title: Maternal BCG scar is associated with increased infant proinflammatory immune responses.
abstract: Prenatal exposures such as infections and immunisation may influence infant responses. We had an opportunity to undertake an analysis of innate responses in infants within the context of a study investigating the effects of maternal mycobacterial exposures and infection on BCG vaccine-induced responses in Ugandan infants.
  
  
  
  Maternal and cord blood samples from 29 mother-infant pairs were stimulated with innate stimuli for 24h and cytokines and chemokines in supernatants were measured using the Luminex® assay. The associations between maternal latent Mycobacterium tuberculosis infection (LTBI), maternal BCG scar (adjusted for each other's effect) and infant responses were examined using linear regression. Principal Component Analysis (PCA) was used to assess patterns of cytokine and chemokine responses. Gene expression profiles for pathways associated with maternal LTBI and with maternal BCG scar were examined using samples collected at one (n=42) and six (n=51) weeks after BCG immunisation using microarray.
  
  
  
  Maternal LTBI was positively associated with infant IP-10 responses with an adjusted geometric mean ratio (aGMR) [95% confidence interval (CI)] of 5.10 [1.21, 21.48]. Maternal BCG scar showed strong and consistent associations with IFN-γ (aGMR 2.69 [1.15, 6.17]), IL-12p70 (1.95 [1.10, 3.55]), IL-10 (1.82 [1.07, 3.09]), VEGF (3.55 [1.07, 11.48]) and IP-10 (6.76 [1.17, 38.02]). Further assessment of the associations using PCA showed no differences for maternal LTBI, but maternal BCG scar was associated with higher scores for principal component (PC) 1 (median level of scores: 1.44 in scar-positive versus -0.94 in scar-negative, p=0.020) in the infants. PC1 represented a controlled proinflammatory response. Interferon and inflammation response pathways were up-regulated in infants of mothers with LTBI at six weeks, and in infants of mothers with a BCG scar at one and six weeks after BCG immunisation.
  
  
  
  Maternal BCG scar had a stronger association with infant responses than maternal LTBI, with an increased proinflammatory immune profile.
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda; London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK. Electronic address: pmawa@uvri.go.ug.
authors.forename: Patrice Akusa
authors.initials: PA
authors.lastname: Mawa
authors.affiliation: London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Webb
authors.affiliation: Case Western Reserve University School of Medicine, 10900 Euclid Ave., LC4960, Wood Bldg. W200, Cleveland, OH 44106, United States.
authors.forename: Abdelali
authors.initials: A
authors.lastname: Filali-Mouhim
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.
authors.forename: Gyaviira
authors.initials: G
authors.lastname: Nkurunungi
authors.affiliation: Case Western Reserve University School of Medicine, 10900 Euclid Ave., LC4960, Wood Bldg. W200, Cleveland, OH 44106, United States.
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sekaly
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda.
authors.forename: Swaib Abubaker
authors.initials: SA
authors.lastname: Lule
authors.affiliation: London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Sarah
authors.initials: S
authors.lastname: Prentice
authors.affiliation: London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Nash
authors.affiliation: London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Hazel M
authors.initials: HM
authors.lastname: Dockrell
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda; London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Alison M
authors.initials: AM
authors.lastname: Elliott
authors.affiliation: MRC/UVRI Uganda Research Unit on AIDS, P.O. Box 49, Entebbe, Uganda; London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Cose
mesh_terms: D000328:Adult; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000276:immunology*; D002921:Cicatrix; D016207:Cytokines / Q000097:blood; D005260:Female; D006801:Humans; D007111:Immunity, Cellular; D007231:Infant, Newborn; D008297:Male; D018811:Maternal Exposure; D008431:Maternal-Fetal Exchange; D011247:Pregnancy; D014454:Uganda; D055815:Young Adult
chemical_list: D001500:BCG Vaccine; D016207:Cytokines
keywords: BCG immunisation; Heterologous effects; Infant innate responses; Latent Mycobacterium tuberculosis infection; Maternal BCG scar; Maternal infections; Tuberculosis