Role of Immune Changes in Neonatal Infections

Neonatal infection remains one of the main problems affecting sick neonates admitted to the neonatal intensive care units and is associated with high mortality and morbidities. Sick neonates with an infection have associated changes in innate and adaptive immune response that markedly affect their outcome. The increase of proinflammatory and decrease in anti-inflammatory mediators are believed to play a significant role in the outcome of multiple neonatal conditions such as bronchopulmonary dysplasia, necrotizing enterocolitis, white matter injury, and cerebral palsy and long-term developmental delay.

T-cell immune system is immature at birth with a marked predominance of naive T-cells. However, neonates are capable of increasing the expression of memory T-cells in response to infection. The increase in memory T-cells expression persisted after recovery from sepsis.[1] Memory T-cells are responsible for the rapid and enhanced immune response on reexposure to previously encountered antigens including autoimmune and allergic diseases, or infectious agents such as bacteria and viruses.[2] [3]

Understanding the immunologic changes during neonatal infection and the role of proinflammatory cytokines in the survival of these critically sick neonates at the expense of extensive tissue damage may play a significant role in our future ability to improve the outcome of these sick neonates.

The postnatal development of the immune system in neonates involves a transition from higher levels of immune regulatory cytokines to higher levels of inflammatory cytokines. Newborns who have defects in upregulating proinflammatory cytokines are more susceptible to infection. An imbalance of proinflammatory and anti-inflammatory cytokines is associated with an increased risk of infection. Characterization of these cytokines can help in developing therapeutic modules to make these newborns more resilient against microbial invaders.[4]

In this special issue of the journal, the role of immunological changes during neonatal infection is reviewed. In the first article, the biology of T-helper cells and their role in neonatal infection is reviewed. These T-helper cells are central players of adaptive immune system that provides protection and surveillance against infections. The differentiation of naive T cells into various subsets of T-helper cells such as Th1, Th2, Th17, and Treg depends on orchestrated and coordinated interplay of cytokines; cytokine-mediated signaling, core, and inducible transcription factors.[5]

In the second article, chorioamnionitis-induced immunological changes and their effects in neonatal outcome are reviewed. This term implies that a pregnant woman has an “inflammatory or an infectious” disorder of the chorion, amnion, or both.[6] [7] Chorioamnionitis is the inflammation of the placenta with associated high levels of cord blood proinflammatory cytokines.[8] [9] The role of the high levels of the chorioamnionitis-associated proinflammatory cytokines in neonatal morbidities such as white matter injury or necrotizing enterocolitis was reviewed.[10] [11] In the third article, the immunological changes during group B streptococcal (GBS) infection in neonates are reviewed. GBS causes invasive infection in neonates and is a leading cause of pneumonia, neonatal sepsis, meningitis, and a high rate of death.[12] The article emphasizes that a greater understanding of the interaction between GBS and the neonatal immune system may aid in the development of novel therapies or preventative measures for invasive GBS disease.

In an attempt to treat these sick extremely premature neonates with immunologic agents, such as granulocyte colony-stimulating factor (G-CSF) or intravenous immunoglobulin (IVIG) data were presented in the fourth and fifth articles. The fourth article is a prospective study to examine the role of recombinant rhG-CSF in modulating the inflammatory response in extremely low gestational age neonates. G-CSF serves an important cellular role in production and maturation of neutrophils as well as a clinical role in response to infection and inflammation and primes granulocytes to enhanced immune defenses.[13] [14] [15] [16] The study showed that rhG-CSF use is associated with lower tumor necrosis factor (TNF) levels. The study concluded that during critical illness or sepsis, rhG-CSF might have benefits as a drug that can elevate neonatal neutrophil number and function while simultaneously limiting collateral injury due to TNF.

In the fifth article, white blood cells, absolute neutrophil count, and monocytes increased in a response to rhG-CSF and IVIG combination treatment in extremely low-birth-weight neonates with necrotizing enterocolitis without effect on survival, need for surgery, time to reach full feed, or time to discharge home.

The advance in the field of genomics, transcriptomics, and proteomics will enhance our ability to understand the specific immunologic changes during neonatal infections. This understanding will help us better treat neonatal infections and develop better antibiotics stewardship, as reviewed in the sixth article, to avoid the side effects associated with the overuse of these antibiotics.

• References

• 1 Omar SA, Wooliever D, Herrington CJ, Lorenz JM, Rawas F, Huard T. Expression of naïve and memory T-cells in newborn infants with early-onset sepsis. J Pediatr Infect Dis 2009; 4: 233-239
• 2 Wallace DL, Beverley PC. Phenotypic changes associated with activation of CD45RA+ and CD45RO+ T cells. Immunology 1990; 69 (03) 460-467
• 3 Bradley LM, Bradley JS, Ching DL, Shiigi SM. Predominance of T cells that express CD45R in the CD4+ helper/inducer lymphocyte subset of neonates. Clin Immunol Immunopathol 1989; 51 (03) 426-435
• 4 Schelonka RL, Maheshwari A, Carlo WA. , et al; NICHD Neonatal Research Network. T cell cytokines and the risk of blood stream infection in extremely low birth weight infants. Cytokine 2011; 53 (02) 249-255
• 5 Coquet JM, Rausch L, Borst J. The importance of co-stimulation in the orchestration of T helper cell differentiation. Immunol Cell Biol 2015; 93 (09) 780-788
• 6 Blanc WA. Pathways of fetal and early neonatal infection. Viral placentitis, bacterial and fungal chorioamnionitis. J Pediatr 1961; 59: 473-496
• 7 Higgins RD, Saade G, Polin RA. , et al; Chorioamnionitis Workshop Participants. Evaluation and Management of Women and Newborns With a Maternal Diagnosis of Chorioamnionitis: Summary of a Workshop. Obstet Gynecol 2016; 127 (03) 426-436
• 8 Yoon BH, Romero R, Kim CJ. , et al. Amniotic fluid interleukin-6: a sensitive test for antenatal diagnosis of acute inflammatory lesions of preterm placenta and prediction of perinatal morbidity. Am J Obstet Gynecol 1995; 172 (03) 960-970
• 9 Pacora P, Chaiworapongsa T, Maymon E. , et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med 2002; 11 (01) 18-25
• 10 Yoon BH, Jun JK, Romero R. , et al. Amniotic fluid inflammatory cytokines (interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha), neonatal brain white matter lesions, and cerebral palsy. Am J Obstet Gynecol 1997; 177 (01) 19-26
• 11 Martinez-Tallo E, Claure N, Bancalari E. Necrotizing enterocolitis in full-term or near-term infants: risk factors. Biol Neonate 1997; 71 (05) 292-298
• 12 Centers for Disease Control and Prevention. Active Bacterial Core Surveillance Report, Emerging Infections Program Network, Group B Streptococcus (2015). Available at: https://www.cdc.gov/abcs/reports-findings/surv-reports.html . Acessed August 1, 2016
• 13 Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (1). N Engl J Med 1992; 327 (01) 28-35
• 14 Roberts AW. G-CSF: a key regulator of neutrophil production, but that's not all!. Growth Factors 2005; 23 (01) 33-41
• 15 Dale DC. Potential role of colony-stimulating factors in the prevention and treatment of infectious diseases. Clin Infect Dis 1994; 18 (12) (Suppl. 02) S180-S188
• 16 Franzke A. The role of G-CSF in adaptive immunity. Cytokine Growth Factor Rev 2006; 17 (04) 235-244