centre Hospitalier Universitaire de Rennes, Rennes, France

Correspondence and requests for reprints should be addressed to Yves Le Tulzo, M.D., Ph.D., Service de Réanimation Médicale et des Maladies Infectieuses, Hôpital Pontchaillou, Rue Henri Le Guilloux, CHU Rennes, 35033 Rennes, France. E-mail: yves.le-tulzo{at}univ-rennes1.fr

Monocyte deactivation has been identified as a major factor of immunosuppression in sepsis and is associated with a loss of surface human leukocyte antigen–DR (HLA-DR) expression on circulating monocytes. Using flow cytometry, quantitative reverse transcription-polymerase chain reaction, we investigated this phenomenon in septic patients. We confirmed the early loss of monocyte HLA-DR expression in all infected patients and demonstrated that this persistent lowered expression at Day 6 correlated with severity scores, secondary infection, and death. This phenomenon occurred at a transcriptional level via a decrease in the class II transactivator A (CIITA) transcription. Furthermore, these abnormalities correlated with the high cortisol levels observed in sepsis and not with those of other putative factors such as catecholamines or interleukin-10. Finally, in vitro studies evidenced that glucocorticoids decrease HLA-DR expression at a transcriptional level via a decrease in CIITA mRNA levels, mainly by down modulating its isoforms I and III. We conclude that in human sepsis, the loss of HLA-DR expression on circulating monocytes is associated with a poor outcome. We suggest that the high endogenous cortisol level observed in septic shock may be a possible new factor involved in the loss of HLA-DR expression on monocytes via its effect on HLA-DR and CIITA transcription.

Key Words: major histocompatibility complex type II • class II transactivator A • immune paralysis • infection

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