Marketa Bloomfield, Czech Republic
2nd Faculty of Medicine, Charles University and University Hospital in Motol Department of ImmunologyPresenter of 1 Presentation
MUTUAL ALTERATION OF BLAU SYNDROME DUE TO A GAIN-OF-FUNCTION NOD2 MUTATION AND MYCOBACTERIAL DISEASE DUE TO A DOMINANT-NEGATIVE IFNGR1 MUTATION
Abstract
Background and Aims
Blau syndrome (BS) is an auto-inflammatory granulomatous disease that involves abnormally increased response to IFNγ due to exaggerated NOD2 activity. Mendelian susceptibility to mycobacterial disease (MSMD) is a primary immune deficiency presenting as an infectious granulomatous disease that involves impaired production of or response to IFNγ.
Methods
NGS was performed by Illumina-based technology, functional assays included complex immune profiling was performed after stimulation by IFNγ (due to IFNGR1) and muramyl dipeptide (MDP) (in a context with NOD2 mutation). To verify the effect of the therapy, functional tests were also performed after initiation of Methotrexate treatment.
Results
We report a mother and daughter who are both heterozygous for a gain of function (GOF) NOD2 mutation previously shown to underlie BS and a dominant-negative IFNGR1 mutation previously shown to underlie MSMD. The 44-year-old mother has remained healthy, without any signs of BS and MSMD, whereas the 17-year-old daughter has displayed an altered form of BS and milder form of MSMD. Their leukocytes produced high amounts of IFNγ upon stimulation but responded poorly to this cytokine. Our findings suggest that the enhanced production of IFNγ mitigated the partial deficiency of IFNγ receptor and that the symptoms of BS were also modified. The rare association of two rare inborn errors of immunity in these kindred has thus resulted in altered forms of both disorders.
Conclusions
This experiment of nature suggests that IFNγ is an important driver of at least some manifestations of BS and that the decreased STAT1-mediated signaling via IFNγ receptor does not ameliorate the disease.