Fetal HLA-G mediated immune tolerance and interferon response in preeclampsia.

BACKGROUND: Fetal immune tolerance is crucial for pregnancy success. We studied the link between preeclampsia, a severe pregnancy disorder with uncertain pathogenesis, and fetal human leukocyte antigen G (HLA-G) and other genes regulating maternal immune responses. METHODS: We assessed sex ratios and regulatory HLA-G haplotypes in population cohorts and series of preeclampsia and stillbirth. We studied placental mRNA expression of 136 genes by sequencing and HLA-G and interferon alpha (IFNα) protein expression by immunohistochemistry. FINDINGS: We found underrepresentation of males in preeclamptic births, especially those delivered preterm or small for gestational age. Balancing selection at HLA-G associated with the sex ratio, stillbirth, and preeclampsia. We observed downregulation of HLA-G, its receptors, and many other tolerogenic genes, and marked upregulation of IFNA1 in preeclamptic placentas. INTERPRETATION: These findings indicate that an evolutionary trade-off between immune tolerance and protection against infections at the maternal-fetal interface promotes genetic diversity in fetal HLA-G, thereby affecting survival, preeclampsia, and sex ratio. We highlight IFNA1 as a potential mediator of preeclampsia and a target for therapeutic trials. FUNDING: Finnish Medical Foundation, Päivikki and Sakari Sohlberg Foundation, Karolinska Institutet Research Foundation, Scandinavia-Japan Sasakawa Foundation, Japan Eye Bank Association, Astellas Foundation for Research on Metabolic Disorders, Japan Society for the Promotion of Science, Knut and Alice Wallenberg Foundation, Swedish Research Council, Medical Society Liv och Hälsa, Sigrid Jusélius Foundation, Helsinki University Hospital and University of Helsinki, Jane and Aatos Erkko Foundation, Academy of Finland, Finska Läkaresällskapet, Novo Nordisk Foundation, Finnish Foundation for Pediatric Research, and Emil Aaltonen Foundation.

Despite Predominance of Uropathogenic/Extraintestinal Pathotypes Among Travel-acquired Extended-spectrum ß-Lactamase-producing Escherichia coli, the Most Commonly Associated Clinical Manifestation Is Travelers' Diarrhea.

BACKGROUND: One-third of the 100 million travelers to the tropics annually acquire extended-spectrum ß-lactamase (ESBL)-producing Enterobacteriaceae (ESBL-PE), with undefined clinical consequences. METHODS: Symptoms suggesting Enterobacteriaceae infections were recorded prospectively among 430 Finnish travelers, 90 (21%) of whom acquired ESBL-PE abroad. ESBL-PE isolates underwent polymerase chain reaction-based detection of diarrheagenic Escherichia coli (DEC) pathotypes (enteroaggregative E. coli [EAEC], enteropathogenic E. coli [EPEC], enterotoxigenic E. coli [ETEC], enteroinvasive E. coli, and Shiga toxin-producing E. coli), and extraintestinal pathogenic/uropathogenic E. coli (ExPEC/UPEC). Laboratory-confirmed ESBL-PE infections were surveyed 5 years before and after travel. RESULTS: Among the 90 ESBL-PE carriers, manifestations of Enterobacteriaceae infection included travelers' diarrhea (TD) (75/90 subjects) and urinary tract infection (UTI) (3/90). The carriers had 96 ESBL-producing E. coli isolates, 51% exhibiting a molecular pathotype: 13 (14%) were DEC (10 EAEC, 2 EPEC, 1 ETEC) (12 associated with TD) and 39 (41%) ExPEC/UPEC (none associated with UTI). Of ESBL-PE, 3 (3%) were ExPEC/UPEC-EAEC hybrids (2 associated with diarrhea, none with UTI). Potential ESBL-PE infections were detected in 15 of 90 subjects (17%). The 10-year medical record survey identified 4 laboratory-confirmed ESBL-PE infections among the 430 travelers, all in subjects who screened ESBL-PE negative after returning home from their index journeys but had traveled abroad before their infection episodes. CONCLUSIONS: Half of all travel-acquired ESBL-producing E. coli strains qualified molecularly as pathogens. Extraintestinal and uropathogenic pathotypes outnumbered enteric pathotypes (41% vs 14%), yet the latter correlated more closely with symptomatic infection (0% vs 92%). Despite more ESBL-PE strains qualifying as ExPEC/UPEC than DEC, travel-acquired ESBL-PE are more often associated with TD than UTI.