Abstract
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare clinical syndrome that is characterized by selective vulnerability to intracellular pathogens. Deficiency in IL12RB1 is the most common type of MSMD but the heterogeneity of its clinical Manifestation Makes precise diagnosis difficult. Here, we report a previously healthy 29 year-old woman who had suffered from disseminated infection with Mycobacterium tilburgii, which is a rare, unculturable environmental mycobacteria, for over 2 years. We used whole exome sequencing to detect a novel compound heterozygous variant in the IL12RB1 gene. Immunological analysis of the patient's peripheral lymphocytes showed a barely detectable level of IL-12Rβ1, a reduced population of follicular helper T (Tfh) cells and impaired production of IFN-γ in response to IL-12/IL-23 stimulation. Metagenomic next-generation sequencing was used to identify the causative pathogen and to analyze drug susceptibility. The infection was contained by a combination of anti-mycobacterial drugs and IFN-γ supplementary treatment. An RNA-seq analysis, using follow-up blood samples, revealed the limited success of these treatments over 6 months. Our findings support the screening for inherited immunological problems in patients with difficult-to-treat mycobacterial infections. The suboptimal response to prolonged anti-mycobacterial drugs and IFN-γ supplementation warrants the development of novel therapeutic strategies for MSMD patients.