Dysfunction of innate immunity and associated pathology in neonates
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《美国医学杂志》
Department of Pediatrics, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
The neutrophils and complement system are the critical elements of innate immunity mainly due to participation in the first line of defense against microorganisms by means of phagocytosis, lysis of bacteria, and activation of naive B-lymphocytes. In this report we provide an overview of the up to date information regarding the neutrophil and complement system's functional ability in newborn infants in association with the maternal conditions that exist during the intrauterine stage, gestational age and post-neonatal pathology. The neonates' capacity to control the neutrophil and complement protein activation process has also been discussed because of the evidence that uncontrolled activation of these immune elements provides a significant contribution to the tissue damage and subsequent pathology. The authors are confident that despite the many unanswered questions this review updates their knowledge and points the need for further research to clarify the role of the age-associated dysfunction of neutrophils and complement system in the infection and inflammation related pathology of newborn infants.
Keywords: Neonates; Innate immunity; Neutrophils; Complement
Defense against infection, especially in neonates with no immunological memory and low ability to develop specific antibody to the bacteria, viruses, protozoa, and fungi that they are exposed to during intrauterine and postpartum life is predominantly dependent on innate immunity. Among the elements of innate immunity that includes neutrophils, monocytes, macrophages, dendritic and natural killer cells, and complement,[1] the neutrophils and complement system are the critical first line of host defense against the invading pathogens.[2],[3] Neutrophils participate in the first line of defense against microorganisms, and can contribute significantly to tissue damage and subsequent pathology, over and above that caused by the original infection or injury.[4] The presence of pathogens is detected by the neutrophils through germ line-encoded receptors such as Toll-like receptors (TLR), which recognize the microbe-associated molecular patterns.[5] Chemotaxis of neutrophils toward bacterial (proteins, capsules, cell wall fragments, endotoxin), complement (C5a), chemokines (interleukin-8), and fibrin split products attractants, and opsonization of neutrophils by immunoglobulin (Ig) G or the complement proteins (C3b and C4b) predisposes the ingestion of microorganism (or other cells) by the released lysosomal enzymes and the toxic oxygen radicals, hydrogen peroxide, and peroxynitrite radicals produced in the neutrophils. During phagocytosis, the neutrophils use large quantities of molecular O 2 to generate O 2- and other oxidants via a respiratory burst catalyzed by NADPH oxidase.[6]
More than 40 proteins of the classical, alternative and mannan-binding lectin pathway of the complement (C) system carry out beneficial innate defense functions by participation in phagocytosis, and cause lysis of bacteria, and activation of naive B-lymphocytes. Activation of the complement cascade results in production of inflammatory mediators (C3a, C5a), opsonization of cells with components (C3b, C4b) for recognition and phagocytosis by macrophages, and formation of membrane attack complex (C5b-9) on target membranes.[7]
Consequently, the modulation of neutrophil and complement activities constitutes an approach designed to regulate inflammatory responses that have a high potential to destroy target tissue. In this review, the authors attempt to provide an overview regarding neutrophil and complement system dysfunction and activation related risk of infection and inflammation pathology in neonates.
