PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis.

Sepsis, a leading cause of death worldwide, involves concomitant expression of an overzealous inflammatory response and inefficient bacterial clearance. Macrophage function is pivotal to the development of these two aspects during sepsis; however, the mechanisms underlying these changes remain unclear. Here we report that the PD-1:PD-L pathway appears to be a determining factor of the outcome of sepsis, regulating the delicate balance between effectiveness and damage by the antimicrobial immune response. To this end we observed that PD-1(-/-) mice were markedly protected from the lethality of sepsis, accompanied by a decreased bacterial burden and suppressed inflammatory cytokine response. To the extent that this is a macrophage-specific aspect of the effects of PD-1, we found the following: first, peritoneal macrophages expressed significantly higher levels of PD-1 during sepsis, which was associated with their development of cellular dysfunction; second, when peritoneal macrophages were depleted (using clodronate liposomes) from PD-1(-/-) mice, the animals' bactericidal capacity was lowered, their inflammatory cytokine levels were elevated, and protection from septic lethality was diminished; and third, blood monocytes from both septic mice and patients with septic shock shared markedly increased PD-1 levels. Together, these data suggest that PD-1 may not only be a dysfunctional marker/effector of macrophages/monocytes, but may also be a potential therapeutic target for designing measures to modulate the innate immune response, thereby preventing the detrimental effects of sepsis.

Programmed death-1 levels correlate with increased mortality, nosocomial infection and immune dysfunctions in septic shock patients.

INTRODUCTION: Septic shock remains a major health care problem worldwide. Sepsis-induced immune alterations are thought to play a major role in patients' mortality and susceptibility to nosocomial infections. Programmed death-1 (PD-1) receptor system constitutes a newly described immunoregulatory pathway that negatively controls immune responses. It has recently been shown that PD-1 knock-out mice exhibited a lower mortality in response to experimental sepsis. The objective of the present study was to investigate PD-1-related molecule expressions in septic shock patients. METHODS: This prospective and observational study included 64 septic shock patients, 13 trauma patients and 49 healthy individuals. PD-1-related-molecule expressions were measured by flow cytometry on circulating leukocytes. Plasmatic interleukin (IL)-10 concentration as well as ex vivo mitogen-induced lymphocyte proliferation were assessed. RESULTS: We observed that septic shock patients displayed increased PD-1, PD-Ligand1 (PD-L1) and PD-L2 monocyte expressions and enhanced PD-1 and PD-L1 CD4+ T lymphocyte expressions at day 1-2 and 3-5 after the onset of shock in comparison with patients with trauma and healthy volunteers. Importantly, increased expressions were associated with increased occurrence of secondary nosocomial infections and mortality after septic shock as well as with decreased mitogen-induced lymphocyte proliferation and increased circulating IL-10 concentration. CONCLUSIONS: These findings indicate that PD-1-related molecules may constitute a novel immunoregulatory system involved in sepsis-induced immune alterations. Results should be confirmed in a larger cohort of patients. This may offer innovative therapeutic perspectives on the treatment of this hitherto deadly disease.

Alpha-1 antitrypsin deficiency in a French General Hospital: fortuitous detection rather than efficient screening.

INTRODUCTION: We studied the characteristics of the screening procedure for alpha-1 antitrypsin at Nevers Hospital (France), together with the performance of serum protein gel electrophoresis for the fortuitous detection of patients with deficiency. MATERIAL AND METHODS: We carried out a retrospective study of requests for alpha-1 antitrypsin determination referred to the laboratory during 3 years. We compared these requests with the numbers of patients seen at the hospital and requiring screening according to international recommendations. In parallel, we reviewed all the serum protein gel electrophoresis results obtained during the same period. RESULTS: The laboratory received 102 direct requests for alpha-1 antitrypsin determination, whereas more than 1397 patients presented an indication for screening. No case of alpha-1 antitrypsin deficiency was detected among the 102 patients screened. In parallel, 5551 serum protein gel electrophoresis analyses were carried out at the laboratory. A decrease in the size of the alpha-1 globulin fraction was detected in 68 patients. Seventeen of these patients underwent alpha-1 antitrypsin determinations and 14 were found to have alpha-1 antitrypsin deficiency. CONCLUSION: Alpha-1 antitrypsin deficiency was more frequently detected fortuitously, by electrophoresis, than through efficient screening. The exploration of alpha-1 globulin deficiencies by serum protein gel electrophoresis thus appears to be still a particularly efficient approach to the detection of alpha-1 antitrypsin deficiency and should be carried out systematically. Furthermore, the testing of all patients with an indication for screening according to international recommendations should be encouraged.

Increased circulating regulatory T cells (CD4(+)CD25 (+)CD127 (-)) contribute to lymphocyte anergy in septic shock patients.

PURPOSE: Sepsis syndrome represents the leading cause of death in intensive care unit. Patients present features consistent with a decline in immune responsiveness potentially contributing to mortality. We investigated whether CD4(+)CD25(+) regulatory T cells (Treg) participate in the induction of lymphocyte anergy after sepsis. METHOD: Observational study in septic shock patients and experimental study in mice. RESULTS: We took advantage of the recently described flow cytometric gating strategy using the measurement of CD25 and CD127 expressions for monitoring Treg (CD4(+)CD25(+)CD127(-)Foxp3(+)). In patients the increased circulating Treg percentage significantly correlated with a decreased lympho-proliferative response. In a murine model of sepsis mimicking these observations, the ex vivo downregulation of Foxp3 expression using siRNA was associated with a restoration of this response. CONCLUSION: The relative increase in circulating Treg might play a role in lymphocyte anergy described after septic shock and represent a standardizable surrogate marker of declining proliferative capacity after sepsis.