Journal ArticleDOI
A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection
Emmanuelle Jouanguy,Salma Lamhamedi-Cherradi,David A. Lammas,Susan E. Dorman,Marie Claude Fondaneche,Stéphanie Dupuis,Rainer Döffinger,Frédéric Altare,John Girdlestone,Jean-François Emile,Henri Ducoulombier,David Edgar,Jane R. Clarke,Vivi-Anne Oxelius,Melchiorre Brai,Vas Novelli,Klaus Heyne,Alain Fischer,Steven M. Holland,Dinakantha S. Kumararatne,Robert D. Schreiber,Jean-Laurent Casanova +21 more
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TLDR
A hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria is reported.Abstract:
The immunogenetic basis of severe infections caused by bacille Calmette-Guerin vaccine and environmental mycobacteria in humans remains largely unknown. We describe 18 patients from several generations of 12 unrelated families who were heterozygous for 1 to 5 overlapping IFNGR1 frameshift small deletions and a wild-type IFNGR1 allele. There were 12 independent mutation events at a single mutation site, defining a small deletion hotspot. Neighbouring sequence analysis favours a small deletion model of slipped mispairing events during replication. The mutant alleles encode cell-surface IFNgamma receptors that lack the intra-cytoplasmic domain, which, through a combination of impaired recycling, abrogated signalling and normal binding to IFNgamma exert a dominant-negative effect. We thus report a hotspot for human IFNGR1 small deletions that confer dominant susceptibility to infections caused by poorly virulent mycobacteria.read more
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Interferon-γ: an overview of signals, mechanisms and functions
TL;DR: The current understanding of IFN‐γ ligand, receptor, ignal transduction, and cellular effects with a focus on macrophage responses and to a lesser extent, responses from other cell types that influence macrophages function during infection are reviewed.
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Molecular Mechanisms RegulatinG Th1 Immune Responses
TL;DR: The mechanisms that control lineage commitment to the Th1 phenotype are discussed, and the basic pathways leading to Th1 differentiation can now be understood in in vitro and a number of infection and disease models.
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Genetic dissection of immunity to mycobacteria: the human model
TL;DR: The human model has potential uses beyond the study of mycobacterial infections and may well become a model of choice for the investigation of immunity to infectious agents.
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The roles of IFNγ in protection against tumor development and cancer immunoediting
TL;DR: The capacity of IFN gamma and lymphocytes to not only provide protection against tumor development but also to sculpt the immunogenic phenotype of tumors that develop in an immunocompetent host is presented and introduced as a "cancer immunoediting" process.
Journal ArticleDOI
Fas Preassociation Required for Apoptosis Signaling and Dominant Inhibition by Pathogenic Mutations
Richard M. Siegel,John K. Frederiksen,David A. Zacharias,Francis Ka-Ming Chan,Michele M. Johnson,David A. Lynch,Roger Y. Tsien,Michael J. Lenardo +7 more
TL;DR: Results show that formation of preassociated receptor complexes is necessary for Fas signaling and dominant interference in human disease.
References
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Journal ArticleDOI
A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection.
Melanie J. Newport,Clare M Huxley,Sara Huston,Catherine M Hawrylowicz,Ben A Oostra,Robert Williamson,Michael Levin +6 more
TL;DR: Four children with severe mycobacterial infections had a mutation in the gene for interferon-gamma receptor 1 that leads to the absence of receptors on cell surfaces and a functional defect in the up-regulation of tumor necrosis factor alpha by macrophages in response to interferOn-Gamma.
Journal ArticleDOI
The structure and evolution of the human β-globin gene family
Argiris Efstratiadis,James W. Posakony,Tom Maniatis,Richard M. Lawn,Catherine O'Connell,Richard A. Spritz,Jon K. deRiel,Bernard G. Forget,Sherman M. Weissman,Jerry L. Slightom,Ann E. Blechl,Oliver Smithies,Francisco E. Baralle,Carol C. Shoulders,Nick J. Proudfoot +14 more
TL;DR: A model for the involvement of short direct repeat sequences in the generation of deletions in the noncoding and coding regions of B-like globin genes during evolution is described.
Journal ArticleDOI
Natural resistance to infection with intracellular parasites: isolation of a candidate for Bcg.
TL;DR: Susceptibility to infection in 13 Bcgr and Bcgs strains tested is associated with a nonconservative Gly-105 to Asp-105 substitution within predicted transmembrane domain 2 of Nramp, suggesting a macrophage-specific membrane transport function.
Journal ArticleDOI
The ifn-gamma receptor: a paradigm for cytokine receptor signaling
TL;DR: A model of IFN gamma signaling that is nearly complete and that serves as a paradigm for signaling by other members of the cytokine receptor superfamily is produced.
The Structure and Evolution of the Human /?-Globin Gene Family
Argiris Efstratiadis,James W. Posakony,Tom Maniatis,Richard M. Lawn,Richard A. Spritz,Jon K. deRiel,Forget Bg,Sherman M. Weissman,Jerry L. Slightom,Ann E. Blechl,Oliver Smithies,F.E. Baralle,Carol C. Shoulders,Nicholas J. ProudfootQ +13 more
TL;DR: Efstratiadis et al. as mentioned in this paper presented the results of a detailed comparison of the primary structure of human p-like globin genes and their flanking sequences.