The mechanism to maintain homeostasis of the gut microbiota remains largely unknown despite its critical role in the body defense. In the intestines of mice with deficiency of activationinduced cytidine deaminase (AID), the absence of hypermutated IgA is partially compensated for by the presence of large amounts of unmutated IgM and normal expression levels of defensins and angiogenins. We show here a predominant and persistent expansion of segmented filamentous bacteria throughout the small intestine of AID ؊/؊ mice. Reconstitution of lamina propria IgA production in AID ؊/؊ mice recovered the normal composition of gut flora and abolished the local and systemic activation of the immune system. The results indicate that secretions of IgAs rather than innate defense peptides are critical to regulation of commensal bacterial flora and that the segmented filamentous bacteria antigens are strong stimuli of the mucosal immune system. M ucosal epithelial surfaces represent points of continuous and intimate interactions between the immune system and the outside environment. Under a constant antigenic pressure from Ͼ400 species of commensal bacteria, the gut immune system has developed highly sophisticated and efficient defensive as well as symbiotic mechanisms (1, 2). Secretion of antibiotic peptides by epithelial cells represents an important component of the innate immune system in the gut. Bacteria or bacterial antigens are capable of stimulating secretion of large amounts of antimicrobial peptides by crypt Paneth cells (3, 4). Also, transgenic (Tg) mice expressing a human intestinal defensin are protected against enteric salmonellosis (5), whereas mice deficient in the metalloproteinase matrilysin MMP-7 and thus lacking mature cryptdins show decreased resistance to some intestinal infections (6). Therefore, antimicrobial peptides appear to be involved in the maintenance of the symbiotic environment in the gut and protection of crypt stem cells from infections.Another front line body defense mechanism that provides protection against microbial agents at mucosal surfaces is production and secretion of IgA (7). Indeed, IgA is the most abundant Ig isotype in mucosal secretions, and at least 80% of all plasma cells in mice are located in the intestinal lamina propria (LP) (8). The gut IgA responses are initiated primarily in organized lymphoid structures present in the intestine, namely Peyer's patches (PP) (9) and the isolated lymphoid follicles (ILFs), which have architecture similar to PP (10, 11). These structures contain a large number of conventional B2 cells, which are derived from precursor cells generated in the bone marrow (BM) (9, 10). In addition, peritoneal cavity B1 cells contribute to intestinal IgA plasma cells. B1 cells are shown to generate large amounts of IgAs independent of T cells and germinal centers (GC) (12, 13). Both B1 and conventional B2 cells are most likely to switch in situ from IgM to IgA in the LP with the help of dendritic cells and factors secreted by stromal cells (14). However, it is...

Peritoneal B1 cells are known to generate large amounts of antibodies outside their residential site. These antibodies play an important role in the early defense against bacteria and viruses, before the establishment of adaptive immune responses. Although many stimuli, including antigen, lipopolysaccharide, or cytokines, have been shown to activate B1 cells and induce their differentiation into plasma cells, the molecular signals required for their egress from the peritoneal cavity are not understood. We demonstrate here that direct signals through Toll-like receptors (TLRs) induce specific, rapid, and transient down-regulation of integrins and CD9 on B1 cells, which is required for detachment from local matrix and a high velocity movement of cells in response to chemokines. Thus, we revealed an unexpected role for TLRs in governing the interplay between integrins, tetraspanins, and chemokine receptors required for B1 cell egress and, as such, in facilitating appropriate transition from innate to adaptive immune responses.

Inconclusive evidence for the efficacy of infliximab in sarcoidosis hinders the global use of this potentially beneficial drug. To study infliximab efficacy in a clinical setting, we performed a prospective open-label trial in patients refractory to conventional treatment.Patients (n=56) received eight infusions of 5 mg·kg -1 infliximab. Pulmonary function, disease activity measured by 18 F-fluorodeoxyglucose (FDG) by positron emission tomography (PET) and quality of life were part of the clinical work-up. Infliximab levels were measured before every infusion.After 26 weeks of infliximab treatment, mean improvement in forced vital capacity (FVC) was 6.6% predicted ( p=0.0007), whereas in the 6 months before start of treatment, lung function decreased. Maximum standardised uptake value (SUVmax) of pulmonary parenchyma on 18 F-FDG PET decreased by 3.93 ( p<0.0001). High SUVmax of pulmonary parenchyma at baseline predicted FVC improvement (R=0.62, p=0.0004). An overall beneficial response was seen in 79% of patients and a partial response was seen in 17% of patients. No correlation between infliximab trough level (mean 18.0 µg·mL -1 ) and initial response was found.In conclusion, infliximab causes significant improvement in FVC in refractory

Besides their role in destruction of altered self-cells, NK cells have been shown to potentiate T-cell responses by interacting with DC. To take advantage of NK-DC crosstalk in therapeutic DC-based vaccination for infectious diseases and cancer, it is essential to understand the biology of this crosstalk. We aimed to elucidate the in vitro mechanisms responsible for NK-cell recruitment and activation by DC during infection. To mimic bacterial infection, DC were exposed to a membrane fraction of Klebsiella pneumoniae, which triggers TLR2/4. DC matured with these bacterial fragments can actively recruit NK cells in a CCR5-dependent manner. An additional mechanism of DC-induced NK-cell recruitment is characterized by the induction of CCR7 expression on CD56 dim CD16 1 NK cells after physical contact with membrane fraction of K. pneumoniae-matured DC, resulting in an enhanced migratory responsiveness to the lymph node-associated chemokine CCL19. Bacterial fragment-matured DC do not only mediate NK-cell migration but also meet the prerequisites needed for augmentation of NK-cell cytotoxicity and IFN-c production, the latter of which contributes to Th1 polarization.Key words: CCR5 . CCR7 . NK-DC interaction . Th1 polarization Supporting Information available online Introduction NK cells are important effector cells in the innate immune response against virally infected or malignantly transformed cells and their cytotoxicity is regulated by a delicate balance of inhibitory and activating signals [1]. Recent studies suggest that the interplay between NK cells and DC, the specialized antigenpresenting cell of the innate immune system [2], is critical in shaping the adaptive immune response [3]. This concept originates from several lines of evidence including: the discovery of NK cells colocalizing with DC in the T-cell areas of lymph nodes [4,5], the coupling of NK-cell recruitment to lymph nodes à These authors contributed equally to this work. 3138with the induction of more potent Th1 skewing [3], and the identification of NK-cell subpopulations with helper properties [6]. Although the exact mechanisms of NK-DC interaction remain to be elucidated, increasing evidence supports the importance of bidirectional NK-DC crosstalk [7,8].On the one hand, NK-DC crosstalk is characterized by the capacity of activated NK cells to induce DC maturation with elevated IL-12p70 production and subsequently an increased capacity to induce Th1 and CTL responses [9]. This NK-induced DC maturation depends at least in part on soluble factors such as and as well as on engagement of the natural cytotoxicity triggering receptor 30 [12]. Moreover, NK cells control the quality of the adaptive immune response by natural cytotoxicity triggering receptor 30-mediated lysis of immature or inadequately matured DC [13], enabling only fully mature DC to migrate into lymph nodes and subsequently prime T cells. On the other hand, DC are able to induce NK-cell proliferation, augmentation of cytotoxicity and cytokine secretion [8]. The DC-induced modulati...

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