Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.

Altare, Frédéric; Lammas, David A.; Revy, Patrick; Jouanguy, Emmanuelle; Döffinger, Rainer; Lamhamedi, Salma; Drysdale, P; Scheel‐Toellner, Dagmar; Girdlestone, John; Darbyshire, P J; Wadhwa, Meenu; Dockrell, Hazel M.; Salmon, Mike; Fischer, Alain; Durandy, Anne; Casanova, Jean‐Laurent; Kumararatne, D. S.

doi:10.1172/jci4950

Cited by 383 publications

(273 citation statements)

References 21 publications

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“…Activation of these cell subsets is primarily regulated by cytokine production and presentation of Mtb Ags by infected macrophages (3,21). Characterization of some human severe immunodeficiencies has highlighted an essential role of IL-12 and IFN-␥ in the control of Mtb (22)(23)(24)(25)(26). Therefore, studies committed to investigate the balance existing in the granulomatous response between mononuclear phagocytes and T cells are essential to understand the changes leading to the dissemination of mycobacteria and disease or to the reactivation of latent infection.…”

Section: Discussionmentioning

confidence: 99%

Infection of Human Macrophages and Dendritic Cells withMycobacterium tuberculosisInduces a Differential Cytokine Gene Expression That Modulates T Cell Response

Giacomini¹,

Iona

Ferroni³

et al. 2001

The Journal of Immunology

387

340

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Macrophages and dendritic cells (DC) play an essential role in the initiation and maintenance of immune response to pathogens. To analyze early interactions between Mycobacterium tuberculosis (Mtb) and immune cells, human peripheral blood monocyte-derived macrophages (MDM) and monocyte-derived dendritic cells (MDDC) were infected with Mtb. Both cells were found to internalize the mycobacteria, resulting in the activation of MDM and maturation of MDDC as reflected by enhanced expression of several surface Ags. After Mtb infection, the proinflammatory cytokines TNF-α, IL-1, and IL-6 were secreted mainly by MDM. As regards the production of IFN-γ-inducing cytokines, IL-12 and IFN-α, was seen almost exclusively from infected MDDC, while IL-18 was secreted preferentially by macrophages. Moreover, Mtb-infected MDM also produce the immunosuppressive cytokine IL-10. Because IL-10 is a potent inhibitor of IL-12 synthesis from activated human mononuclear cells, we assessed the inhibitory potential of this cytokine using soluble IL-10R. Neutralization of IL-10 restored IL-12 secretion from Mtb-infected MDM. In line with these findings, supernatants from Mtb-infected MDDC induced IFN-γ production by T cells and enhanced IL-18R expression, whereas supernatants from MDM failed to do that. Neutralization of IFN-α, IL-12, and IL-18 activity in Mtb-infected MDDC supernatants by specific Abs suggested that IL-12 and, to a lesser extent, IFN-α and IL-18 play a significant role in enhancing IFN-γ synthesis by T cells. During Mtb infection, macrophages and DC may have different roles: macrophages secrete proinflammatory cytokines and induce granulomatous inflammatory response, whereas DC are primarily involved in inducing antimycobacterial T cell immune response.

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Section: Discussionmentioning

confidence: 99%

Infection of Human Macrophages and Dendritic Cells withMycobacterium tuberculosisInduces a Differential Cytokine Gene Expression That Modulates T Cell Response

Giacomini¹,

Iona

Ferroni³

et al. 2001

The Journal of Immunology

387

340

View full text Add to dashboard Cite

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“…The clinical manifestations of the disease are heterogenous and range from abdominal abscesses and adenitis to severe sepsis. Several Salmonella serotypes have been identified and include Salmonella Paratyphi 139,140 or non-typhoid Salmonella serotypes such as Salmonella Typhimurium, 140 Salmonella Enteritidis, 139,[141][142][143] Salmonella group B 139,140 or untyped Salmonella. 139,144,145 Host resistance loci identified using QTL analysis…”