Neutrophil and complement function in the maternal-fetal interface
In the developing fetus, the earliest neutrophil progenitors are observed at the end of the first trimester in the multipotent hematopoietic cells but not in the yolk sac blood islands.[8],[9],[10],[11],[12] After the second trimester, the bone marrow becomes the major hematopoietic organ.[13] A variety of perinatal conditions can impair production and functional activity of neutrophils in neonates, such as; pregnancy-induced hypertension was identified as a significant factor for aberrant intrauterine myelopoiesis and the development of neonatal neutropenia.[14] Up to 50% to 80% of neonates born to mothers with preeclampsia, a severe form of pregnancy-related hypertension, develop neutropenia.[14] During the hypertensive gestation, decreased colony-stimulating activity occurs in placental conditioned media[15] and neonates,[16],[17] and this may influence proliferation, maturation, and differentiation of neutrophils.[18] Moreover, increased apoptosis of neutrophils has been observed in neonates whose gestation was complicated by preeclampsia.[19],[20] Autoimmune disease associated as well as transplacentally acquired maternal anti-neutrophil antibodies may cause alloimmune/isoimmune neutropenia in the neonate,[21],[22] and can clinically present with omphalitis, delayed separation of the cord, mild skin infections, fever, or pneumonia in the 1st weeks of life. Maternal diabetes has been identified as a condition that affects the chemotactic activity of cord blood neutrophils.[23],[24] The authors have previously shown that gestational diabetes leads to the impairment of cord blood neutrophil motility and postphagocytic bactericidal capacity independently from the insulin requirement for the maintenance of normoglycemia during pregnancy.[25] In addition, prenatal exposure to magnesium sulfate, a drug that is frequently used for attempted tocolysis in preterm labor contributes to the alteration of neutrophil motility and post-phagocytic bactericidal capacity.[26] The intrauterine induction of chemotactic activity and metabolic oxygenation of neutrophils may predispose to the development of pulmonary hemorrhage early after birth, in extremely low birthweight infants with respiratory distress.[27]
Equilibrium in the complement system is also important for the maintenance of a normal pregnancy. The normal human pregnancy is associated with evidence of complement activation, as determined by higher concentrations of the anaphylotoxins C3a, C4a and C5a in the maternal circulation.[28] Since the fetus is semiallogenic to the mother, mechanisms have evolved to protect fetal tissue from the maternal immune response. Among these mechanisms is the expression of cell-surface complement regulatory proteins at the maternal-fetal interface.[29] Complement factors do not cross the placenta and the fetus begins synthesizing complement proteins at 6-14 weeks of gestation. The trophoblastic cells express high levels of complement-inhibitory proteins to control the complement-mediated damage.[30] The high levels of complement inhibitory proteins (decay-accelerating factor, membrane cofactor protein, and CD59) that are present in the trophoblasts prevent uncontrolled complement activation that would otherwise lead to fetal injury or death in utero . Antiphospholipid antibody-induced fetal loss is associated with complement C3 activation.[31] In maternal plasma, the concentration of anaphylatoxin (C5a) increases in association with preterm delivery.[32] Elimian et al have shown amniotic fluid complement C3 is of value in the diagnosis of intra-amniotic infection during preterm labor with intact membranes.[33] The upregulation of gene expression for the complement factors has been identified in association with premature rupture of membranes.[34]
Neutrophils and complement during the neonatal period
Within the first 24 hours of the neonate's life, the circulating neutrophil count increases abruptly and then gradually stabilizes by 48 to 72 hours.[35] This transient rise in the neutrophil count is paralleled by an increase in the circulating neutrophil progenitors, which gradually decrease over the first weeks of life.[36] Furthermore, cycling rates of hematopoietic cells and absolute numbers of immature and mature circulating neutrophils are elevated in neonates compared with adults.[37],[38] Neutrophil counts at 12 hours after birth range from 7,000 to 15,000/mcL in term infants, and at times are higher in preterm neonates compared with children and adults.[38],[39]
Complement protein concentrations increase after birth and approximate mean adult values between 6 and 18 months of age.[40] Reference values of C1r, C2, C5, C7, Properdin, and factors D, H, and I and C3a and C5a have been determined in cord blood samples from healthy term newborns.[41] Gestational age dependent reduction of complement activity and its regulation has been reported in prematurely born neonates.[42],[43],[44],[45] The authors have previously shown that in preterm born infants without evidence of infection, the cord blood levels of effective molecule of the complement components are significantly lower than in maternal serum.[46] Despite very low levels of native complement proteins, preterm babies are able to generate remarkable amounts of activation products of the complement cascade.[47] Miyano et al[48] have shown that the C3 activation system seems to be well developed even before week 25 of gestation. They reported that among the complement components, C3d was the most sensitive indicator of placenta inflammation.[48] In a previous study,[49] they authors found increased C5 on day 3-4 of life in infants born prematurely after preterm premature rupture of membranes.
