Jean Maguire van Seventer

Timing of IFN-β Exposure during Human Dendritic Cell Maturation and Naive Th Cell Stimulation Has Contrasting Effects on Th1 Subset Generation: A Role for IFN-β-Mediated Regulation of IL-12 Family Cytokines and IL-18 in Naive Th Cell Differentiation

Type I IFNs, IFN-α and IFN-β, are early effectors of innate immune responses against microbes that can also regulate subsequent adaptive immunity by promoting antimicrobial Th1-type responses. In contrast, the ability of IFN-β to inhibit autoimmune Th1 responses is thought to account for some of the beneficial effects of IFN-β therapy in the treatment of relapsing remitting multiple sclerosis. To understand the basis of the paradoxical effects of IFN-β on the expression of Th1-type immune responses, we developed an in vitro model of monocyte-derived dendritic cell (DC)-dependent, human naive Th cell differentiation, in which one can observe both positive and negative effects of IFN-β on the generation of Th1 cells. In this model we found that the timing of IFN-β exposure determines whether IFN-β will have a positive or a negative effect on naive Th cell differentiation into Th1 cells. Specifically, the presence of IFN-β during TNF-α-induced DC maturation strongly augments the capacity of DC to promote the generation of IFN-γ-secreting Th1 cells. In contrast, exposure to IFN-β during mature DC-mediated primary stimulation of naive Th cells has the opposite effect, in that it inhibits Th1 cell polarization and promotes the generation of an IL-10-secreting T cell subset. Studies with blocking mAbs and recombinant cytokines indicate that the mechanism by which IFN-β mediates these contrasting effects on Th1 cell generation is at least in part by differentially regulating DC expression of IL-12 family cytokines (IL-12 and/or IL-23, and IL-27) and IL-18.

Murine B Cell Response to TLR7 Ligands Depends on an IFN-β Feedback Loop

Type I IFNs play an important, yet poorly characterized, role in systemic lupus erythematosus. To better understand the interplay between type I IFNs and the activation of autoreactive B cells, we evaluated the effect of type I IFN receptor (IFNAR) deficiency in murine B cell responses to common TLR ligands. In comparison to wild-type B cells, TLR7-stimulated IFNAR−/− B cells proliferated significantly less well and did not up-regulate costimulatory molecules. By contrast, IFNAR1−/− B cells did not produce cytokines, but did proliferate and up-regulate activation markers in response to other TLR ligands. These defects were not due to a difference in the distribution of B cell populations or a failure to produce a soluble factor other than a type I IFN. Instead, the compromised response pattern reflected the disruption of an IFN-β feedback loop and constitutively low expression of TLR7 in the IFNAR1−/− B cells. These results highlight subtle differences in the IFN dependence of TLR7 responses compared with other TLR-mediated B cell responses.

Interferon-β differentially regulates expression of the IL-12 family members p35, p40, p19 and EBI3 in activated human dendritic cells

Abstract Interferon-β is thought to provide clinical improvement to multiple sclerosis (MS) patients, in part, through its ability to suppress the generation of IL-12-dependent autoimmune T helper type 1 (Th1) cells by monocyte-derived dendritic cells (DC). We now describe how pre-incubation with 1000 U/ml of IFN-β differentially regulates expression of multiple IL-12 family members in activated, immature human DC, inhibiting CD40/IFN-γ-induced p35 and p40 message levels, while enhancing p19 and Epstein–Barr virus-induced gene 3 (EBI3) levels. IFN-β-mediated inhibition of p40 mRNA and augmentation of p19 mRNA both require de novo protein synthesis. These findings indicate that IFN-β will be found to have contrasting effects on DC secretion of the various IL-12 family homo- and heterodimers.

TLR4 ligands induce IFN-alpha production by mouse conventional dendritic cells and human monocytes after IFN-beta priming.

Exacerbation of disease in systemic lupus erythematosus (SLE) is associated with bacterial infection. In conventional dendritic cells (cDCs), the TLR4 ligand bacterial LPS induces IFN-β gene expression but does not induce IFN-α. We hypothesized that when cDCs are primed by cytokines, as may frequently be the case in SLE, LPS would then induce the production of IFN-α, a cytokine believed to be important in lupus pathogenesis. In this study we show that mouse cDCs and human monocytes produce abundant IFN-α following TLR4 engagement whether the cells have been pretreated either with IFN-β or with a supernatant from DCs activated by RNA-containing immune complexes from lupus patients. This TLR4-induced IFN-α induction is mediated by both an initial TRIF-dependent pathway and a subsequent MyD88-dependent pathway, in contrast to TLR3-induced IFN-α production, which is entirely TRIF-dependent. There is also a distinct requirement for IFN regulatory factors (IRFs), with LPS-induced IFN-α induction being entirely IRF7- and partially IRF5-dependent, in contrast to LPS -induced IFN-β gene induction which is known to be IRF3-dependent but largely IRF7-independent. This data demonstrates a novel pathway for IFN-α production by cDCs and provides one possible explanation for how bacterial infection might precipitate disease flares in SLE.

