Cytokine responses correlate differentially with age in infancy and early childhood

Härtel, Christoph; Adam, Nina; Strunk, Tobias; Temming, Petra; Müller‐Steinhardt, Michael; Schultz, Christian

doi:10.1111/j.1365-2249.2005.02928.x

Cited by 124 publications

(115 citation statements)

References 27 publications

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“…Indeed, when administered to animals, exogenous GOH was able to bypass the aminobisphosphonate biochemical block, reconstituting the mevalonate pathway and thus normalizing cytokine and chemokine values (23).…”

Section: Discussionmentioning

confidence: 99%

Mouse model of mevalonate kinase deficiency: comparison of cytokine and chemokine profile with that of human patients

et al. 2013

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Background: Mevalonate kinase deficiency (MKD) is a rare genetic autoinflammatory disease caused by blocking of the enzyme mevalonate kinase in the pathway of cholesterol and isoprenoids. The pathogenic mechanism originating an immune response in MKD patients has not been clearly understood. Methods:We investigated the dysregulation of expression of selected cytokines and chemokines in the serum of MKD patients. The results have been compared with those observed in an MKD mouse model obtained by treating the mice with aminobisphosphonate, a molecule that is able to inhibit the cholesterol pathway, mimicking the genetic block characteristic of the disease. results: Interleukin (IL)-1β, IL-5, IL-6, IL-9, IL-17, granulocyte colony-stimulating factor, monocyte chemotactic protein-1, tumor necrosis factor-α, and IL-4 expression were dysregulated in sera from MKD patients and mice. Moreover, geraniol, an exogenous isoprenoid, when administered to MKD mice, restored cytokines and chemokines levels with values similar to those of untreated mice. conclusion: Our findings, which were obtained in patients and a mouse model mimicking the human disease, suggest that these cytokines and chemokines could be MKD specific and that isoprenoids could be considered as potential therapeutic molecules. The mouse model, even if with some limitations, was robust and suitable for routine testing of potential MKD drugs. Mevalonate kinase deficiency (MKD; OMIM no. 251170), is a rare autoinflammatory disease caused by mutations within the second enzyme of the mevalonate pathway (mevalonate kinase (MK), encoded by MVK) (1). MK is an essential enzyme in isoprenoid biosynthesis; this pathway produces cholesterol and nonsterol intermediate compounds (farnesyl pyrophosphate and geranyl-geranyl pyrophosphate), which are known to be involved in the control of several cell functions through protein prenylation (farnesylation and geranyl-geranylation, respectively) (2) (Figure 1). The shortage of geranyl-geranyl pyrophosphate, and the consequent decreased rate of protein geranyl-geranylation, leads to increased interleukin (IL)-1β secretion (3-6); this observation gives new insights into MKD pathogenesis, such as the causal link between the cholesterol pathway dysfunction and the patient's phenotype.Although in the past decade the knowledge of MKD pathogenesis has increased, an etiologic therapy for this orphan drug disease is still unavailable.Different treatments, including steroids, statins, anti-tumor necrosis factor-α (TNF-α), and anti-IL-1 therapy, have been used with variable success to prevent and cure MKD inflammatory symptoms (7,8), whereas only supportive therapies are available for mevalonic aciduria, the more severe form of MKD.The search for new drugs and therapies for MKD could take advantage of an animal model mimicking the characteristics of the human disease. For this reason, we developed a mouse model of MKD (9), showing that the chemical inhibition of the mevalonate pathway through the use of an aminobisphosphonate (alendronate ...

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Section: Discussionmentioning

confidence: 99%

Mouse model of mevalonate kinase deficiency: comparison of cytokine and chemokine profile with that of human patients

et al. 2013

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“…Interestingly, neonates appear to exhibit a predisposition toward production of Th2 cytokines after exposure to environmental allergens [85,2], followed by an age-dependent change toward Th-1-like responses [86,87]. This Th2 bias is usually considered to be a major underlying mechanism for the development of atopy in early life, and could again be a consequence of APC defects.…”

Section: The Immune Response In Early Childhood Yearsmentioning

confidence: 99%

Defective antigen-presenting cell function in human neonates

Velilla¹,

Rugeles²,

Chougnet³

2006

Clinical Immunology

152

132

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Immaturity of the immune system has been suggested as an underlying factor for the high rate of morbidity and mortality from infections in newborns. Functional impairment of neonatal T cells is frequently quoted as the main underlying mechanism for such immaturity. However, recent studies suggest that neonatal antigen-presenting cells (APCs) also exhibit functional alterations, which could lead to secondary defects of adaptive T cell responses. In this review, we summarize what is known on the functionality of APC at birth and during early childhood. Compared to adults, neonatal APCs display markers of immaturity and produce low levels of cytokines. Multiple factors could be involved in neonatal APC alteration, such as intrinsic immaturity, defective interaction between APCs and T cells, and regulatory T cell-mediated inhibition. Characterization of the relative contribution of each mechanism is clearly needed to better understand the functional capability of the neonatal immune system.

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“…A multiplexed flow cytometric assay (the Th1/Th2 cytokine CBA kit; BD Biosciences) was used to test the production of TNF-a, IL-4, IL-5, and IFN-g in serum of immunized mice as described previously (16,17).…”

Section: Facs Analysismentioning

confidence: 99%

Caveolin-1–Mediated Negative Signaling Plays a Critical Role in the Induction of Regulatory Dendritic Cells by DNA and Protein Coimmunization

Geng

Xie³

et al. 2012

The Journal of Immunology

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Induction of Ag-specific regulatory T cells (iTregs) by vaccination is a promising strategy for treating autoimmune diseases. We previously demonstrated that DNA and protein covaccination converted naive T cells to Ag-specific iTregs by inducing CD11c+CD40lowIL-10+ regulatory dendritic cells (DCregs). However, it is unclear how coimmunization induces the DCregs. In this paper, we report that the event is initiated by coentry of sequence-matched DNA and protein immunogens into the same DC via caveolae-mediated endocytosis, which leads to inhibition of phosphorylation of caveolin-1 (Cav-1), the main component of caveolae, and upregulation of Tollip. This triggers downstream signaling that upregulates suppressor of cytokine signaling 1 and downregulates NF-κB and STAT-1α. Silencing either Cav-1 or Tollip blocks the negative signaling, leading to upregulated expression of CD40, downregulated production of IL-10, and loss of iTreg-inducing function. We further show that DCregs can be induced in culture from primary DCs and JAWS II DC lines by feeding them sequence-matched DNA and protein immunogens. The in vitro-generated DCregs are effective in ameliorating autoimmune and inflammatory diseases in several mouse models. Our study thus suggests that DNA and protein coimmunization induces DCregs through Cav-1– and Tollip-mediated negative signaling. It also describes a novel method for generating therapeutic DCregs in vitro.

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Cytokine responses correlate differentially with age in infancy and early childhood

Cited by 124 publications

References 27 publications

Mouse model of mevalonate kinase deficiency: comparison of cytokine and chemokine profile with that of human patients

Mouse model of mevalonate kinase deficiency: comparison of cytokine and chemokine profile with that of human patients

Defective antigen-presenting cell function in human neonates

Caveolin-1–Mediated Negative Signaling Plays a Critical Role in the Induction of Regulatory Dendritic Cells by DNA and Protein Coimmunization

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