In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ
Emmanuelle Jouanguy, Stéphanie Dupuis, Annaïck Pallier, Rainer Döffinger, Marie-Claude Fondanèche, Claire Fieschi, Salma Lamhamedi-Cherradi, Frédéric Altare, Jean-François Emile, Patrick Lutz, Pierre Bordigoni, Haluk Cokugras, Necla Akcakaya, Judith Landman-Parker, Jean Donnadieu, Yildiz Camcioglu, Jean-Laurent Casanova
Emmanuelle Jouanguy, Stéphanie Dupuis, Annaïck Pallier, Rainer Döffinger, Marie-Claude Fondanèche, Claire Fieschi, Salma Lamhamedi-Cherradi, Frédéric Altare, Jean-François Emile, Patrick Lutz, Pierre Bordigoni, Haluk Cokugras, Necla Akcakaya, Judith Landman-Parker, Jean Donnadieu, Yildiz Camcioglu, Jean-Laurent Casanova
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Article

In a novel form of IFN-γ receptor 1 deficiency, cell surface receptors fail to bind IFN-γ

Abstract

Complete IFN-γ receptor ligand-binding chain (IFNγR1) deficiency is a life-threatening autosomal recessive immune disorder. Affected children invariably die of mycobacterial infection, unless bone marrow transplantation is undertaken. Pathogenic IFNGR1 mutations identified to date include nonsense and splice mutations and frameshift deletions and insertions. All result in a premature stop codon upstream from the segment encoding the transmembrane domain, precluding cell surface expression of the receptors. We report herein two sporadic and two familial cases of a novel form of complete IFNγR1 deficiency in which normal numbers of receptors are detected at the cell surface. Two in-frame deletions and two missense IFNGR1 mutations were identified in the segment encoding the extracellular ligand-binding domain of the receptor. Eight independent IFNγR1-specific mAb’s, including seven blocking antibodies, gave recognition patterns that differed between patients, suggesting that different epitopes were altered by the mutations. No specific binding of 125I–IFN-γ to cells was observed in any patient, however, and the cells failed to respond to IFN-γ. The mutations therefore cause complete IFNγR1 deficiency by disrupting the IFN-γ–binding site without affecting surface expression. The detection of surface IFNγR1 molecules by specific antibodies, including blocking antibodies, does not exclude a diagnosis of complete IFNγR1 deficiency.

Authors

Emmanuelle Jouanguy, Stéphanie Dupuis, Annaïck Pallier, Rainer Döffinger, Marie-Claude Fondanèche, Claire Fieschi, Salma Lamhamedi-Cherradi, Frédéric Altare, Jean-François Emile, Patrick Lutz, Pierre Bordigoni, Haluk Cokugras, Necla Akcakaya, Judith Landman-Parker, Jean Donnadieu, Yildiz Camcioglu, Jean-Laurent Casanova

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Four types of inheritable IFNγR1 deficiency. A wild-type IFNγR1 molecule...
Four types of inheritable IFNγR1 deficiency. A wild-type IFNγR1 molecule is represented (left), with its extracellular (EC), transmembrane (TM), and intracellular (IC) domains. The horizontal bars in the intracellular region represent the JAK-1– and STAT-1–binding motifs and the receptor recycling motif (17). Four types of mutant IFNγR1 molecules are represented (right; see text for more details). The first (from left to right) mutant receptor (e.g., that encoded by the IFNGR1 allele 818del4) lacks most of the intracellular domain; the second (e.g., mutant I87T) probably binds IFN-γ with a reduced affinity; the third (e.g., mutant C77Y) does not bind IFN-γ at all; the fourth (e.g., mutant 107ins4) is not expressed at the cell surface because of a stop codon upstream from the TM domain. The mutations therefore define four types of IFNγR1 deficiency that differ in terms of inheritance (autosomal dominant, AD; autosomal recessive, AR), IFNγR1 cell surface expression (+++, hyperexpression; +, normal expression; –, lack of expression), 125I–IFN-γ binding to the cells (+, normal; +/–, reduced but not abolished; –, abolished), and/or IFN-γ–signaling defect (partial, impaired but not abrogated cellular responses to IFN-γ; complete, abrogated cellular responses to IFN-γ).