Type I Interferons Inhibition of Inflammatory T Helper Cell Responses in Systemic Lupus Erythematosus

Abstract:  T helper (Th) cells play a central role in systemic lupus erythematosus (SLE). Activated autoreactive Th cells provide the help required for autoreactive B cells to differentiate and produce pathogenic autoAbs. Both autoAb‐containing immune complexes and direct effects of inflammatory Th cells promote tissue injury and organ damage. In SLE, triggering of plasmacytoid dendritic cell (pDC) Toll‐like receptors by autoimmune complexes containing nucleic acid autoantigens stimulates pDC secretion of high levels of type I interferons (IFN‐α/β). Study of SLE patients and murine disease models implicate these type I IFNs as key disease effectors. However, the role of pDC‐derived type I IFNs in regulating the inflammatory function of Th cells in SLE is unknown. Although, type I IFNs are classically considered to promote Th1‐mediated inflammation, they can also act as potent inhibitors of both Th1 and Th17 inflammatory cell responses. Work of ourselves and others leads us to hypothesize that if initiated during stages of SLE when Th cell‐mediated tissue inflammation is absent or minimal, such as early in the disease or during periods of remission, type I IFN neutralization will disrupt the cycle of systemic autoimmune induction and disease. However, if initiated during advanced stages of disease when there is substantial ongoing Th1 (and possibly Th17) cell‐mediated inflammation, targeting type I IFNs will exacerbate the Th cell‐mediated inflammatory disease and thus potentiate end‐organ damage and destruction. This has important implications for the application of the numerous anti‐type I IFN therapies currently under development for SLE treatment.

Human fetal retinal pigment epithelium induces apoptosis in human T-cell line Jurkat which is independent from its expression of TRAIL

Purpose. To evaluate whether human fetal retinal pigment epithelial (HFRPE) cells express TRAIL (tumor necrosis factor related apoptosis inducing ligand). The role of TRAIL in HFRPE induced apoptosis was evaluated. Methods. Pure cultures of HFRPE cells were isolated. The expression of TRAIL protein and mRNA in non-activated and IFN-? activated HFRPE cells was evaluated with RT-PCR. The role of TRAIL in HFRPE induced apoptosis was assessed by incubating HFRPE cells with human T-cell leukemia line Jurkat (Jkt) in the presence or absence of neutralizing TRAIL antibodies. Cultures were pulsed with [ 3 H]-thymidine to measure Jkt cell proliferation. The role of TRAIL was further examined by western blott evaluating the cleavage of caspases 8 and 10 in Jkt cells after their incubation with HFRPE cells. Results. HFRPE cells expressed TRAIL mRNA. The expression of TRAIL mRNA and protein was up-regulated by IFN-? activation. However, anti-TRAIL antibodies were not able to prevent the HFRPE induced suppression of Jkt cell proliferation. The caspases 8 and 10 were also not cleaved in Jkt cells after their incubation with IFN-? activated HFRPE cells. Conclusions. Although HFRPE cells express TRAIL and its expression is upregulated by IFN-? activation, TRAIL is not involved in HFRPE induced apoptosis in Jkt cells. Currently the role of TRAIL in HFRPE cells is under investigation.

Principles of Infectious Diseases: Transmission, Diagnosis, Prevention, and Control

Abstract Infectious disease control and prevention relies on a thorough understanding of the factors determining transmission. This article summarizes the fundamental principles of infectious disease transmission while highlighting many of the agent, host, and environmental determinants of these diseases that are of particular import to public health professionals. Basic principles of infectious disease diagnosis, control, and prevention are also reviewed.

Emerging New Infections: Importance in Child Health

A complex interplay of environmental and human factors, including ecological, genetic, political and socioeconomic factors, is responsible for the emergence and re-emergence of infectious diseases. These factors often have a distinct effect on children and, as a result, emerging infections can have unique impacts on younger populations in terms of both physical health and mental as well as social wellbeing. Children are the most vulnerable members of our society. In order to best protect them from the impact of emerging infectious diseases, it is imperative to understand how factors that determine disease emergence and emerging diseases themselves can affect the young. This will allow us to focus on the most appropriate measures to not only prevent infection of pediatric populations but also prepare for the treatment and care of children when an infectious disease emerges. Influenza is a prototypical emerging/re-emerging infectious disease. Epidemic influenza re-emerges annually in periods between influenza pandemics. Both epidemic and pandemic influenza can have considerable impacts on the wellbeing of children. For over a decade, we have anticipated the mutation of avian influenza (H5N1) into a virus that can be efficiently transmitted between humans. This has resulted in substantial efforts to prepare for a virulent influenza pandemic. Although the pandemic potential of avian influenza has not (yet) been realized, efforts to prepare for a widespread pandemic have not been in vain. The unexpected emergence and rapid spread of the swine flu [influenza A(H1N1)v] has resulted in a worldwide pandemic that has already had profound effects on children and adults. Schools, day care centers, modern transport and international travel have all facilitated the spread of this new influenza strain. Swine flu exemplifies well how environmental and human factors interact to result in the emergence of an infectious disease with unique impacts on children.

