The two main components of the adaptive immune system, the T and B cell compartments, undergo maturation during human fetal life, with progressive and regulated acquisition of B and T cell repertoire diversity and complexity (35). susceptibility to specific infections, we hypothesize that GBS WZ4003 disease occurring in otherwise healthy infants could reflect an immunodeficiency caused either by rare genetic defects in the infant or by transmitted maternal neutralizing antibodies. These hypotheses are consistent with available epidemiological data, with clinical and epidemiological observations, and with the state of the art of neonatal physiology and disease. Studies should now be designed to comprehensively search for genetic or immunological factors involved in susceptibility to severe neonatal infections. reports that sepsis and other neonatal infections account for 336,300 neonatal deaths each WZ4003 year worldwide (18). The distribution of infecting microorganisms varies between term and preterm infants and is different in the neonatal period compared to other age groups. Early-onset and late-onset infections are defined as contamination occurring during and after the first 6?days of life, respectively. According to other definitions, 48C96?h of life could be used as cutoff (19). Group B streptococcus (GBS), or contamination, mostly associated with urinary tract contamination, in previously healthy, full-term infants aged 1?week to 3?months (22, 23). Other pathogens responsible for invasive contamination in full-term infants include Gram-positive (spp., spp., and, less frequently, spp., spp., spp., spp. and other fungal microorganisms are exceedingly rare in full-term infants. In very low-birth-weight (VLBW; 1,500?g at birth) infants, Gram-negative pathogens are the most frequently isolated microorganism in early-onset infections, while Gram-positive bacteria are the most frequently isolated pathogens in late-onset infections in the neonatal intensive care units (NICUs), followed by Gram-negative bacteria and fungal organisms (24C29). WZ4003 Susceptibility to Neonatal Infections Maturation of the Neonatal Immune System The neonatal immune WZ4003 responses differ in many aspects from immune responses in other age groups. A fine-tuning is required to balance the need for tolerance to beneficial antigens (microbial flora and nutrients) and the need for defense against harmful microorganisms. The cord blood is usually enriched in CD4+CD25+ T regulatory cells with potent suppressor activity (30, 31) and other immunosuppressive cell populations including some B cell populations and CD71+ erythroid cells (32, 33). Despite this strong immunosuppressive component, the neonatal immune system has been demonstrated to be able to mount pro-inflammatory responses that are appropriate for the protection against common pathogens in most infants (34). The two main components of the adaptive immune system, the T and B cell compartments, undergo maturation during human fetal life, with progressive and regulated acquisition of B and T cell repertoire diversity and complexity (35). In addition, the human cord blood possesses several pro-inflammatory cell populations, including newborn-specific interleukin (IL)8-generating DNMT T cells (36) and a populace of CD4+ T cells with a memory-like phenotype and a variety of effector functions (37). Cells of the neonatal adaptive immune system are capable of mounting a wide range of responses, from poor or deviant T helper 2 (Th2)-skewed antiinflammatory responses to balanced Th1/Th2 responses, and even strong adult-like pro-inflammatory responses (2C4, 38). A series of elegant experiments have shown that neonatal T cells, unlike adult cells, are able to produce large amounts of the Th2 cytokines, IL4 and IL13, upon polyclonal activation (39, 40). This phenomenon is linked to extensive epigenetic modifications at the Th2 locus (genes) WZ4003 and in particular to hypomethylation of the conserved non-coding sequence 1 locus, an enhancer and coordinate regulator of Th2 cytokine production (38,.