Neutrophil functional deficiency and associated neonatal pathology
In general, neonatal neutrophil progenitors have a limited capacity to increase neutrophil production in response to infection, which becomes especially important as preterm born neonates have lower numbers of circulating neutrophils.[50] Neutropenia and depleted neutrophil storage pools have been found to be associated with neonatal bacterial sepsis and are predictive of a poor prognosis.[51],[52],[53],[54] In addition to the quantitative defects, numerous qualitative impairments such as defects in endothelial adherence, transendothelial migration, chemotaxis, phagocytosis, and intracellular killing[55],[56],[57],[58] adversely affect the neonatal neutrophils' capacity to fight infection.[59],[60],[61] This interconnects with larger evidence that newborn infants, especially when delivered prematurely, are at considerable risk for bacterial and fungal infections.[62],[63],[64]
Neonatal neutrophils have adhesion defects because of their defective expression and storage of CD18/CD11b, a member of the β 2 integrin family of adhesion molecules.[65],[66] The total cellular CD11b is diminished in neonatal neutrophils.[56] The lower functional expression of CD11b on neonatal neutrophils correlates with the defect in neutrophil-endothelial adherence.[67] A possible contributory role of defective CD11b function to neonatal infections is supported by the reports of severe recurrent bacterial infections in patients with leukocyte adhesion deficiency.[68] In addition, L-selectin, with ligands expressed on the endothelial surface mediate neutrophil cell adhesion during inflammation, and although L-selectin is expressed at higher levels on hematopoietic progenitor cells of neonates compared with those of adults,[69] neonatal neutrophils in the human and in animal models have lower levels of L-selectin.[55],[70],[71] Moreover, L-selectin levels decrease during the first 24 to 72 hours of life[50] in association with transient leukocytosis[72] and remain low compared with neutrophils of adults, and are even lower in the neutrophils of premature neonates.[55],[73] The decreased surface expression of L-selectin on neutrophils correlates with their impaired capacity to "roll" on vascular endothelium, a process that is important to the initiation of subsequent adhesive events.[55]
In addition to the adhesive defects, neutrophils from neonates respond poorly to a variety of inflammatory stimuli[71] due to impaired calcium metabolism[74] and abnormal actin polymerization.[75] The Guanosine triphosphate-binding protein (Rac2), an essential regulator of human neutrophil migration and chemotaxis, is significantly lower in the neutrophil protein lysates isolated from cord blood compared with adult blood.[76] Reduced neutrophil migration has been suggested as a reason for the serious bacterial infections seen in preterm neonates despite antibiotic prophylaxis in the mother.[77]
In addition to the disadvantages with respect to the phagocytic activity of neutrophils, neonates, especially those born prematurely, have an age-specific diminution of opsonins such as fibronectin, immunoglobulins, and complement including mannose-binding lectin,[78],[79],[80],[81],[82] Deficiency of such opsonins impairs the neutrophils' phagocytic capacity in neonates.[63],[83] Moreover, neutrophils, especially from immature neonates have variable in vitro efficiency in killing certain bacteria.[84] Impaired bactericidal activity of the neonatal neutrophils is associated with lower capacity to activate the respiratory burst and lower concentrations of elastase and lactoferrin in the neutrophil granules,[85], [86] which can also be activated by reactive oxygen species, signaling molecules that eventually lead to apoptosis of target cells. Defects in newborn neutrophil function such as decreased ability to generate O 2- in response to neutrophil stimulation increases susceptibility to infection.[87] Subnormal respiratory burst function and intracellular killing has been observed in children diagnosed with myeloperoxidase, glutathione synthetase, and glucose-6-phosphate dehydrogenase deficiency.[88],[89]
Dysfunctional inflammatory responses have been implicated in several neonatal inflammatory disorders following infection and/or hypoxia, especially among neonates born prematurely. The mechanism of this association is not clear. However, lower responsiveness to lipopolysaccharide (LPS) stimulation during hypoxia and altered apoptosis may increase the rate of chronic inflammatory disorders in the neonatal population.[90],[91],[92]
There is evidence that apoptosis is necessary for maintenance of neutrophil homeostasis and elimination of functional neutrophils, and therefore, the resolution of inflammation.[93],[94] Generally, circulating neutrophils undergo apoptosis within 24 to 48 hours of their egress from the bone marrow.[94] Continued presence of neutrophils with functional longevity can be an inciting factor in the pathogenesis of chronic inflammatory disorders.[95],[96] In contrast, prolonged survival of activated neutrophils may promote the elimination of bacteria and further leukocyte recruitment in the presence of severe sepsis.[94],[97]
Neonatal neutrophils have a constitutive delay in apoptosis[98] that can be explained in part by the decreased functional expression of caspase-3, a common component of several key pathways of apoptosis.[99] Some studies suggest that neonatal neutrophils with prolonged survival retain specific cytotoxic and inflammatory functions and may have the functional capacity to contribute to the pathogenesis of inflammatory disorders[100],[101] such as chronic lung disease.[92],[91] An imbalance between neutrophil elastase and its inhibitors such as serine protease and cathepsin has been also implicated in development of chronic lung disease.[102]
