Interleukin 8 Receptor Deficiency Confers Susceptibility to Acute Experimental Pyelonephritis and May Have a Human Counterpart

Neutrophils migrate to infected mucosal sites that they protect against invading pathogens. Their interaction with the epithelial barrier is controlled by CXC chemokines and by their receptors. This study examined the change in susceptibility to urinary tract infection (UTI) after deletion of the murine interleukin 8 receptor homologue (mIL-8Rh). Experimental UTIs in control mice stimulated an epithelial chemokine response and increased chemokine receptor expression. Neutrophils migrated through the tissues to the epithelial barrier that they crossed into the lumen, and the mice developed pyuria. In mIL-8Rh knockout (KO) mice, the chemokine response was intact, but the epithelial cells failed to express IL-8R, and neutrophils accumulated in the tissues. The KO mice were unable to clear bacteria from kidneys and bladders and developed bacteremia and symptoms of systemic disease, but control mice were fully resistant to infection. The experimental UTI model demonstrated that IL-8R–dependent mechanisms control the urinary tract defense, and that neutrophils are essential host effector cells. Patients prone to acute pyelonephritis also showed low CXC chemokine receptor 1 expression compared with age-matched controls, suggesting that chemokine receptor expression may also influence the susceptibility to UTIs in humans. The results provide a first molecular clue to disease susceptibility of patients prone to acute pyelonephritis

CCR2⁺CD103⁻ intestinal dendritic cells develop from DC-committed precursors and induce interleukin-17 production by T cells

The identification of intestinal macrophages (m phi s) and dendritic cells (DCs) is a matter of intense debate. Although CD103(+) mononuclear phagocytes (MPs) appear to be genuine DCs, the nature and origins of CD103(-) MPs remain controversial. We show here that intestinal CD103(-)CD11b(+) MPs can be separated clearly into DCs and m phi s based on phenotype, gene profile, and kinetics. CD64(-)CD103(-)CD11b(+) MPs are classical DCs, being derived from Flt3 ligand-dependent, DC-committed precursors, not Ly6C hi monocytes. Surprisingly, a significant proportion of these CD103(-)CD11b(+) DCs express CCR2 and there is a selective decrease in CD103(-)CD11b(+) DCs in mice lacking this chemokine receptor. CCR2(+)CD103(-) DCs are present in both the murine and human intestine, drive interleukin (IL)-17a production by Tcells in vitro, and show constitutive expression of IL-12/IL-23p40. These data highlight the heterogeneity of intestinal DCs and reveal a bona fide population of CCR2(+) DCs that is involved in priming mucosal T helper type 17 (Th17) responses

Dendritic cell subsets in the intestinal lamina propria: ontogeny and function

The intestinal mucosa is exposed to large amounts of foreign antigen (Ag) derived from commensal bacteria, dietary Ags, and intestinal pathogens. Dendritic cells (DCs) are believed to be involved in the induction of tolerance to harmless Ags and in mounting protective immune responses to pathogens and, as such, to play key roles in regulating intestinal immune homeostasis. The characterization of classical DCs (cDCs) in the intestinal lamina propria has been under intense investigation in recent years but the use of markers (including CD11c, CD11b, MHC class II), which are also expressed by intestinal MΦs, has led to some controversy regarding their definition. Here we review recent studies that help to distinguish cDCs subsets from monocyte-derived cells in the intestinal mucosa. We address the phenotype and ontogeny of these cDC subsets and highlight recent findings indicating that these subsets play distinct roles in the regulation of mucosal immune responses in vivo

