Innate immunity plays a very important role in the activation of the immune system and the ability to develop specific acquired immune responses. Through their Ag-presenting activity and the synthesis of numerous pro-inflammatory chemokines and cytokines (IL-8, IL-1, IL-6, TNF-a, and IL-12), macrophages, and DCs play a key role in the regulation of immune responses. They are the gatekeepers of the host, generating innate resistance to pathogens, and specific immune responses by the stimulation of T-cell-acquired immunity and regulation of the TH1/Th2 balance.
It has been postulated that the immune defects in neonates may result from a developmental immaturity of APC functions (78), and bacterial components resulting from intestinal colonization could be an important factor for maturation of APCs (95). Recently, Sun and coworkers (96) investigated the ontogeny of peripheral DCs and their capacity to provide innate responses to microbial stimuli in early life. They show that neonatal murine spleen DCs have intrinsic capacity to produce bioactive IL-12. Moreover, after microbial stimulation given in vitro by LPS, they are able to up-regulate MHC and costimulatory molecule expression required for productive interaction with naive T cells. Thus, neonatal DCs could be fully competent in their innate functions but they need to be activated, through TLR recognition as described previously, by bacterial stimuli afforded by the intestinal microbiota. Another interesting study supports this hypothesis. Nicaise and coworkers (97) demonstrated that the presence of the intestinal microbiota underlies IL-12 synthesis by macrophages derived from splenic precursors.
On the basis of those experimental data, one can wonder whether the first bacteria colonizing the intestinal tract, E. coli, rich in LPS, and subsequently bifidobacteria rich in peptidoglycan and CpG dinucleotides, do not play such crucial activating roles? It is conceivable that in newborns, the abrupt colonization of the intestinal tract by the microbiota may induce a physiological inflammatory reaction with, as a consequence, an increase in intestinal permeability, bacterial translocation and systemic activation of immune cells, especially APCs. Experimental evidence supports that hypothesis. Studies in mice have shown that the presence of the intestinal microbiota induces the synthesis of pro-inflammatory cytokines IL-1, IL-6, and TNF-a by peritoneal macrophages. Such effects can be reproduced in gnotobiotic mice colonized with E. coli alone while a Bifidobacterium bifidum strain isolated from baby's feces had no effect (Table 3) (98).
Other non-specific resistance factors play an important role in host defense mechanisms to infection. GF and gnotobiotic animal models have showed that some functional parameters involved in innate immunity, phagocytosis, complement system, and opsonins, are expressed to a lesser extent than in CV animals (99).
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