Complement deficiency and associated neonatal pathology
It has been shown that complement activation is largely responsible for the neutrophil inflammatory response.[103] However, the consistent deficiencies in complement components and receptors seen in neonates, especially those born prematurely may be associated with different pathology, relative to the neonatal period of life. Lassiter et al showed that diminution of C9 in newborn plasma, which is 10-20% compared with adult values, affects their ability to kill E-coli .[104] The profound C9 deficiency found in neonates' correlates with gestational age and limits the capacity to form membrane attack complex (MAC), and may predispose to severe invasive bacterial infections.[105]
Different cells synthesize complement proteins such as the complement proteins synthesized and secreted by the type III epithelial cells and alveolar macrophages. Structural and functional similarity between surfactant proteins A and D (SP-A and SP-D) and complement activators including C1q and mannose binding lectin (MBL) has been observed. In addition, both surfactant and MBL structurally belong to the collectin family. Turker et al showed that among preterm neonates with respiratory distress syndrome, poor response to surfactant therapy is associated with lower serum levels of C4 at admission and C4 and C3c on the first day of life.[106] Interestingly, SP-A blocks complement activation (binds to C1q) and therefore, minimizes complement-induced lung damage.[107] Complement activation precedes cytokine release, which may suggest a primary role for complement in the pathophysiology of meconium aspiration syndrome that is a serious condition in newborns, and is associated with a poorly characterized inflammatory reaction. Membrane attack complex is increased substantially in the plasma of neonates with meconium aspiration syndrome and closely correlates with the severity of the lung dysfunction.[108] The development of respiratory distress in preterm born neonates is associated with significantly lower levels of CH50, C3, C4, C3d3 and factor B compared as to infants without lung diseases.[109]
Studies have shown that complement is activated in the cord blood of neonates born with significant acidosis. The association between acidosis and complement activation is characterized by increasing levels of complement degradation products (C5a, C3a) and MAC in the cord blood.[110] Sonntag et al showed that in infants with fetal acidosis complicated with hypoxic-ischemic encephalopathy, plasma C1q and factor B as well as hemolytic activity of the complement system is decreased because of increased release of the sub-cellular constituents, mostly mitochondrial proteins which bind to C1q and activate the complement cascade in vitro and in vivo.[111] It has been shown that IgG down regulates the complement attack on host tissues by controlling complement binding to target tissues or cells.[112]
Infection in neonates also induces complement activation through the activation of the alternative complement pathway. As a result, the release of the anaphylatoxin C3a mediates inflammatory reactions such as vasodilatation and an increase in the micro-vascular permeability.[113] Recently reported evidence indicates that complement activation is the pathologic mechanism of injury in the post-hypoxic-ischemic neonatal brain because complement activation participates in the ischemia-reperfusion injury associated with temporary loss of blood flow.[114] Diminished C9 and increased MAC have been reported in the spinal fluid of newborn infants with moderate to severe hypoxic-ischemic encephalopathy.[115] The analysis of post-mortem cerebral tissue showed deposition of C9 on all the neurons, including the morphologically apoptotic neurons.
The possibility of regulating complement activation to protect tissue damage has been discussed in the literature. Frank et al have reported on the ability of IgG to down regulate complement attack on host tissue by controlling complement binding to target tissues or cells.[112] Their finding becomes pertinent because prematurely born neonates have a poor capacity to control complement activation due to lower levels of circulating IgG,[116],[117] and are therefore more vulnerable to complement-mediated damage of the lung and brain.[43],[44],[45]
Conclusion
This review highlights the most prominent results of current research regarding the association between common pathology in newborn infants, and the quantitative and qualitative functional capability of their neutrophils and complement proteins.
Different maternal conditions that exist during the intrauterine stage and preterm delivery affect myelopoiesis, and neutrophil and complement function in the newborn infant. Neutrophils from neonates, particularly those born prematurely, show dysfunction in chemotaxis, integrin-mediated adhesion, oxygen-dependent and independent microbial killing. In addition, neonatal serum has low opsonization capacity and complement protein deficiency that significantly contributes to the susceptibility and development of serious neonatal infection and inflammation-related morbidity. Moreover, the poor capacity to control spontaneous complement activation makes preterm neonates extremely vulnerable to complement-mediated damage of the lung and brain.
Further research is needed to better define: (i) the role of neutrophils and complement in neonatal infection and inflammation related pathology, and (ii) the pharmacologic agents that enhance the immune response to infection and safely inhibit uncontrolled complement activation in order to protect against major organ injury.
