Abstract
Newborns and especially preterm infants show a unique susceptibility to severe bacterial infections that cause significant morbidity and mortality. As very few data are available on innate immune functions in human fetuses, we conducted a comprehensive study to investigate the expression of several adhesion molecules essentially involved in migration (CD11a, CD11b, CD11c, CD18, and CD62L). Furthermore, phagocytic activity, generation of respiratory burst products, and production of several proinflammatory cytokines were assessed. Various functions of the fetal innate immune system were demonstrated to be essentially different from those observed in term neonates or adults. Expression of several surface markers was significantly diminished on fetal granulocytes. Furthermore, a significantly reduced phagocytic activity of fetal granulocytes and monocytes was found, contrasted by an enhanced generation of reactive oxygen products. In addition, we demonstrate that significant numbers of fetal monocytes are capable of the production of proinflammatory cytokines in response to stimulation. However, the pattern of cytokine production is different from the more mature individuals: the number of IL-6 – and tumor necrosis factor-α–positive monocytes were significantly diminished, whereas more IL-8 –producing monocytes were found compared with adults. The results of our study add significantly to our understanding of the maturation and impairment of the innate immune response.
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Abbreviations
- fMLP:
-
N-formyl-methionyl-leucyl-phenylalanine
- MFI:
-
mean fluorescence intensity
- NRBA:
-
neutrophil respiratory burst activity
- TNF-α:
-
tumor necrosis factor-α
References
Gladstone IM, Ehrenkranz RA, Edberg SC, Baltimore RS 1990 A ten-year review of neonatal sepsis and comparison with the previous fifty-year experience. Pediatr Infect Dis J 9: 819–825.
Gessler P, Luders R, Konig S, Haas N, Lasch P, Kaschel W 1995 Neonatal neutropenia in low birthweight premature infants. Am J Perinatol 12: 34–38.
Carr R 2000 Neutrophil production and function in newborn infants. Br J Hematol 110: 18–28.
Stoll BJ, Gordon T, Korones SB, Shankaran D, Tyson JE, Bauer CR, Fanaroff AA, Lemons JA, Donovan EF, Oh W, Stevenson DK, Ehrenkranz RA, Papile LA, Verter J, Wright LL 1996 Late-onset sepsis in very low birthweight neonates: a report from the National Institute of Child Health and Human Development Neonatal Research Network. J Pediatr 129: 63–71.
Mease AD 1990 Tissue neutropenia: the newborn neutrophil in perspective. J Perinatol 10: 55–59.
Ohls RK, Li Y, Abdel-Mageed A, Buchanan G, Mandell L, Christensen RD 1995 Neutrophil pool sizes and granulocyte colony-stimulating factor production in human mid-trimester fetuses. Pediatr Res 37: 806–811.
Shigeoka AO, Charette RP, Wyman ML, Hill HR 1981 Defective oxidative metabolic responses of neutrophils from stressed neonates. J Pediatr 98: 392–398.
Peden DB, VanDyke K, Ardekani A, Mullett MD, Myerberg DZ, VanDyke C 1987 Diminished chemiluminescent responses of polymorphonuclear leukocytes in severely and moderately preterm neonates. J Pediatr 111: 904–906.
Bektas S, Goetze B, Speer CP 1990 Decreased adherence, chemotaxis and phagocytic activities of neutrophils from preterm neonates. Acta Paediatr Scand 79: 1031–1038.
Driscoll MS, Thomas VL, Ramamurthy RS, Casto DT 1990 Longitudinal evaluation of polymorphonuclear leukocyte chemiluminescence in premature infants. J Pediatr 116: 429–434.
Usmani SS, Schlessel JS, Sia CG, Kamran S, Orner SD 1991 Polymorphonuclear leukocyte function in the preterm neonate: effect of chronologic age. Pediatrics 87: 675–679.
