Messenger RNA expression of major histocompatibility complex class II genes in whole blood from septic shock patients.
OBJECTIVE
The decreased expression of human leukocyte antigen (HLA)-DR on monocytes is proposed as a major feature of sepsis-induced immunodepression. The objective of the present study was to investigate, in whole blood from septic shock patients, the messenger RNA (mRNA) expression of a gene panel, which is essential to ensure major histocompatibility complex class II protein structure, transport, and peptide loading.


METHODS
The authors conducted a cohort study.


METHODS
This study was conducted in intensive care units at a university hospital.


METHODS
The study included septic shock patients (n = 41) and healthy volunteers (n = 15).


RESULTS
Using quantitative reverse transcriptase-polymerase chain reaction, we found that the highly polymorphic HLA-DRB1 and nonpolymorphic-DRA mRNA levels were significantly decreased in whole blood from patients with septic shock compared with healthy volunteer both on days 1-3 and 4-10 after the onset of shock. This profile was also observed for genes encoding the invariant chain, the transcription factor class II transactivator (CIITA), and the enzymes involved in the peptide loading cathepsin S, HLA-DMA, and -DMB. The monocyte surface expression of HLA-DR measured by flow cytometry was significantly correlated with the whole-blood mRNA levels of HLA-DRB1 and -DRA and to a lesser extent with the other CIITA-regulated genes HLA-DMA and invariant chain. The correlation between HLA-DRB mRNA and cell-surface expression levels was also observed in a small subset of purified monocyte samples. Regarding the temporal relationship, a significant increase of whole-blood HLA-DRA, -DMA, -DMB, invariant chain, and CIITA mRNA level was observed in survivors (p = .001), whereas expressions remained low in nonsurvivors.


CONCLUSIONS
A global transcriptional down regulation of a gene panel required for MHC II-restricted antigen presentation may occur in the course of septic shock. Our results suggest that the transcriptional resumption of CIITA-regulated genes might contribute to the recovery of membrane HLA-DR expression observed in survivors. These results obtained at the mRNA level support previous reports describing the loss of monocyte HLA-DR at the protein level and thus confirm the potential of measuring monocyte HLA-DR in septic patient followup.
Pachot
Alexandre
A
Department of Human Genetics, bioMérieux, Parc Club du Moulin à Vent, 33, avenue du Docteur LEVY, 69693 Vénissieux Cedex, France. alexandre.pachot@eu.biomerieux.com
Monneret
Guillaume
G
Brion
Aurélie
A
Venet
Fabienne
F
Bohé
Julien
J
Bienvenu
Jacques
J
Mougin
Bruno
B
Lepape
Alain
A
D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence / Q000235:genetics; D017951:Antigen Presentation / Q000235:genetics; D003422:Critical Care; D015536:Down-Regulation; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics*; D006684:HLA-DR Antigens / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D012333:RNA, Messenger / Q000097:blood / Q000235:genetics*; D012016:Reference Values; D012772:Shock, Septic / Q000097:blood / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis; D015534:Trans-Activators / Q000235:genetics; D014158:Transcription, Genetic / Q000235:genetics
D006684:HLA-DR Antigens; D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D015534:Trans-Activators