Special Issue on Perinatal InflammationImmune responses in perinatal brain injury
Introduction
The immune system can be broadly divided into the innate and the adaptive branch. Traditionally, the innate immune system is defined as fast acting and responds to a broad array of pathogens, whereas the adaptive immune system is tailored towards specific pathogens and has memory. However, there is immense cross-talk between the two branches of the immune system and between different immune organs (Gensollen et al., 2016, Tamburini et al., 2016), and emerging evidence suggest that even innate immune cells have memory (Netea et al., 2016).
The immune system is comprised of circulating blood cells, cells in secondary lymphoid organs (e.g. lymph nodes, tonsils, spleen) and cells resident in specific tissues (such as the skin, gut and the brain). Under pathological conditions, such as multiple sclerosis, peripheral cells are also found in tertiary lymphoid structures, such as the brain (Kuerten et al., 2012). Immune cell types are extremely heterogeneous and the phenotype and functional properties of each subset depends on the microenvironment, and hence the tissue that the cells reside in. All mature cells are derived from pluripotent hematopoietic stem cells, which in early development, can emerge from the yolk sac, chorioallantoic placenta and aorta-gonad-mesonephros region (Dzierzak and Speck, 2008). These progenitor cells give rise to both lymphoid and myeloid progenitor cells that sequentially seed the liver, thymus, spleen and finally the bone marrow where hematopoiesis takes place throughout life (Boiers et al., 2013, Migliaccio et al., 1986). Microglia, the brain macrophage, originate from precursor cells in the yolk sac and invade the brain in early embryonic life, where they are long-lived (Ginhoux et al., 2010).
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Circulating immune cells in the human newborn
Upon birth, the immune system changes rapidly within hours to adapt to the ex utero milieu and then slowly matures over the following weeks to months (Christensen et al., 2012, Dowling and Levy, 2014, Xanthou, 1970). In general, infants have higher absolute white cell (leukocytes) counts in the blood than adults and their numbers slowly decline until early childhood to teenage years when they reach adult levels (Quinello et al., 2014, Schmutz et al., 2008) (Table 1, Fig. 1). Neutrophil numbers
Immune responses in the human newborn
Although innate immune responses can be identified in the fetus early in gestation, they are not fully mature at birth. Similarly, fetal adaptive immune functions are largely inactive until term and develop specificity and memory after birth, which is completed only in early childhood (Hannet et al., 1992). The newborn receives some passive immunity via maternal transfer of IgG antibodies. However, maternal T cell-mediated immunity is not normally transferred to the offspring. Further, major
Immune cells in the neonatal rodent
Few studies have investigated the blood composition over time in neonatal rodents, likely due to the fact that neonatal mice have a small blood volume, thus preventing comprehensive investigations. However, there are studies of the neonatal murine spleen demonstrating that CD45+ leukocytes are the most abundant immune cell population in the first 4–5 days after birth. Then a massive accumulation of NRBCs in the murine spleen occurs on day 6 where they remain as one of the most predominant
Perinatal brain injury and activation of immune cells
Neonatal hypoxia-ischemia (HI) activates the immune system in the blood, peripheral organs, as well as in the brain. While excessive local inflammation in the brain evidently have some detrimental effects, emerging evidence is suggesting that microglia activation after injury can be protective. Also, there is a complex interplay between the peripheral immune system and the central nervous system (CNS). Peripheral immune cells and mediators can enter the brain to modulate CNS responses, while
Inflammatory responses in the periphery following hypoxia-ischemia
Experimental stroke in adult mice induces a peripheral inflammatory response that peaks at 4 h after stroke and precedes the peak in brain inflammation at 24 h (Chapman et al., 2009). This peripheral response is dominated by the induction of the chemokine (C-X-C motif) ligand 1 (CXCL-1) and the pro-inflammatory cytokine IL-6. Interestingly, CXCL-1 expression was similar in the liver and lung with significant increases at 4 h, corresponding to the pattern seen in the brain. Following neonatal HI,
Blood-brain barrier damage and perinatal brain injury
The BBB is the collective name for barrier systems situated at several blood-brain interfaces that tightly control the molecular exchange of compounds as well as immune cells in and out of the brain. The most studied of these interfaces is the brain vasculature and the choroid plexus, known as the blood-cerebral spinal fluid (CSF) barrier, but other interfaces such as at the meninges also exists. The endothelial cells are supported by pericytes and astrocytic endfoot processes, altogether known
Immune cell infiltration and perinatal brain injury
The BBB, apart from controlling the molecular flux of compounds into the brain, acts as a sophisticated gateway for immune cells crossing into the CNS. Peripheral cells can access the brain through different blood-brain portals, with the main ones being the parenchymal blood vessels, the choroid plexus and meningeal vessels. Under normal conditions in adults, CSF mainly contains memory CD4+ T-cell and a few monocytes, which are both present in low numbers (1–3 cells/uL). The function of these
Conclusions
Although the immune system is not fully mature at birth, it clearly has the ability to react to numerous stimuli. Neonatal HI activates immune cells in the blood, peripheral organs as well as in the brain and there are complex dynamic interactons between these different body compartments. During or after HI, circulating innate and adaptive immune cells are activated and proliferate, and some extravasate into the brain parenchyma (Fig. 2). Activation of peripheral immune organs, such as the
Acknowledgments
The research was supported by the Swedish Research Council (2012-2992), Government grant in Public Health Service at the Sahlgrenska University Hospital (ALFGBG-142881), The Leducq Foundation (DSRR_P34404), the Swedish Brain Foundation (FO2014-008), Åhlén Foundation and Torsten Söderberg Foundation (M98/15).
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