Mechanismen der Allergieprotektion mittels Aktivierung des angeborenen Immunsystems durch Kuhstallbakterien: Rezeptoren, Signaltransduktion und Mediatorfreisetzung

Eine Vielzahl an epidemiologischen Studien zeigt, dass der frühkindliche Kontakt zu einer traditionell geführten, bäuerlichen Umgebung das Risiko vermindert, im späteren Leben allergische Erkrankungen zu entwickeln. Neuere Studien geben Hinweise, dass die mikrobielle Vielfalt in der bäuerlichen Umgebung eine besondere Rolle bei diesem allergieprotektiven Effekt spielen könnte. Die beiden Gram+ Kuhstallisolate Lactococcus lactis G121 (L. lactis G121) und Staphylococcus sciuri W620 (S. sciuri W620) erwiesen sich in einem in vivo Mausmodell der akuten allergischen Entzündung als allergieprotektiv, jedoch mit großen Unterschieden bezüglich der induzierten Immunantwort. Aus diesem Grund wurden die beiden Bakterien in dieser Arbeit hinsichtlich ihrer Immunzell-aktivierenden Eigenschaften vergleichend charakterisiert. Ein Kontakt mit bestimmten Mikroorgansimen kann TH1- oder Treg-Zellen induzieren, was zu einer Inhibierung der Allergie-assoziierten TH2-Antwort führen kann. Bei diesem Prozess nehmen besonders die dendritischen Zellen (DCs) eine wichtige Rolle ein. Microarray-Daten von humanen dendritischen Zellen stimuliert mit L. lactis G121 und S. sciuri W620 zeigen eine große Anzahl gemeinsam, aber auch unterschiedlich induzierter Gene. Eine Stimulation von humanen DCs mit L. lactis G121 induzierte einen immunogenen Phänotyp der Zellen, während S. sciuri W620-stimulierte Zellen einen eher intermediären Reifungszustand aufwiesen, was vermutlich zu einer Tolerogenität führt. Es konnte gezeigt werden, dass L. lactis G121 ein inflammatorisches, TH1-polarisierendes Programm in DCs induziert, welches in einer starken TH1-Polarisation naïver T-Zellen resultiert. Bei S. sciuri W620-behandelten DCs hingegen fehlte die deutliche Induktion entscheidender proinflammatorischer, TH1-assoziierter Zytokine. Daraus resultierte eine schwache TH1-Polarisation von CD4+ T-Zellen, mit Tendenzen zur Aktivierung von TH2-Zellen. Es fanden sich Hinweise, dass TH9-, TH17-, TH22- und Treg-Zellen bei der adaptiven Immunantwort nach L. lactis G121- und S. sciuri W620-Stimulation eine Rolle spielen. Die Aktivierung der DCs durch S. sciuri W620 fand hauptsächlich über TLR2 und NOD2 statt. Die TH1-Polarisation von DCs durch L. lactis G121 hingegen, war im starken Maße von der endosomalen Ansäuerung abhängig und beruhte mindestens zum Teil auf den intrazellulären Rezeptoren NOD2 und TLR8. Insgesamt konnte gezeigt werden, dass die Aktivierung des Immunsystems durch L. lactis G121 und S. sciuri W620 auf sehr unterschiedlichen Mechanismen beruht. In Anbetracht dessen, das sich beide Bakterien im Mausmodel als allergieprotektiv erwiesen haben, liefert diese Arbeit Hinweise darauf, dass der Effekt der Bakterien-vermittelten Allergieprotektion durch die Aktivierung vielfältiger Rezeptoren und Mechanismen erreicht werden kann.A great number of epidemiological studies show that farming environment in early childhood reduces the risk of developing allergic reactions later in life. Recent studies indicate that the microbial diversity might be responsible for the allergy-protective effect by such rural environment. The Gram+ cowshed-isolates Lactococcus lactis G121 (L. lactis G121) and Staphylococcus sciuri W620 (S. sciuri W620) prevented allergic immune responses in a mouse model of acute allergic inflammation. However, the immune response induced by both bacteria differed profoundly. Contact with microbes can induce TH1 or Treg cells resulting in the inhibition of the allergy-associated TH2 immune response. Dendritic cells (DCs) play an important role in this process. Microarray data of L. lactis G121- and S. sciuri W620-stimulated DCs revealed a number of mutually but also differentially regulated genes. A stimulation of human DCs with L. lactis G121 induced an immunogenic phenotype of these cells, while S. sciuri W620 stimulation resulted in a more intermediate maturation status, probably leading to tolerance. It could be shown that L. lactis G121 induced a proinflammatory, TH1-polarising program in DCs, therefore resulting in a strong TH1-activation. In contrast, S. sciuri W620-stimulated DCs showed only poor induction of proinflammatory, TH1-associated cytokines. Accordingly, activation of TH1 cells was weak and tendencies to TH2 cell induction could be observed. Development of TH17, TH22, TH9 and Treg cells by both bacteria is possible but has to be further investigated. The activation of DCs by S. sciuri W620 involved TLR2 and NOD2. In contrast, L. lactis G121-induced TH1-polarisation was strongly dependent on endosomal acidification and was based on at least the intracellular receptors NOD2 and TLR8. Overall, it was shown that the activation by L. lactis G121 and S. sciuri W620 relies on different mechanisms. Considering the prevention of an allergic reaction by both bacteria in a mouse model, this work indicates that bacteria-derived allergy-protection might result from activation of different receptors and mechanisms