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The neutrophils and complement system are the critical elements of innate immunity mainly due to participation in the first line of defense against microorganisms by means of phagocytosis, lysis of bacteria, and activation of naive B-lymphocytes. In this report we provide an overview of the up to date information regarding the neutrophil and complement system's functional ability in newborn infants in association with the maternal conditions that exist during the intrauterine stage, gestational age and post-neonatal pathology. The neonates' capacity to control the neutrophil and complement protein activation process has also been discussed because of the evidence that uncontrolled activation of these immune elements provides a significant contribution to the tissue damage and subsequent pathology. The authors are confident that despite the many unanswered questions this review updates their knowledge and points the need for further research to clarify the role of the age-associated dysfunction of neutrophils and complement system in the infection and inflammation related pathology of newborn infants.
Keywords: Neonates; Innate immunity; Neutrophils; Complement
Defense against infection, especially in neonates with no immunological memory and low ability to develop specific antibody to the bacteria, viruses, protozoa, and fungi that they are exposed to during intrauterine and postpartum life is predominantly dependent on innate immunity. Among the elements of innate immunity that includes neutrophils, monocytes, macrophages, dendritic and natural killer cells, and complement,[1] the neutrophils and complement system are the critical first line of host defense against the invading pathogens.[2],[3] Neutrophils participate in the first line of defense against microorganisms, and can contribute significantly to tissue damage and subsequent pathology, over and above that caused by the original infection or injury.[4] The presence of pathogens is detected by the neutrophils through germ line-encoded receptors such as Toll-like receptors (TLR), which recognize the microbe-associated molecular patterns.[5] Chemotaxis of neutrophils toward bacterial (proteins, capsules, cell wall fragments, endotoxin), complement (C5a), chemokines (interleukin-8), and fibrin split products attractants, and opsonization of neutrophils by immunoglobulin (Ig) G or the complement proteins (C3b and C4b) predisposes the ingestion of microorganism (or other cells) by the released lysosomal enzymes and the toxic oxygen radicals, hydrogen peroxide, and peroxynitrite radicals produced in the neutrophils. During phagocytosis, the neutrophils use large quantities of molecular O 2 to generate O 2- and other oxidants via a respiratory burst catalyzed by NADPH oxidase.[6]
More than 40 proteins of the classical, alternative and mannan-binding lectin pathway of the complement (C) system carry out beneficial innate defense functions by participation in phagocytosis, and cause lysis of bacteria, and activation of naive B-lymphocytes. Activation of the complement cascade results in production of inflammatory mediators (C3a, C5a), opsonization of cells with components (C3b, C4b) for recognition and phagocytosis by macrophages, and formation of membrane attack complex (C5b-9) on target membranes.[7]
Consequently, the modulation of neutrophil and complement activities constitutes an approach designed to regulate inflammatory responses that have a high potential to destroy target tissue. In this review, the authors attempt to provide an overview regarding neutrophil and complement system dysfunction and activation related risk of infection and inflammation pathology in neonates.
Neutrophil and complement function in the maternal-fetal interface
In the developing fetus, the earliest neutrophil progenitors are observed at the end of the first trimester in the multipotent hematopoietic cells but not in the yolk sac blood islands.[8],[9],[10],[11],[12] After the second trimester, the bone marrow becomes the major hematopoietic organ.[13] A variety of perinatal conditions can impair production and functional activity of neutrophils in neonates, such as; pregnancy-induced hypertension was identified as a significant factor for aberrant intrauterine myelopoiesis and the development of neonatal neutropenia.[14] Up to 50% to 80% of neonates born to mothers with preeclampsia, a severe form of pregnancy-related hypertension, develop neutropenia.[14] During the hypertensive gestation, decreased colony-stimulating activity occurs in placental conditioned media[15] and neonates,[16],[17] and this may influence proliferation, maturation, and differentiation of neutrophils.