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Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs

Summary Introduction Among sensitized infants, those with high, as compared with low levels, of salivary secretory IgA (SIgA) are less likely to develop allergic symptoms. Also, early colonization with certain gut microbiota, e.g. Lactobacilli and Bifidobacterium species, might be associated with less allergy development. Although animal and in vitro studies emphasize the role of the commensal gut microbiota in the development of the immune system, the influence of the gut microbiota on immune development in infants is unclear. Objective To assess whether early colonization with certain gut microbiota species associates with mucosal and systemic immune responses i.e. salivary SIgA and the spontaneous Toll‐like receptor (TLR) 2 and TLR4 mRNA expression and lipopolysaccharide (LPS)‐induced cytokine/chemokine responses in peripheral blood mononuclear cells (PBMCs). Methods Fecal samples were collected at 1 week, 1 month and 2 months after birth from 64 Swedish infants, followed prospectively up to 5 years of age. Bacterial DNA was analysed with real‐time PCR using primers binding to Clostridium difficile, four species of bifidobacteria, two lactobacilli groups and Bacteroides fragilis. Saliva was collected at age 6 and 12 months and at 2 and 5 years and SIgA was measured with ELISA. The PBMCs, collected 12 months after birth, were analysed for TLR2 and TLR4 mRNA expression with real‐time PCR. Further, the PBMCs were stimulated with LPS, and cytokine/chemokine responses were measured with Luminex. Results The number of Bifidobacterium species in the early fecal samples correlated significantly with the total levels of salivary SIgA at 6 months. Early colonization with Bifidobacterium species, lactobacilli groups or C. difficile did not influence TLR2 and TLR4 expression in PBMCs. However, PBMCs from infants colonized early with high amounts of Bacteroides fragilis expressed lower levels of TLR4 mRNA spontaneously. Furthermore, LPS‐induced production of inflammatory cytokines and chemokines, e.g. IL‐6 and CCL4 (MIP‐1β), was inversely correlated to the relative amounts of Bacteroides fragilis in the early fecal samples. Conclusion Bifidobacterial diversity may enhance the maturation of the mucosal SIgA system and early intense colonization with Bacteroides fragilis might down‐regulate LPS responsiveness in infancy.

IntroductionThe development of novel therapies for sepsis depends on the understanding of the basic mechanisms of the disease. 1 The principal active agent involved in the pathogenesis of sepsis is bacterial lipopolysaccharide (LPS), an essential component of the surface of gram-negative bacteria. LPS exerts its toxic effects by potently activating macrophages and endothelial cells, and inducing the expression of inflammatory cytokines such as tumor necrosis factor ␣ (TNF␣) and interleukin 6 (IL-6). [2][3][4][5] Thus, elucidating how LPS signals through cell-surface receptors to induce inflammatory gene expression in humans is of major importance.Central to the recognition of LPS and also many other microbial products by the host is a family of transmembrane proteins that have leucine-rich repeats in their extracellular domains known as the toll-like receptors (TLRs). 6 LPS interacts with a heterologous receptor that contains TLR4 7,8 as well as CD14 9,10 and MD2. [11][12][13] As CD14 is a glycosyl phosphatidylinositol-anchored protein and MD2 is on the cell surface, transduction of the LPS signal across the membrane is mediated by TLR4. TLR4, as all TLR family members, contains a cytoplasmic domain that is homologous to a cytoplasmic domain found in the IL-1 receptor known as the Toll/IL-1 receptor (IL-1R) homology (TIR) domain that is essential for downstream signaling. [14][15][16] The presence of the TIR domain in both TLR and IL-1 receptor family members suggested that these receptors use an identical framework of signaling molecules to exert their downstream effects. This was supported by subsequent studies in mouse and human cell lines. Thus, IL-1R and TLR4 were shown to engage the TIR-containing cytosolic adaptor molecule myeloid differentiation protein 88 (MyD88) through homotypic interactions, [17][18][19] with subsequent recruitment of IL-1R-associated kinase (IRAK) and IRAK2, IRAK4, and TRAF6. 17,18,20,21 TRAF6 is thought to subsequently activate nuclear factor (NF)-B either through the IB kinase (IKK) complex and the kinases TAB-1 and TAK-1, 22 or through evolutionarily conserved signaling intermediate in Toll pathways (ECSIT) and mitogen-activated protein kinase/ERK kinase kinase 1 (MEKK-1). 23 The recent derivation of MyD88 Ϫ/Ϫ mice, however, challenged a universal role for MyD88 in LPS signaling. Although there was the expected complete ablation of IL-1 signaling, LPS still activated NF-B although the ability to induce TNF␣ from macrophages was lost. 24 In addition, LPS-induced NF-B activation and up-regulation of costimulatory molecules in bone marrowderived dendritic cells from these mice was not compromised. 25 To account for a MyD88-independent pathway of NF-B activation, a novel MyD88 homologue termed MyD88 adaptor-like (Mal) 26 or TIR domain-containing adaptor protein (TIRAP) 27 was described. This was shown to act as an adaptor protein specifically involved in TLR4 but not other TLRs or IL-1R-induced NF-B activation. 26,27 As Mal/TIRAP does not contain the death domain (DD) found in MyD88...

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