IntroductionProtection against different classes of pathogens requires the activation of Ag-presenting dendritic cells (DCs) to express factors that promote the development of distinct effector Th-cell subsets, which are specialized to combat the class of pathogen involved. 1 Effective T cell-mediated immunity against extracellular bacteria requires DCs to produce IL-1␤, IL-6, and IL-23 that contribute to the development of Th17 cells. 2,3 The pathogen-induced production of cytokines by DCs is induced on sensing of pathogens by pattern-recognition receptors (PRRs), including TLRs, C-type lectins, Nod-like receptors, and RIG-I-like receptors. [4][5][6][7] Although triggering of individual PRRs is known to induce cytokine production, it is becoming increasingly clear that the ultimate amount and the profile of cytokine production by DCs crucially depends on cross-talk between multiple PRRs. 8-10 However, our knowledge on these cross-talk mechanisms is likely to be still largely incomplete. 10 In this respect, the role of Fc␥Rs, the family of high-and low-affinity receptors for IgG, in the induction of cytokine production did not receive much attention. IgG is the most prevalent immunoglobulin in the blood and body tissues. 11,12 Because of the high levels of IgG directed against numerous polyreactive bacterial Ags, invading bacteria are efficiently opsonized as soon as they penetrate the body's barriers, even during primary infection. [13][14][15][16][17] IgG opsonization can directly lead to pathogen inactivation via complement activation, but can also result in a variety of responses by different effector immune cells such as cell degranulation, production of reactive oxygen species (ROS), or Ab-dependent cellular cytotoxicity (ADCC). 18,19 In addition, binding of opsonized pathogens to low-affinity Fc␥Rs on DCs mediates phagocytosis, degradation and subsequent presentation of pathogen-derived Ags to T cells. 20 Fc␥R stimulation also induces DC maturation. [21][22][23] However, the triggering of Fc␥Rs on DCs results in no or only low production of cytokines and has not been demonstrated to play a major role in polarization of human T-cell responses in healthy donors. 21,22 In the present study, we have taken into account that in most conditions DCs will engage bacteria that are IgG opsonized and that such DCs will be simultaneous triggered via Fc␥Rs and bacterial sensors. We here report that the engagement of DCs with opsonized bacteria resulted in strongly up-regulated production of selected cytokines, including IL-1␤ and IL-23, which favored the development of Th17 cells. This effect was fully dependent on stimulation of the low-affinity IgG receptor Fc␥RIIa (also known as CD32a), which synergized with TLRs for the amplification of Th17-promoting cytokines by both enhancing cytokine transcription and by activating caspase-1. Taken together, these data identified cross-talk between TLRs and Fc␥RIIa as a novel mechanism by which DCs promote the development of protective effector T cells in response to bacteria. ...

Orthopaedic and trauma device-related infection (ODRI) remains one of the major complications in modern trauma and orthopaedic surgery.Despite best practice in medical and surgical management, neither prophylaxis nor treatment of ODRI is effective in all cases, leading to infections that negatively impact clinical outcome and significantly increase healthcare expenditure.The following review summarises the microbiological profile of modern ODRI, the impact antibiotic resistance has on treatment outcomes, and some of the principles and weaknesses of the current systemic and local antibiotic delivery strategies.The emerging novel strategies aimed at preventing or treating ODRI will be reviewed. Particular attention will be paid to the potential for clinical impact in the coming decades, when such interventions are likely to be critically important.The review focuses on this problem from an interdisciplinary perspective, including basic science innovations and best practice in infectious disease. IntroductionOrthopaedic and trauma device-related infection (ODRI) remains a major complication in modern trauma and orthopaedic surgery. 1 Despite best practice in medical and surgical management, neither prophylaxis nor treatment of ODRI is effective in all cases, and can lead to infections that negatively impact clinical outcome and significantly increase healthcare expenditure. 2 Pre-operative and correctly-timed prophylactic antibiotic intervention is mandatory for a majority of orthopaedic procedures. However, despite this, the incidence of infection following elective orthopaedic surgery is in the range of 0.7% to 4.2%, 3-7 while the incidence can be much higher in trauma cases where infection rates range from approximately 1% after operative fixation of closed low-energy fractures, to more than 30% in complex open tibia fractures. 8,9 Treatment success rates vary, with between 57% and 88% often reported. [10][11][12] Current curative approaches (radical debridement, revision surgery and prolonged antibiotic therapy) often result in significant socioeconomic costs, not to mention the risk of life-long functional impairment for the patient. Against this background, and with the increasing issue of antibiotic-resistant bacteria, the problem of ODRI is set to continue to pose a challenge for practising clinicians in the coming decades. The clinical and microbiological challenges of modern device-related infectionsThe most prevalent species in ODRIs are Staphylococci. [13][14][15][16][17] Staphylococcus (S.) aureus accounts for between 20% and 30% of cases of infection after fracture fixation and prosthetic joint infections (PJI), with coagulase-negative staphylococci (CoNS) accounting for 20%-40% of cases, [13][14][15][16] including small colony variants. 18 Other Gram-positive cocci including Streptococci (1%-10%) and Enterococci (3%-7%) are less frequently encountered. Infections caused by Gram-negative bacilli, including Pseudomonas aeruginosa and Enterobacteriaceae account for approximately 6%-17%, [13][14][15][16...