[18] Moreover, increased apoptosis of neutrophils has been observed in neonates whose gestation was complicated by preeclampsia.[19],[20] Autoimmune disease associated as well as transplacentally acquired maternal anti-neutrophil antibodies may cause alloimmune/isoimmune neutropenia in the neonate,[21],[22] and can clinically present with omphalitis, delayed separation of the cord, mild skin infections, fever, or pneumonia in the 1st weeks of life. Maternal diabetes has been identified as a condition that affects the chemotactic activity of cord blood neutrophils.[23],[24] The authors have previously shown that gestational diabetes leads to the impairment of cord blood neutrophil motility and postphagocytic bactericidal capacity independently from the insulin requirement for the maintenance of normoglycemia during pregnancy.[25] In addition, prenatal exposure to magnesium sulfate, a drug that is frequently used for attempted tocolysis in preterm labor contributes to the alteration of neutrophil motility and post-phagocytic bactericidal capacity.[26] The intrauterine induction of chemotactic activity and metabolic oxygenation of neutrophils may predispose to the development of pulmonary hemorrhage early after birth, in extremely low birthweight infants with respiratory distress.[27]
Equilibrium in the complement system is also important for the maintenance of a normal pregnancy. The normal human pregnancy is associated with evidence of complement activation, as determined by higher concentrations of the anaphylotoxins C3a, C4a and C5a in the maternal circulation.[28] Since the fetus is semiallogenic to the mother, mechanisms have evolved to protect fetal tissue from the maternal immune response. Among these mechanisms is the expression of cell-surface complement regulatory proteins at the maternal-fetal interface.[29] Complement factors do not cross the placenta and the fetus begins synthesizing complement proteins at 6-14 weeks of gestation. The trophoblastic cells express high levels of complement-inhibitory proteins to control the complement-mediated damage.[30] The high levels of complement inhibitory proteins (decay-accelerating factor, membrane cofactor protein, and CD59) that are present in the trophoblasts prevent uncontrolled complement activation that would otherwise lead to fetal injury or death in utero . Antiphospholipid antibody-induced fetal loss is associated with complement C3 activation.[31] In maternal plasma, the concentration of anaphylatoxin (C5a) increases in association with preterm delivery.[32] Elimian et al have shown amniotic fluid complement C3 is of value in the diagnosis of intra-amniotic infection during preterm labor with intact membranes.[33] The upregulation of gene expression for the complement factors has been identified in association with premature rupture of membranes.[34]
Neutrophils and complement during the neonatal period
Within the first 24 hours of the neonate's life, the circulating neutrophil count increases abruptly and then gradually stabilizes by 48 to 72 hours.[35] This transient rise in the neutrophil count is paralleled by an increase in the circulating neutrophil progenitors, which gradually decrease over the first weeks of life.[36] Furthermore, cycling rates of hematopoietic cells and absolute numbers of immature and mature circulating neutrophils are elevated in neonates compared with adults.[37],[38] Neutrophil counts at 12 hours after birth range from 7,000 to 15,000/mcL in term infants, and at times are higher in preterm neonates compared with children and adults.[38],[39]
Complement protein concentrations increase after birth and approximate mean adult values between 6 and 18 months of age.[40] Reference values of C1r, C2, C5, C7, Properdin, and factors D, H, and I and C3a and C5a have been determined in cord blood samples from healthy term newborns.[41] Gestational age dependent reduction of complement activity and its regulation has been reported in prematurely born neonates.[42],[43],[44],[45] The authors have previously shown that in preterm born infants without evidence of infection, the cord blood levels of effective molecule of the complement components are significantly lower than in maternal serum.[46] Despite very low levels of native complement proteins, preterm babies are able to generate remarkable amounts of activation products of the complement cascade.[47] Miyano et al[48] have shown that the C3 activation system seems to be well developed even before week 25 of gestation. They reported that among the complement components, C3d was the most sensitive indicator of placenta inflammation.[48] In a previous study,[49] they authors found increased C5 on day 3-4 of life in infants born prematurely after preterm premature rupture of membranes.