Drossou V, Kanakoudi F, Tzimouli V, Sarafidis K, Taparkou A, Bougiouklis D, Petropoulou T, Kremenopoulos G 1997 Impact of prematurity, stress and sepsis on the neutrophil respiratory burst activity of neonates. Biol Neonate 72: 201–209.
Källman J, Schollin J, Schalèn C, Erlandsson A, Kihlström E 1998 Impaired phagocytosis and opsonisation towards group B streptococci in preterm neonates. Arch Dis Child Fetal Neonatal Ed 78: F46–F50.
Levy O, Martin S, Eichenwald E, Ganz T, Valore E, Carroll SF, Lee K, Goldmann D, Thorne GM 1999 Impaired innate immunity in the newborn: newborn neutrophils are deficient in bactericidal/permeability-increasing protein. Pediatrics 104: 1327–1333.
Nupponen I, Turunen R, Nevalainen T, Peuravuori H, Pohjavuori M, Repo H, Andersson S 2002 Extracellular release of bactericidal/permeability-increasing protein in newborn infants. Pediatr Res 51: 670–674.
Mills EL, Thompson T, Björksten B, Filipovich D, Quie PG 1979 The chemiluminescence response and bactericidal activity of polymorphonuclear neutrophils from newborns and their mothers. Pediatrics 63: 429–434.
Habermehl P, Hauer T, Mannhardt W, Knuf M, Zepp F, Schofer O 1999 Granulocyte function in premature infants before the 34th week of pregnancy and in mature newborn infants. Klin Padiatr 211: 149–153.
McEvoy LT, Zakem-Cloud H, Tosi MF 1996 Total cell content of CR3 (CD11b/ CD18) and LFA-1 (CD11a/CD18) in neonatal neutrophils: relationship to gestational age. Blood 87: 3929–3933.
Murphy FJ, Reen DJ 1996 Differential expression of function-related antigens on newborn and adult monocyte subpopulations. Immunology 89: 587–591.
Kim SK, Keeney SE, Alpard SK, Schmalstieg FC 2002 Comparison of L-selectin and CD11b on neutrophils of adults and neonates during the first month of life. Pediatr Res 53: 132–136.
Smith JB, Tabsh KM 1993 Fetal neutrophils and eosinophils express normal levels of L-selectin. Pediatr Res 34: 253–257.
Schultz C 2002 Intracytoplasmic detection of proinflammatory cytokines and chemokines in monocytes by flow cytometry. In: Körholz D, Kiess W (eds) Cytokines and Colony Stimulating Factors, Methods and Protocols—Part II: Detection Assays for Cytokines and Growth Factors. Methods in Molecular Biology. Humana Press, Totowa, pp 29–39.
Schultz C, Rott C, Temming P, von Puttkammer J, Bucsky P 2002 Influence of specimen age and use of different negative controls in determination of intracytoplasmic levels of cytokine after whole-blood culture assay. Clin Diagn Lab Immunol 9: 295–298.
Schultz C, Rott C, Temming P, Schlenke P, Möller JC, Bucsky P 2002 Enhanced interleukin-6 and interleukin-8 synthesis in term and preterm infants. Pediatr Res 51: 317–322.
De Groote D, Zangerle PF, Gevaert Y, Fasotte MF, Beguin Y, Noizat-Pirenne F, Pirenne J, Gathy R, Lopez M, Dehart I, Igot D, Baufrihaye M, Delacroix, Franchimont P 1992 Direct stimulation of cytokines (IL-1β, TNF-α, IL-6, IL-2, IFN-γ, and GM-CSF) in whole blood. I. Comparison with isolated PBMC stimulation. Cytokine 4: 239–248.
Kinoshita Y, Masuda K, Kobayashi Y 1991 Adherence of cord blood neutrophils: effect of mode of delivery. J Pediatr 118: 115–117.
Gessler P, Dahinden C 2003 Increased respiratory burst and increased expression of complement receptor-3 (CD11b/CD18) and of IL-8 receptor-A in neutrophil granulocytes from newborns after vaginal delivery. Biol Neonate 83: 107–112.