Section: Cytokines: Tnf Ifng and Il12mentioning

confidence: 99%

Genetic regulation of host responses to Salmonella infection in mice

Malo

2002

Genes Immun

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Salmonella spp are Gram-negative bacteria capable of infecting a wide range of host species, including humans, domesticated and wild mammals, reptiles, birds and insects. The outcome of an encounter between Salmonella and its host is dependent upon multiple factors including the host genetic background. To facilitate the study of the genetic factors involved in resistance to this pathogen, mouse models of Salmonella infection have been developed and studied for years, allowing identification of several genes and pathways that may influence the disease outcome. In this review, we will cover some of the genes involved in mouse resistance to Salmonella that were identified through the study of congenic mouse strains, cloning of spontaneous mouse mutations, use of site-directed mutagenesis or quantitative trait loci analysis. In parallel, the relevant information pertaining to genes involved in resistance to Salmonella in humans will be discussed.

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“…Live M. bovis BCG vaccine is normally well tolerated, however, in children with severe immunodeficiency or mutations of the interferon-␥R1, IL-12, or IL-12R genes, vaccination or infection with BCG leads to lethal dissemination or severe infection (Altare et al, 1998a(Altare et al, , 1998bCasanova et al, 1995;de Jong et al, 1998;Jouanguy et al, 1996Jouanguy et al, , 1997Jouanguy et al, , 1999. Cytokines controlling susceptibility to M. tuberculosis and M. bovis infections have been extensively studied in genetically modified animals.…”

Section: Ycobacterium Bovis (M Bovis) Bacillusmentioning

confidence: 99%

Lethal Mycobacterium Bovis Bacillus Calmette Guérin Infection in Nitric Oxide Synthase 2-Deficient Mice: Cell-Mediated Immunity Requires Nitric Oxide Synthase 2

García

Guler

Vesin

et al. 2000

Laboratory Investigation

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SUMMARY:The role of nitric oxide (NO) in Mycobacterium bovis Bacillus Calmette Gué rin (BCG) infection was investigated using nitric oxide synthase 2 (nos2)-deficient mice, because NO plays a pivotal protective role in M. tuberculosis infection. We demonstrate that nos2-deficient mice were unable to eliminate BCG and succumbed within 8 to 12 weeks to BCG infection (10 6 CFU) with cachexia and pneumonia, whereas all infected wild-type mice survived. The greatest mycobacterial loads were observed in lung and spleen. Nos2-deficient mice developed large granulomas consisting of macrophages and activated T cells and caseous necrotic lesions in spleen. The macrophages in granulomas from nos2-deficient mice had reduced acid phosphatase activities, suggesting that NO is required for macrophage activation. The absence of NOS2 affected the cytokine production of the Th1 type of immune response, except IL-18. Serum amounts of IL-12p40 were increased and IFN-␥ was decreased compared with wild-type mice. The lack of NOS2 resulted in an overproduction of TNF, observed throughout the infection period. Additionally, TNFR1 and TNFR2 shedding was altered compared with wild-type mice. Up-regulation of TNF may be compensatory for the lack of NOS2. The late neutralization of TNF by soluble TNF receptors resulted in heightened disease severity and accelerated death in nos2-deficient mice but had no effect in wild-type mice. In conclusion, the inability of nos2-deficient mice to kill M. bovis BCG resulted in an accumulation of mycobacteria with a dramatic activation of the immune system and overproduction of pro-inflammatory cytokines, which resulted in death. (Lab Invest 2000, 80:1385-1397.

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Inherited interleukin 12 deficiency in a child with bacille Calmette-Guérin and Salmonella enteritidis disseminated infection.

Abstract: Interferon-␥ receptor ligand-binding chain (IFN-␥

Cited by 383 publications

References 21 publications

Infection of Human Macrophages and Dendritic Cells withMycobacterium tuberculosisInduces a Differential Cytokine Gene Expression That Modulates T Cell Response

Infection of Human Macrophages and Dendritic Cells withMycobacterium tuberculosisInduces a Differential Cytokine Gene Expression That Modulates T Cell Response

Genetic regulation of host responses to Salmonella infection in mice

Lethal Mycobacterium Bovis Bacillus Calmette Guérin Infection in Nitric Oxide Synthase 2-Deficient Mice: Cell-Mediated Immunity Requires Nitric Oxide Synthase 2

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