Neutrophil functional deficiency and associated neonatal pathology
In general, neonatal neutrophil progenitors have a limited capacity to increase neutrophil production in response to infection, which becomes especially important as preterm born neonates have lower numbers of circulating neutrophils.[50] Neutropenia and depleted neutrophil storage pools have been found to be associated with neonatal bacterial sepsis and are predictive of a poor prognosis.[51],[52],[53],[54] In addition to the quantitative defects, numerous qualitative impairments such as defects in endothelial adherence, transendothelial migration, chemotaxis, phagocytosis, and intracellular killing[55],[56],[57],[58] adversely affect the neonatal neutrophils' capacity to fight infection.[59],[60],[61] This interconnects with larger evidence that newborn infants, especially when delivered prematurely, are at considerable risk for bacterial and fungal infections.[62],[63],[64]
Neonatal neutrophils have adhesion defects because of their defective expression and storage of CD18/CD11b, a member of the β 2 integrin family of adhesion molecules.[65],[66] The total cellular CD11b is diminished in neonatal neutrophils.[56] The lower functional expression of CD11b on neonatal neutrophils correlates with the defect in neutrophil-endothelial adherence.[67] A possible contributory role of defective CD11b function to neonatal infections is supported by the reports of severe recurrent bacterial infections in patients with leukocyte adhesion deficiency.[68] In addition, L-selectin, with ligands expressed on the endothelial surface mediate neutrophil cell adhesion during inflammation, and although L-selectin is expressed at higher levels on hematopoietic progenitor cells of neonates compared with those of adults,[69] neonatal neutrophils in the human and in animal models have lower levels of L-selectin.[55],[70],[71] Moreover, L-selectin levels decrease during the first 24 to 72 hours of life[50] in association with transient leukocytosis[72] and remain low compared with neutrophils of adults, and are even lower in the neutrophils of premature neonates.[55],[73] The decreased surface expression of L-selectin on neutrophils correlates with their impaired capacity to "roll" on vascular endothelium, a process that is important to the initiation of subsequent adhesive events.[55]
In addition to the adhesive defects, neutrophils from neonates respond poorly to a variety of inflammatory stimuli[71] due to impaired calcium metabolism[74] and abnormal actin polymerization.[75] The Guanosine triphosphate-binding protein (Rac2), an essential regulator of human neutrophil migration and chemotaxis, is significantly lower in the neutrophil protein lysates isolated from cord blood compared with adult blood.[76] Reduced neutrophil migration has been suggested as a reason for the serious bacterial infections seen in preterm neonates despite antibiotic prophylaxis in the mother.[77]
In addition to the disadvantages with respect to the phagocytic activity of neutrophils, neonates, especially those born prematurely, have an age-specific diminution of opsonins such as fibronectin, immunoglobulins, and complement including mannose-binding lectin,[78],[79],[80],[81],[82] Deficiency of such opsonins impairs the neutrophils' phagocytic capacity in neonates.[63],[83] Moreover, neutrophils, especially from immature neonates have variable in vitro efficiency in killing certain bacteria.[84] Impaired bactericidal activity of the neonatal neutrophils is associated with lower capacity to activate the respiratory burst and lower concentrations of elastase and lactoferrin in the neutrophil granules,[85], [86] which can also be activated by reactive oxygen species, signaling molecules that eventually lead to apoptosis of target cells. Defects in newborn neutrophil function such as decreased ability to generate O 2- in response to neutrophil stimulation increases susceptibility to infection.[87] Subnormal respiratory burst function and intracellular killing has been observed in children diagnosed with myeloperoxidase, glutathione synthetase, and glucose-6-phosphate dehydrogenase deficiency.[88],[89]
Dysfunctional inflammatory responses have been implicated in several neonatal inflammatory disorders following infection and/or hypoxia, especially among neonates born prematurely. The mechanism of this association is not clear. However, lower responsiveness to lipopolysaccharide (LPS) stimulation during hypoxia and altered apoptosis may increase the rate of chronic inflammatory disorders in the neonatal population.[90],[91],[92]
There is evidence that apoptosis is necessary for maintenance of neutrophil homeostasis and elimination of functional neutrophils, and therefore, the resolution of inflammation.[93],[94] Generally, circulating neutrophils undergo apoptosis within 24 to 48 hours of their egress from the bone marrow.[94] Continued presence of neutrophils with functional longevity can be an inciting factor in the pathogenesis of chronic inflammatory disorders.[95],[96] In contrast, prolonged survival of activated neutrophils may promote the elimination of bacteria and further leukocyte recruitment in the presence of severe sepsis.[94],[97]
Neonatal neutrophils have a constitutive delay in apoptosis[98] that can be explained in part by the decreased functional expression of caspase-3, a common component of several key pathways of apoptosis.[99] Some studies suggest that neonatal neutrophils with prolonged survival retain specific cytotoxic and inflammatory functions and may have the functional capacity to contribute to the pathogenesis of inflammatory disorders[100],[101] such as chronic lung disease.[92],[91] An imbalance between neutrophil elastase and its inhibitors such as serine protease and cathepsin has been also implicated in development of chronic lung disease.[102]