Entréträdgårdens utformning och egenskaper

Arbetet bygger på en litteraturstudie, med kompletterande intervjuer. Syftet var att undersöka faktorer och element som påverkar människans beteende kring en entréträdgård. Det vill säga en ingång till ett avgränsat område i anslutning till en bostad. Undersökningen som vi utfört visar på att ett flertal faktorer kan påverkar människans beteendemönster. Faktorer som vi tar upp och som kan påverka en entréträdgårds utformning och därav beteendemönstret hos människan är bland annat, skala och proportioner, element, ekonomisk påverkan och inte minst hur och vart gränser dras och utformas mellan privat och offentligt. Beroende på vilket uttryck entréträdgården ger, kan den fysiska tillgängligheten påverkas genom att den utformas mer eller mindre privat. Exempelvis får förbipasserande och grannar en individuell uppfattning om platsen, beroende på om det är en hög häck vid tomtgränsen eller ett öppet synfält. Iakttagelserna avgör graden av sociala interaktioner mellan ägaren och allmänheten (Swapan, Bay och Marinova, 2018a). Vi har granskat ett urval av länder där vi undersöker villa- och radhusområden och jämfört faktorer som påverkar utformningen av en entréträdgård. Lagar och restriktioner samt ekonomiska aspekter är några av de faktorer som påverkar utformning av en entréträdgård och skiljer sig något mellan länderna. Det finns många olika faktorer som påverkar utformningen av entréträdgårdar och därav människans uppfattning. Det går inte att generalisera en utformning eftersom människor prioriterar olika. Beroende på entréträdgårds utformning kan sociala interaktioner främjas.The work is carried out as a literature study with interviews as a supplement where we have researched factors and elements that affect human behavior around an entrance garden also known as the “front yard”. The study we conducted shows that several factors can affect human behavior patterns and social interactions. Factors that we address that can reduce or strengthen the design of an entrance garden and hence the behavioral pattern in humans include: scale and proportions, elements, economic impact and not least boundaries between private and public spaces. Depending on the expression of the entrance garden, the physical accessibility can be affected and make the plot more or less private. For example, passers-by and neighbors get an individual view of the place, depending on whether it is a high hedge at the plot boundary or an open view. The observations determine the degree of social interactions between the owner and the public (Swapan, Bay and Marinova, 2018a). We have examined a selection of countries where we studied residential and row house areas and compared factors that affect the design of an entrance garden. Laws and restrictions as well as economic aspects are factors that affect the design of an entrance garden and differ somewhat between countries. There are many different factors that effect the design of entrence gardens and hence the human perception. People have diffrent prioreties in life and therefore it is not possible to generalize the design of an entrance garden. Depending on the design of an entrance garden, social interactions can be encouraged

IL-18Rα-deficient CD4+T cells induce intestinal inflammation in the CD45RBhitransfer model of colitis despite impaired innate responsiveness

IL-18 has been implicated in inflammatory bowel disease (IBD), however its role in the regulation of intestinal CD4+ T-cell function remains unclear. Here we show that murine intestinal CD4+ T cells express high levels of IL-18Rα and provide evidence that IL-18Rα expression is induced on these cells subsequent to their entry into the intestinal mucosa. Using the CD45RBhi T-cell transfer colitis model, we show that IL-18Rα is expressed on IFN-γ+, IL-17+, and IL-17+IFN-γ+ effector CD4+ T cells in the inflamed colonic lamina propria (cLP) and mesenteric lymph node (MLN) and is required for the optimal generation and/or maintenance of IFN-γ-producing cells in the cLP. In the steady state and during colitis, TCR-independent cytokine-induced IFN-γ and IL-17 production by intestinal CD4+ T cells was largely IL-18Rα−dependent. Despite these findings however, IL-18Rα−deficient CD4+ T cells induced comparable intestinal pathology to WT CD4+ T cells. These findings suggest that IL-18-dependent cytokine induced activation of CD4+ T cells is not critical for the development of T-cell-mediated colitis

Selective Generation of Gut Tropic T Cells in Gut-associated Lymphoid Tissue (GALT): Requirement for GALT Dendritic Cells and Adjuvant

In the current study, we address the underlying mechanism for the selective generation of gut-homing T cells in the gut-associated lymphoid tissues (GALT). We demonstrate that DCs in the GALT are unique in their capacity to establish T cell gut tropism but in vivo only confer this property to T cells in the presence of DC maturational stimuli, including toll-like receptor-dependent and -independent adjuvants. Thus, DCs from mesenteric LNs (MLNs), but not from spleen, supported expression of the chemokine receptor CCR9 and integrin α4β7 by activated CD8+ T cells. While DCs were also required for an efficient down-regulation of CD62L, this function was not restricted to MLN DCs. In an adoptive CD8+ T cell transfer model, antigen-specific T cells entering the small intestinal epithelium were homogeneously CCR9+α4β7+CD62Llow, and this phenotype was only generated in GALT and in the presence of adjuvant. Consistent with the CCR9+ phenotype of the gut-homing T cells, CCR9 was found to play a critical role in the localization of T cells to the small intestinal epithelium. Together, these results demonstrate that GALT DCs and T cell expression of CCR9 play critical and integrated roles during T cell homing to the gut