Vitiligo-like manifestations of graft-versus-host disease in a pediatric population

Vitiligo-like changes are an uncommon cutaneous manifestation of graft-versus-host disease (GVHD). We report three cases and review the literature of pediatric patients with vitiligo-like changes associated with GVHD. Improved characterization of this phenomenon may lend insight into the biologic pathways that underlie both vitiligo and GVHD

Occurrence of FVIII Inhibitors in Hemophilia A Patients Following an Institutional Switch to a Third Generation B-Domain-Deleted FVIII

In 2018, Refacto AFR, a B-domain-deleted third-generation FVIII concentrate, became our preferential product. After the introduction, the development of inhibitors was prospectively monitored; retrospectively, we sought for risk factors in the patients who developed a de-novo inhibitor. Over a period of 15 months, 4/19 adult patients with non-severe haemophilia who were treated on demand for surgery, developed high titer antibodies to FVIII after administration of Refacto AFR; 5/52 mostly severe patients on prophylaxis, developed an inhibitor (3 ≥ 0.1 BU; 1 &gt; 0.6 BU, 1 high titre) after they switched to Refacto AFR; all were children &lt;14 years of age and with &gt;100 exposure days, none related to surgery or intensive treatment; all received KovaltryR before. In conclusion: inhibitors were encountered in on demand patients and previously treated prophylaxis patients; this observation might be a coincidental finding, but also risk factors like genotype and surgery and/or that Refacto AFR is more immunogenic should be considered. For the patients on prophylaxis we hypothesize that loss of tolerance by preceding KovaltryR might have contributed to inhibitor development.</p

Occurrence of FVIII Inhibitors in Hemophilia A Patients Following an Institutional Switch to a Third Generation B-Domain-Deleted FVIII

In 2018, Refacto AFR, a B-domain-deleted third-generation FVIII concentrate, became our preferential product. After the introduction, the development of inhibitors was prospectively monitored; retrospectively, we sought for risk factors in the patients who developed a de-novo inhibitor. Over a period of 15 months, 4/19 adult patients with non-severe haemophilia who were treated on demand for surgery, developed high titer antibodies to FVIII after administration of Refacto AFR; 5/52 mostly severe patients on prophylaxis, developed an inhibitor (3 ≥ 0.1 BU; 1 &gt; 0.6 BU, 1 high titre) after they switched to Refacto AFR; all were children &lt;14 years of age and with &gt;100 exposure days, none related to surgery or intensive treatment; all received KovaltryR before. In conclusion: inhibitors were encountered in on demand patients and previously treated prophylaxis patients; this observation might be a coincidental finding, but also risk factors like genotype and surgery and/or that Refacto AFR is more immunogenic should be considered. For the patients on prophylaxis we hypothesize that loss of tolerance by preceding KovaltryR might have contributed to inhibitor development.</p

Occurrence of FVIII Inhibitors in Hemophilia A Patients Following an Institutional Switch to a Third Generation B-Domain-Deleted FVIII

In 2018, Refacto AFR, a B-domain-deleted third-generation FVIII concentrate, became our preferential product. After the introduction, the development of inhibitors was prospectively monitored; retrospectively, we sought for risk factors in the patients who developed a de-novo inhibitor. Over a period of 15 months, 4/19 adult patients with non-severe haemophilia who were treated on demand for surgery, developed high titer antibodies to FVIII after administration of Refacto AFR; 5/52 mostly severe patients on prophylaxis, developed an inhibitor (3 ≥ 0.1 BU; 1 &gt; 0.6 BU, 1 high titre) after they switched to Refacto AFR; all were children &lt;14 years of age and with &gt;100 exposure days, none related to surgery or intensive treatment; all received KovaltryR before. In conclusion: inhibitors were encountered in on demand patients and previously treated prophylaxis patients; this observation might be a coincidental finding, but also risk factors like genotype and surgery and/or that Refacto AFR is more immunogenic should be considered. For the patients on prophylaxis we hypothesize that loss of tolerance by preceding KovaltryR might have contributed to inhibitor development.</p

Occurrence of FVIII Inhibitors in Hemophilia A Patients Following an Institutional Switch to a Third Generation B-Domain-Deleted FVIII