Complement deficiency and associated neonatal pathology
It has been shown that complement activation is largely responsible for the neutrophil inflammatory response.[103] However, the consistent deficiencies in complement components and receptors seen in neonates, especially those born prematurely may be associated with different pathology, relative to the neonatal period of life. Lassiter et al showed that diminution of C9 in newborn plasma, which is 10-20% compared with adult values, affects their ability to kill E-coli .[104] The profound C9 deficiency found in neonates' correlates with gestational age and limits the capacity to form membrane attack complex (MAC), and may predispose to severe invasive bacterial infections.[105]
Different cells synthesize complement proteins such as the complement proteins synthesized and secreted by the type III epithelial cells and alveolar macrophages. Structural and functional similarity between surfactant proteins A and D (SP-A and SP-D) and complement activators including C1q and mannose binding lectin (MBL) has been observed. In addition, both surfactant and MBL structurally belong to the collectin family. Turker et al showed that among preterm neonates with respiratory distress syndrome, poor response to surfactant therapy is associated with lower serum levels of C4 at admission and C4 and C3c on the first day of life.[106] Interestingly, SP-A blocks complement activation (binds to C1q) and therefore, minimizes complement-induced lung damage.[107] Complement activation precedes cytokine release, which may suggest a primary role for complement in the pathophysiology of meconium aspiration syndrome that is a serious condition in newborns, and is associated with a poorly characterized inflammatory reaction. Membrane attack complex is increased substantially in the plasma of neonates with meconium aspiration syndrome and closely correlates with the severity of the lung dysfunction.[108] The development of respiratory distress in preterm born neonates is associated with significantly lower levels of CH50, C3, C4, C3d3 and factor B compared as to infants without lung diseases.[109]
Studies have shown that complement is activated in the cord blood of neonates born with significant acidosis. The association between acidosis and complement activation is characterized by increasing levels of complement degradation products (C5a, C3a) and MAC in the cord blood.[110] Sonntag et al showed that in infants with fetal acidosis complicated with hypoxic-ischemic encephalopathy, plasma C1q and factor B as well as hemolytic activity of the complement system is decreased because of increased release of the sub-cellular constituents, mostly mitochondrial proteins which bind to C1q and activate the complement cascade in vitro and in vivo.[111] It has been shown that IgG down regulates the complement attack on host tissues by controlling complement binding to target tissues or cells.[112]
Infection in neonates also induces complement activation through the activation of the alternative complement pathway. As a result, the release of the anaphylatoxin C3a mediates inflammatory reactions such as vasodilatation and an increase in the micro-vascular permeability.[113] Recently reported evidence indicates that complement activation is the pathologic mechanism of injury in the post-hypoxic-ischemic neonatal brain because complement activation participates in the ischemia-reperfusion injury associated with temporary loss of blood flow.[114] Diminished C9 and increased MAC have been reported in the spinal fluid of newborn infants with moderate to severe hypoxic-ischemic encephalopathy.[115] The analysis of post-mortem cerebral tissue showed deposition of C9 on all the neurons, including the morphologically apoptotic neurons.
The possibility of regulating complement activation to protect tissue damage has been discussed in the literature. Frank et al have reported on the ability of IgG to down regulate complement attack on host tissue by controlling complement binding to target tissues or cells.[112] Their finding becomes pertinent because prematurely born neonates have a poor capacity to control complement activation due to lower levels of circulating IgG,[116],[117] and are therefore more vulnerable to complement-mediated damage of the lung and brain.[43],[44],[45]
Conclusion
This review highlights the most prominent results of current research regarding the association between common pathology in newborn infants, and the quantitative and qualitative functional capability of their neutrophils and complement proteins.
Different maternal conditions that exist during the intrauterine stage and preterm delivery affect myelopoiesis, and neutrophil and complement function in the newborn infant. Neutrophils from neonates, particularly those born prematurely, show dysfunction in chemotaxis, integrin-mediated adhesion, oxygen-dependent and independent microbial killing. In addition, neonatal serum has low opsonization capacity and complement protein deficiency that significantly contributes to the susceptibility and development of serious neonatal infection and inflammation-related morbidity. Moreover, the poor capacity to control spontaneous complement activation makes preterm neonates extremely vulnerable to complement-mediated damage of the lung and brain.
Further research is needed to better define: (i) the role of neutrophils and complement in neonatal infection and inflammation related pathology, and (ii) the pharmacologic agents that enhance the immune response to infection and safely inhibit uncontrolled complement activation in order to protect against major organ injury.
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