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IgA is predominantly recognized to play an important role in host defense at mucosal sites, where it prevents invasion of pathogens by neutralization. Although it has recently become clear that IgA also mediates other immunological processes, little remains known about the potential of IgA to actively contribute to induction of inflammation, particularly in nonmucosal organs and tissues. In this article, we provide evidence that immune complex formation of serum IgA plays an important role in orchestration of inflammation in response to pathogens at various nonmucosal sites by eliciting proinflammatory cytokines by human macrophages, monocytes, and Kupffer cells. We show that opsonization of bacteria with serum IgA induced cross-talk between FcαRI and different TLRs, leading to cell type-specific amplification of proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-23. Furthermore, we demonstrate that the increased protein production of cytokines was regulated at the level of gene transcription, which was dependent on activation of kinases Syk and PI3K. Taken together, these data demonstrate that the immunological function of IgA is substantially more extensive than previously considered and suggest that serum IgA-induced inflammation plays an important role in orchestrating host defense by different cell types in nonmucosal tissues, including the liver, skin, and peripheral blood.

For diagnosis of Mycoplasma pneumoniae infection we compared two rapid tests, PCR and the immunoglobulin M immunofluorescence assay (IgM IFA), with culture and the complement fixation test (CFT), in a prospective study among 92 children with respiratory tract infection and 74 controls. Based on positivity of culture and/or CFT as the diagnostic criterion, nine patients (10%) were diagnosed with M. pneumoniae infection. All patients positive by culture were also positive by PCR. In all controls cultures, PCRs, and serological assays were negative, except in one with a positive IgM IFA. The IgM IFA had a low positive predictive value of 50%. Only a combination of PCR (seven patients) and CFT (seven patients) allowed diagnosis of all cases.

CD103+ dendritic cells (DC) are crucial for regulation of intestinal tolerance in humans. However, upon infection of the lamina propria this tolerogenic response is converted to an inflammatory response. Here we show that immunoglobulin A (IgA) immune complexes (IgA-IC), which are present after bacterial infection of the lamina propria, are important for the induction of inflammation by the human CD103+SIRPα+ DC subset. IgA-IC, by recognition through FcαRI, selectively amplify the production of proinflammatory cytokines TNF, IL-1β and IL-23 by human CD103+ DCs. These cells then enhance inflammation by promoting Th17 responses and activating human intestinal innate lymphoid cells 3. Moreover, FcαRI-induced cytokine production is orchestrated via upregulation of cytokine translation and caspase-1 activation, which is dependent on glycolytic reprogramming mediated by kinases Syk, PI3K and TBK1-IKKε. Our data suggest that the formation of IgA-IC in the human intestine provides an environmental cue for the conversion of a tolerogenic to an inflammatory response.