In 2018, Refacto AFR, a B-domain-deleted third-generation FVIII concentrate, became our preferential product. After the introduction, the development of inhibitors was prospectively monitored; retrospectively, we sought for risk factors in the patients who developed a de-novo inhibitor. Over a period of 15 months, 4/19 adult patients with non-severe haemophilia who were treated on demand for surgery, developed high titer antibodies to FVIII after administration of Refacto AFR; 5/52 mostly severe patients on prophylaxis, developed an inhibitor (3 ≥ 0.1 BU; 1 &gt; 0.6 BU, 1 high titre) after they switched to Refacto AFR; all were children &lt;14 years of age and with &gt;100 exposure days, none related to surgery or intensive treatment; all received KovaltryR before. In conclusion: inhibitors were encountered in on demand patients and previously treated prophylaxis patients; this observation might be a coincidental finding, but also risk factors like genotype and surgery and/or that Refacto AFR is more immunogenic should be considered. For the patients on prophylaxis we hypothesize that loss of tolerance by preceding KovaltryR might have contributed to inhibitor development.</p

Occurrence of FVIII Inhibitors in Hemophilia A Patients Following an Institutional Switch to a Third Generation B-Domain-Deleted FVIII

In 2018, Refacto AFR, a B-domain-deleted third-generation FVIII concentrate, became our preferential product. After the introduction, the development of inhibitors was prospectively monitored; retrospectively, we sought for risk factors in the patients who developed a de-novo inhibitor. Over a period of 15 months, 4/19 adult patients with non-severe haemophilia who were treated on demand for surgery, developed high titer antibodies to FVIII after administration of Refacto AFR; 5/52 mostly severe patients on prophylaxis, developed an inhibitor (3 ≥ 0.1 BU; 1 &gt; 0.6 BU, 1 high titre) after they switched to Refacto AFR; all were children &lt;14 years of age and with &gt;100 exposure days, none related to surgery or intensive treatment; all received KovaltryR before. In conclusion: inhibitors were encountered in on demand patients and previously treated prophylaxis patients; this observation might be a coincidental finding, but also risk factors like genotype and surgery and/or that Refacto AFR is more immunogenic should be considered. For the patients on prophylaxis we hypothesize that loss of tolerance by preceding KovaltryR might have contributed to inhibitor development.</p

Política de Formação de Professores no Brasil: alcance das ações por meio da educação a distância.

O estudo apresenta um panorama da formação de professores realizada por meio da educação a distância (EaD), procurando evidenciar que esta modalidade de ensino tem sido utilizada de forma prioritária para dar conta da histórica necessidade de formação de professores no Brasil. As universidades públicas são chamadas para, num curto período de tempo, formar um grande número de professores.  Neste artigo trazemos um recorte de uma pesquisa que tem como objetivo acompanhar e avaliar a política de formação de professores realizada por meio da EaD, pelo Programa Universidade Aberta do Brasil (UAB). A metodologia utilizada  neste artigo é resultado de uma pesquisa de natureza exploratória, descritiva e de abordagem qualitativa e quantitativa.  O processo de mapeamento dos dados sobre a formação de professores realizada na modalidade a distância evidenciou a discrepância das informações entre as instituições públicas de ensino superior (IPES) e UAB. Os dados  demonstram que as universidades federais responderam fortemente  à política governamental, com uma oferta expressiva de cursos de licenciatura nas diferentes regiões do país,  mas que,  no entanto, a oferta dos cursos não corresponde  ainda às reais necessidades de formação de professores apontadas pelas estatísticas oficiais

Lipophilic Allergens, Different Modes of Allergen-Lipid Interaction and Their Impact on Asthma and Allergy

Molecular allergology research has provided valuable information on the structure and function of single allergenic molecules. There are several allergens in food and inhalant allergen sources that are able to interact with lipid ligands via different structural features: hydrophobic pockets, hydrophobic cavities, or specialized domains. For only a few of these allergens information on their associated ligands is already available. Several of the allergens are clinically relevant, so that it is highly probable that the individual structural features with which they interact with lipids have a direct effect on their allergenic potential, and thus on allergy development. There is some evidence for a protective effect of lipids delaying the enzymatic digestion of the peanut (Arachis hypogaea) allergen Ara h 8 (hydrophobic pocket), probably allowing this molecule to get to the intestinal immune system intact (sensitization). Oleosins from different food allergen sources are part of lipid storage organelles and potential marker allergens for the severity of the allergic reaction. House dust mite (HDM), is more often associated with allergic asthma than other sources of inhalant allergens. In particular, lipid-associated allergens from Dermatophagoides pteronyssinus which are Der p 2, Der p 5, Der p 7, Der p 13, Der p 14, and Der p 21 have been reported to be associated with severe allergic reactions and respiratory symptoms such as asthma. The exact mechanism of interaction of these allergens with lipids still has to be elucidated. Apart from single allergens glycolipids have been shown to directly induce allergic inflammation. Several—in parts conflicting—data exist on the lipid (and allergen) and toll-like receptor interactions. For only few single allergens mechanistic studies were performed on their interaction with the air-liquid interface of the lungs, in particular with the surfactant components SP-A and SP-D. The increasing knowledge on protein-lipid-interaction for lipophilic and hydrophobic food and inhalant allergens on the basis of their particular structure, of their capacity to be integral part of membranes (like the oleosins), and their ability to interact with membranes, surfactant components, and transport lipids (like the lipid transfer proteins) are essential to eventually clarify allergy and asthma development