C3 convertase cleavage of C3 generates C3b, the primary effector molecule of the complement system, and cleavage product C3a, a mediator of inflammation

C3 convertase cleavage of C3 generates C3b, the primary effector molecule of the complement system, and cleavage product C3a, a mediator of inflammation. of soluble mediators in plasma for which age-dependent differences in abundance may influence the ontogeny of immune function, particularly direct innate interaction and skewing of adaptive lymphocyte activity in response to infectious microorganisms and adjuvanted vaccines. Keywords: plasma, serum, immunoregulatory, immune, NK314 neonatal Introduction Plasma, the fluid component of blood, is a complex mixture of water, NK314 proteins, electrolytes, lipids, sugars, hormones, and gas molecules. Plasma components also infiltrate the extravascular space and tissues and have a considerable influence on many physiological processes, including being an efficient transport medium for systemic signaling. The study of plasma is complicated by the complexity of its composition C several hundred distinct proteins (1), and hundreds of small molecules (2) have been analyzed in plasma by mass spectrometry. While many of these molecules have uncharacterized functions, there is a growing evidence that many of the factors in plasma that are well-characterized help to shape the response to infection, inflammation, and immunity (3C6). Many plasma molecules vary in concentration as a function of age, and we seek here to describe both the immunoregulatory capacity of some of the best-studied molecules and the age-dependent regulation of their abundance in circulation (see Table ?Table1)1) in the context of well-described deficits in neonatal immune system NK314 function (7, 8). Particular consideration is given to molecules, including cytokines, hormones, lipids, vitamins, and purines that influence the differentiation, activation, and effector functions of subsets of T cells (Figure ?(Figure1).1). Additionally, several classes of proteins, including immunoglobulins (Igs), the complement system, and anti-microbial proteins and peptides (APPs), aid in the innate response to invading microorganisms and display age-dependent maturation (Figure ?(Figure1).1). The critical role that plasma components play in immune function NK314 also highlights the importance of including autologous or pooled species- and age-specific plasma in the extracellular milieu in assay systems, instead of xenologous media (e.g., fetal calf serum), which is more commonly utilized. Table 1 Age-dependent changes in various soluble factors that influence innate and adaptive immune function, and list of references to literature regarding their concentrations in blood (Levels) and their function related to immune cell function (function). and studies have demonstrated an impairment of neonatal leukocytes to produce Th1-polarizing cytokines, such as IL-12p70 and tumor-necrosis factor alpha (TNF-), as compared to adult leukocytes (11, 24C26). A comparison of newborn and adult serum levels of the T-cell polarizing cytokines TNF- and IL-6 reveals that the ratio between these cytokines during the first 7?days of life is significantly NK314 different from adults (11). TNF-, a Th1-polarizing cytokine, is consistently Rabbit Polyclonal to ACOT1 low in cord blood and peripheral blood drawn during the first days of life, as compared to adult blood. In marked contrast to TNF-, IL-6 levels in cord blood are higher than in adult blood, and continue to rise during the first days of life. IL-6 is a cytokine that is capable of inducing Th2-polarization (9) or Th17 polarization, in combination with IL-23 and TGF- (140). In addition, it induces the production of acute-phase proteins C-reactive protein (CRP) and LPS-binding protein (LBP) (141), and has anti-inflammatory properties such as inhibition of neutrophil migration (10, 142). In addition to distinct basal levels of serum cytokines, newborns also demonstrate a distinct pattern of cytokine production after immunization, including impairment in the production of the pro-inflammatory/Th1-polarizing cytokine IFN- to many vaccines (33C35), with the possible exception of bacille CalmetteCGurin (BCG) (143). IFN- is expressed by Th1 cells, activating macrophages to kill microbes, promoting leukocyte cytotoxicity, and inducing apoptosis of epithelial cells in the skin and mucosa (29, 30) In addition to its role in the development of a Th1 response and B-cell isotype switching (31), IFN- regulates MHC class I and II protein expression and antigen presentation as well (32). Overall, neonatal impairment in infection- or immunization-induced IFN- production is believed to be an important contributing factor in their susceptibility to intracellular pathogens. In addition, mononuclear cells from preterm newborn blood produce significantly less IFN- following stimulation than mononuclear cells from term newborns (27). Several studies comparing neonatal cord and adult peripheral blood mononuclear cells have demonstrated a discordance in the secretion of T-cell polarizing cytokines after stimulation with (144). Whole blood assays comparing cord blood and adult peripheral blood have confirmed that newborn cells produce less TNF- in response to common TLR agonists, such as polyinosinic:polycytidylic acid (Poly I:C, TLR3), Pam3CSK4 (TLR1/2), and lipopolysaccharide (LPS, TLR4) (138, 144, 145). Later studies supported these observations and established that newborn monocytes as well.