IFN-α exercises multiple immune modulatory and antiviral activities and has been suggested to play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Plasmacytoid dendritic cells (pDCs) release IFN-α upon TLR7 and TLR9 ligation. With respect to the nine times higher incidence of SLE in women and the clinical use of synthetic TLR ligands as novel immune adjuvants, we analyzed IFN-α and TNF-α production in healthy human individuals. Blood samples were incubated with synthetic TLR7 and TLR9 ligands. In three independent groups (n1 = 120, n2 = 101, and n3 = 123), analysis revealed a capacity of female PBLs to produce significantly higher IFN-α levels after TLR7 stimulation (p1 < 0.0000001, p2 < 0.0000001, and p3 < 0.0001) compared with male PBLs. In contrast, no sex differences were evident after TLR9 stimulation. TNF-α production after TLR7 stimulation and also total pDC numbers were not different between females and males. X-inactivation escape of the TLR7 gene was investigated in monoclonal B cell lines and, independently, in pDCs after cell sorting and single-cell picking, indicating regular silencing of one TLR7 allele in females. Additionally, exogenous 17β-estrogen and estrogen receptor antagonism did not indicate a significant role on TLR7-induced IFN-α production. Our data reveal for the first time a profound sex-dependent pathway of TLR7-induced IFN-α with higher production in females. These findings may explain the higher prevalence of SLE in females and the reported decreased therapeutic efficacy of synthetic TLR7 ligands in male individuals.

Cytomegalovirus (CMV) infection is an important cause of disease in immunocompromised patients. In a prospective longitudinal study of 34 septic patients, the incidence of active CMV infection was examined. Eleven of 34 patients (32.4%) had active CMV infection, diagnosed by immunocytochemical staining of CMV pp65 antigen in blood leukocytes and/or detection of CMV DNA by PCR. Positive results for CMV infection were obtained in a median of 4 days (by PCR) or 11 days (by staining of pp65 antigen) after onset of sepsis. Twenty patients for whom more than one sample was examined were selected for further analysis. Among the patients with active CMV infection (nine of 20) there was a trend toward higher median values of tumor necrosis factor a, interleukin1b, alanine aminotransferase, and aspartate aminotransferase in plasma, in comparison with the values for patients without CMV infection. Sepsis in patients with CMV infection may affect outcome of the disease. Cytomegalovirus (CMV) is an important cause of morbiditySee the editorial response by Ho on pages 1083 -4. and death in immunocompromised patients, such as those with AIDS or immunosuppressed transplant recipients [1, 2]. After Furthermore, it has been hypothesized that TNF-a is of some primary infection, which usually takes place during childhood, importance in activation of CMV and HIV replication and CMV (as with all herpesviruses) resides in the host throughout immunopathology in in vitro experiments or during in vivo life; therefore, 50% -100% of the population -depending on circumstances [11 -15]. In 1994 results of a study were pubcountry of residence and social status -have become CMVlished supporting the hypothesis that TNF-a influences CMV seropositive by adulthood [3]. Disturbance of the fine balance reactivation, and clinical observation in septic patients seemed between the immune system and the latently existing virus by to confirm this hypothesis [16]. The aim of the present longituimmunosuppressive therapy, HIV infection, or another form of dinal prospective study was to define the incidence of CMV immunosuppression results in viral reactivation and clinical reactivation in patients with sepsis and to investigate the reladisease.tionship between severity of disease, cytokine concentration in Severe dysregulation of central mediators of the immune plasma, and clinical outcome. system, as occurs during sepsis, may induce such a state of immunosuppression. Sepsis is defined as a systemic inflammatory response that results from infection [4]. It is increasingly Patients and Methods common and was shown to be associated with a mortality ranging from Ç20% to 30%, up to 56% in controlled clinical Inclusion Criteria and Definitions trials [5 -8]. TNF-a, IL-1, and IL-6 were shown to represent As no uniform definition of sepsis has been generally acimportant factors in the pathogenesis of sepsis [9]. Despite cepted, the definition of sepsis used in this study followed the their physiological benefits for the host, they may also cause criteria of the Am...

Our observation indicates that an IgG-ELISA provides the best diagnostic information of all antigen-binding assays.