An FcγRIIa polymorphism with decreased C-reactive protein binding is associated with sepsis and decreased monocyte HLA-DR expression in trauma patients.

BACKGROUND: A dysregulated immune response leading to sepsis is the most frequent cause of late posttraumatic deaths. We have found a novel anti-inflammatory pathway that is initiated by the acute phase protein, C-reactive protein (CRP), interacting with Fcγ receptor (FcγR) on monocytes. This pathway is protective in animal models of endotoxin shock. We hypothesized that genetic polymorphisms in the FcγR might contribute to monocyte responses and susceptibility to infectious complications after severe trauma. METHODS: We conducted an observational study on a prospectively identified cohort of adult patients with convenience enrollment admitted after severe trauma. We enrolled 66 patients and collected blood samples at enrollment and again at 48 hours and 72 hours. Patients were followed through their hospital stay, and any septic events before 14 days were recorded. Cytokine and CRP levels were determined in the plasma from all three blood draws. In addition, DNA was extracted from blood and analyzed for the 131 H/R FcγRIIa polymorphism that strongly affects the binding of IgG and CRP to this receptor. RESULTS: Elevated levels of interleukin 8 (IL-8), IL-6, IL-10, monocyte chemotactic protein 1, and CRP were associated with reduced time to posttraumatic sepsis in Cox regression analysis. Expression of monocyte human leukocyte antigen DR less than 45% on patient monocytes was also associated with sepsis (hazard ratio, 3.15; 95% confidence interval, 1.45-6.93). Genetic analysis found that individuals with the polymorphism of the FcγRIIa receptor that binds CRP poorly were also more likely to have decreased monocyte human leukocyte antigen DR and posttraumatic sepsis. In vitro studies showed that CRP could attenuate monocyte deactivation in volunteers with the polymorphism of the FcγRIIa receptor that binds CRP. CONCLUSION: Our findings suggest that a common genetic variation in the FcγRIIa receptor may contribute to infectious susceptibility in trauma patients. In vitro experiments suggest that this association is related to the inability of CRP to bind to this FcγRIIa receptor variant. LEVEL OF EVIDENCE: Prognostic study, level III.

Transforming growth factor-ß, macrophage colony-stimulating factor and C-reactive protein levels correlate with CD14(high)CD16+ monocyte induction and activation in trauma patients.

Severe injury remains a leading cause of death and morbidity in patients under 40, with the number of annual trauma-related deaths approaching 160,000 in the United States. Patients who survive the initial trauma and post-traumatic resuscitation are at risk for immune dysregulation, which contributes to late mortality and accounts for approximately 20% of deaths after traumatic injury. This post-traumatic immunosuppressed state has been attributed to over-expression of anti-inflammatory mediators in an effort to restore host homeostasis. We measured a panel of monocyte markers and cytokines in 50 severely injured trauma patients for 3 days following admission. We made the novel observation that the subpopulation of monocytes expressing high levels of CD14 and CD16 was expanded in the majority of patients. These cells also expressed CD163 consistent with differentiation into alternatively activated macrophages with potential regulatory or wound-healing activity. We examined factors in trauma plasma that may contribute to the generation and activation of these cells. The percentage of CD14(high)CD16(+) monocytes after trauma correlated strongly with plasma C-reactive protein (CRP) transforming growth factor-ß (TGF-ß), and macrophage colony-stimulating factor (M-CSF) levels. We demonstrate a role for TGF-ß and M-CSF, but not CRP in generating these cells using monocytes from healthy volunteers incubated with plasma from trauma patients. CD16 is a receptor for CRP and IgG, and we showed that monocytes differentiated to the CD14(high)CD16(+) phenotype produced anti-inflammatory cytokines in response to acute phase concentrations of CRP. The role of these cells in immunosuppression following trauma is an area of ongoing investigation.