Nouvelles infections émergentes: Impact sur la santé de l’enfant

L’interaction complexe de facteurs humains et environnementaux (facteurs écologiques, génétiques, politiques et socioéconomiques) est responsable de l’émergence et la réémergence de maladies infectieuses. Ces facteurs ont souvent un effet particulier sur les enfants et par conséquent, les infections émergentes peuvent avoir des effets spécifiques sur les populations pédiatriques en termes de santé physique et mentale mais aussi de bien-être social. Les enfants sont les acteurs les plus vulnérables de notre société. Afin de les protéger au mieux de l’impact des maladies émergentes, il est impératif de comprendre comment les facteurs déterminant l’émergence de maladies et les maladies émergentes elles-mêmes peuvent les affecter. Cela nous permettra de nous concentrer sur les mesures les plus adéquates, non seulement pour prévenir l’infection des populations pédiatriques mais aussi pour mettre au point le traitement et les soins à dispenser en cas d’émergence d’une maladie infectieuse. La grippe est le prototype même de la maladie émergente/réémergente. L’épidémie de grippe réémerge chaque année entre les périodes de pandémies grippales. À la fois épidémique et pandémique, la grippe peut avoir des effets considérables sur le bien-être des enfants. Depuis une dizaine d’années, nous craignons des mutations du virus de la grippe aviaire (H5N1) le rendant capable de se transmettre efficacement entre l’homme et nous nous préparons à une pandémie de grippe virulente. Le potentiel pandémique de la grippe aviaire ne s’est pas (encore) concrétisé mais les efforts de préparation à une pandémie de grande ampleur n’ont pas été vains. En effet, l’émergence inattendue et la propagation rapide de la grippe porcine A(H1N1) a entraîné une pandémie mondiale qui a déjà eu de profonds effets sur les enfants et les adultes. Les écoles et les crêches, les moyens de transports modernes et les voyages internationaux ont facilité la propagation de cette nouvelle souche du virus de la grippe. La grippe porcine illustre bien comment l’intéraction des facteurs environnementaux et humains conduisent à l’émergence d’une maladie infectieuse avec des effets spécifiques sur les enfants.

Nuevas infecciones emergentes: importancia en la salud de los niños

Una interacción compleja entre factores ambientales y humanos, incluyendo factores ecológicos, genéticos, políticos y socioeconómicos, es responsable de la emergencia y la resurgencia de enfermedades infecciosas. Estos factores poseen a menudo un efecto claro sobre los niños y, en consecuencia, las infecciones emergentes pueden ejercer impactos únicos sobre las poblaciones más jóvenes en términos de salud física y mental, así como de bienestar social. Los niños son los miembros más vulnerables de nuestra sociedad. Con el objeto de protegerles mejor frente al impacto de las enfermedades infecciosas emergentes, es imperativo comprender cómo factores que determinan la emergencia de enfermedades y las enfermedades emergentes de por sí pueden afectar al niño. Esto nos permitirá centrarnos en las medidas más apropiadas para no sólo prevenir la infección de poblaciones pediátricas sino también prepararnos para el tratamiento y el cuidado de los niños cuando emerge una enfermedad infecciosa. La gripe es un prototipo de enfermedad infecciosa emergente/resurgente. La gripe epidémica emerge de nuevo cada año en periodos entre las pandemias gripales. Tanto la gripe epidémica como la gripe pandémica pueden ejercer impactos considerables sobre el bienestar de los niños. Durante más de una década hemos previsto la mutación de la gripe aviaria (H5N1) en un virus que puede ser transmitido eficientemente entre humanos. Esto ha dado lugar a esfuerzos considerables para prepararnos frente a una pandemia gripal virulenta. Aunque el potencial pandémico de la gripe aviaria no ha sido tomado (todavía) en consideración, los esfuerzos realizados para prepararnos frente a una pandemia generalizada no han sido en vano. La emergencia imprevista y la rápida propagación de la gripe porcina [gripe A(H1N1)] han dado lugar a una pandemia mundial que ha producido ya efectos considerables sobre niños y adultos. Las escuelas, los hospitales de día, el transporte moderno y los viajes internacionales han facilitado la propagación de esta nueva cepa gripal. La gripe porcina ejemplifica perfectamente cómo interactúan factores ambientales y humanos para dar lugar a la emergencia de una enfermedad infecciosa con impactos únicos sobre los niños.