Nodulation of Vicia sativa subsp. nigra L. by Rhizobium bacteria is coupled to the development of thick and short roots (Tsr). This root phenotype as well as root-hair induction (Hai) and root-hair deformation (Had) are caused by a factor(s) produced by the bacteria in response to plant flavonoids. When very low inoculum concentrations (0.5-5 bacteria·ml(-1)) were used, V. sativa plants did not develop the Tsr phenotype and became nodulated earlier than plants with Tsr roots. Furthermore, the nodules of these plants were located on the primary root in contrast to nodules on Tsr roots, which were all located at sites of lateral-root emergence. The average numbers of nodules per plant were not significantly different for these two types of nodulation. Root-growth inhibition and Hai, but not Had, could be mimicked by ethephon, and inhibited by aminoethoxyvinylglycine (AVG). Addition of AVG to co-cultures of Vicia sativa and the standard inoculum concentration of 5·10(5) bacteria·ml(-1) suppressed the development of the Tsr phenotype and restored nodulation to the pattern that was observed with very low concentrations of bacteria (0.5-5 bacteria·ml(-1)). The delay in nodulation on Tsr roots appeared to be caused by the fact that nodule meristems did not develop on the primary root, but only on the emerging laterals. The relationship between Tsr, Hai, Had, and nodulation is discussed.

Rhizobium kguminosarum produced a factor(s) that caused thick, short roots (Tsr phenotype) as well as root hair induction (Hai phenotype) and deformation (Had phenotype) in Vicia salva plants upon bation with root exudate or with one of the nod gene inducers naringenin or apgenin; this was a n DABC gendndent process. Detection of the Hai and Had phenotypes was much more sensitive than that of the Tsr phenotype.Rhizobium leguminosarum forms nitrogen-fixing root nodules on plants of the pea cross-inoculation group. The bacteria invade the host via infection threads formed by the plant in root hairs, which are curled under the influence of the bacteria (18). This curling process requires the nodDABC genes of the bacteria, which are located on the Sym (symbiosis) plasmid (5,19). Activation of the nodABC promoter is mediated by the nodD regulatory gene product and requires a flavonoid inducer (7,(9)(10)(11)21). Mutations in these genes abolish the ability of the bacteria to induce both root hair curling and the "thick and short roots" (Tsr) phenotype in Vicia sativa subsp. nigra test plants (14,19), which is caused by a soluble factor(s) that is produced by R. leguminosarum in response to a factor(s) in sterile V. sativa root exudate (15). As naringenin, apigenin, and some other flavonoids can replace exudate for the induction of the nodABC promoter (21), we investigated whether naringenin or apigenin alone is sufficient to replace total root exudate in the process of Tsr factor synthesis by R. leguminosarum.The flavonoids induced the production of Tsr factor only in a strain harboring a Sym plasmid, with maximal effects at concentrations of 700 nM and higher (Table 1). Production of Tsr factor was not detected when the Sym plasmid-cured strain RBL1387 or strains carrying mutations in either nodD, nodA, nodB, or nodC (RBL1402, RBL1409, RBL1410, and RBL1412, respectively) were used in otherwise identical experiments, showing that naringenin-or apigenin-induced Tsr factor synthesis followed the same requirements as defined previously for exudate-induced Tsr factor production (19). Quercetin, whose structure closely resembles that of naringenin but which does not induce the R. leguminosarum nodABC promoter (21), did not significantly induce Tsr factor production ( Table 1). The growth of the bacterial strains was not affected by the flavonoids in the tested concentrations. Inocula of 5 x 105 CFU/ml reached concentrations of 2 x 106 to 5 x 106 CFU/ml after incubation, which is comparable to the growth observed in exudate.The fact that only one flavonoid, either naringenin or apigenin, is sufficient for induction of the nodABC promoter (21) as well as for the production of Tsr factor (Table 1) eliminates models of Tsr factor synthesis in which one compound in root exudate induces the nodABC genes and * Corresponding author. one or more other compounds function as substrates for Tsr factor synthesis. However, activation of the nodABC promoter may not be the only role of naringenin or apigenin, since a naringenin concentrat...