Bruce MC, Baley JE, Medvik KA, Berger M 1987 Impaired surface membrane expression of C3bi but not C3b receptors on neonatal neutrophils. Pediatr Res 21: 306–311.
Falconer AE, Carr R, Edwards SW 1995 Neutrophils from preterm neonates and adults show similar cell surface receptor expression: analysis using a whole blood assay. Biol Neonate 67: 26–33.
Smith JB, Kunjummen RD, Raghavender BH 1991 Eosinophils and neutrophils of human neonates have similar impairments of quantitative up-regulation of Mac-1 (CD11b/CD18) expression in vitro. Pediatr Res 30: 355–361.
Rebuck N, Gibson A, Finn A 1995 Neutrophil adhesion molecules in term and premature infants: normal or enhanced leukocyte integrins but defective L-selectin expression and shedding. Clin Exp Immunol 101: 183–189.
Inwald D, Davies EG, Klein N 2001 Demystified: adhesion molecule deficiencies. Mol Pathol 54: 1–7.
Bevilacqua MP, Nelson RM 1993 Selectins. J Clin Invest 91: 379–387.
Surbek DV, Steinmann C, Burk M, Hahn S, Tichelli A, Holzgreve W 2000 Developmental changes in adhesion molecule expressions in umbilical cord blood CD34 hematopoietic progenitor and stem cells. Am J Obstet Gynecol 183: 1152–1157.
Buhrer C, Stibenz D, Graulich J, Gernhold U, Butcher EC, Dudenhausen JW, Obladen M 1995 Soluble L-selectin (sCD62L) umbilical cord plasma levels increase with gestational age. Pediatr Res 38: 336–341.
Torok C, Lundahl J, Hed J, Lagercrantz H 1993 Diversity in regulation of adhesion molecules (Mac-1 and L-selectin) in monocytes and neutrophils from neonates and adults. Arch Dis Child 68: 561–565.
Buhrer C, Graulich J, Stibenz D, Dudenhausen JW, Obladen M 1994 L-selectin is down-regulated in umbilical cord blood granulocytes and monocytes of newborn infants with acute bacterial infection. Pediatr Res 36: 799–804.
Falconer AE, Carr R, Ewards SW 1995 Impaired neutrophil phagocytosis in preterm neonates: lack of correlation with expression of immunoglobulin or complement receptors. Biol Neonate 68: 264–269.
Boxer LA 2000 Disorders of phagocyte function. In: Behrman RE, Kliegman RM, Jenson HB (eds) Nelson Textbook of Pediatrics. WB Saunders Company, Philadelphia, pp 619–621.
Ambruso DR, Altenburger KM, Johnston RB 1979 Defective oxidative metabolism in newborn neutrophils: discrepancy between superoxide anion and hydroxyl radical generation. Pediatrics 64: 722–725.
Yamazaki M, Matsuoka T, Yasui K, Komiyama, Akabane T 1988 Increased production of superoxide anion by neonatal polymorphonuclear leukocytes stimulated with a chemotactic peptide. Am J Hematol 27: 169–173.
Newburger PE 1982 Superoxide generation by human fetal granulocytes. Pediatr Res 16: 373–376.
Weiss SJ 1989 Tissue destruction by neutrophils. N Engl J Med 320: 365–376.
Gomez R, Romero R, Ghezzi F, Yoon BH, Mazor M, Berry SM 1998 The fetal inflammatory response syndrome. Am J Obstet Gynecol 179: 194–202.
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This study was supported in part by the “Friedrich Bluhme and Else Jebsen Stiftung-Lübeck” and Research Grant of the University of Lübeck, Grant No. 3601.
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Strunk, T., Temming, P., Gembruch, U. et al. Differential Maturation of the Innate Immune Response in Human Fetuses. Pediatr Res 56, 219–226 (2004). https://doi.org/10.1203/01.PDR.0000132664.66975.79
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DOI: https://doi.org/10.1203/01.PDR.0000132664.66975.79
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