Disseminated <i>Mycobacterium avium</i> Infection in a 20-Year-Old Female with Partial Recessive IFNγR1 Deficiency

Abstract

We report the case of a 20-year-old female with disseminated Mycobacterium avium disease involving bones, lungs and brain. She was completely healthy up until the present illness and had been vaccinated with BCG in infancy without complications. Mycobacteriosis progressed in spite of treatment with antituberculous drugs and was controlled only after addition of interferon-γ subcutaneously. A homozygous hypomorphic I87T mutation was found in the gene encoding the ligand-binding chain of the IFN-γ receptor (IFNγR1). This mutation is the only known recessive hypomorphic lesion in IFNGR1 and had been reported before in only 1 child with curable BCG infection and his sibling with primary tuberculosis. Our report illustrates the clinical heterogeneity of patients sharing exactly the same form of partial recessive IFNγR1 deficiency. A diagnosis of partial recessive IFNγR1 deficiency should be contemplated in adults with unexplained environmental mycobacterial diseases.

Adjuvant modulation of the cytokine balance in Mycobacterium tuberculosis subunit vaccines; immunity, pathology and protection

“…1,2 Furthermore, humans with a disruption of the IFN-c signalling pathway show abnormal susceptibility to mycobacteria, 3 a condition that is reversed by the administration of synthetic IFN-c. 4 The central role of IFN-c means that most novel TB vaccine strategies have focused on generating strong T helper type 1 (Th1) responses either by using strong, Th1-polarizing adjuvants 5,6 or by heterologous prime-boost approaches. 7 The relevance of Th1 priming by these vaccines is indisputable and is supported by challenge studies involving experimental vaccines that induce different levels of IFN-c. 8 With the first novel vaccines now entering clinical trials, IFN-c has emerged as a surrogate marker for the protection conferred by the trial vaccine.…”

Host susceptibility to non-tuberculous mycobacterial infections

“…30 Recessive complete IFNGR2 defi ciency can result in absence of IFNGR2 expression 30 or non-functional IFNGR2, 76,77 whereas the fi ve reported patients with recessive partial IFNGR2 defi ciency had normal to slightly lower IFNGR2 expression and residual interferon γ responses. 33,38,39 IFNGR2 haploinsuffi ciency can also confer dominant partial IFNGR2 defi ciency, 41 as can dominant negative mutations. 42 Generally, recessive com plete mutations result in more severe disease than partial defi ciencies.…”

“…42 Generally, recessive com plete mutations result in more severe disease than partial defi ciencies. 30,38,42,76 Flow cytometry can be used to detect surface IFNGR1 on peripheral blood mononuclear cells.…”

“…11,47,78,79 IFNGR2 expression is low and might need Epstein-Barr virus-transformed B cells to improve detection. 11,33 Some rare instances of patients with recessive complete IFNGR2 defi ciency and recessive partial IFNGR1 or IFNGR2 defi ciencies who have normal surface expression of hypofunctional receptors exist, 32,34,38,76 suggesting that genetic sequencing, a test for IFNGR function, or both must be used to confi rm the diagnosis. …”

Genetic Causes of Bronchiectasis: Primary Immune Deficiencies and the Lung

“…Production of IFN-γ by activated T and natural killer cells is under the control of IL-12 and IL-23, which are secreted by activated macrophages. Mutations of IL-12 p40, IL-12 receptor β-1 subunit, IFN-γ receptor 1, IFN-γ receptor 2 and of the signaling molecule STAT1 have been shown to cause genetically determined susceptibility to mycobacterial disease in humans, in which dissemination to lungs is common and often fatal [103, 104]. …”