*4.3. Inborn Errors of Innate Immunity*

No studies of the methylation changes that could occur in this subgroup of disorders have been conducted. However, given that the signaling pathways affected in these diseases, such as that of TLR4, have been described in some cases to cause modifications in DNA methylation, it is conceivable to hypothesize that DNA methylation may potentially exert a mechanistic role in the pathogenesis of undefined disorders or, putatively, in modulating the natural history.

Mendelian susceptibility to Mycobacterial disease (MSMD) is a rare inherited condition characterized by selective predisposition to clinical disease caused by weakly virulent mycobacteria, such as bacillus Calmette–Guerin vaccines and non-tuberculous environmental mycobacteria [79] in otherwise healthy patients with no overt abnormalities in routine hematological and immunological functionality. MSMD patients are also at higher risk of tuberculosis, salmonellosis, candidiasis and, more rarely, to infections with other intra-macrophagic bacteria, fungi, or parasites [80]. Nine MSMD-causing genes, including seven autosomal (*IFNGR1*, *IFNGR2*, *STAT1*, *IL12B*, *IL12RB1*, *ISG15* and *IRF8*) and two X-linked (*NEMO* and *CYBB*) genes, have been described so far; all are involved in IFN-γdependent immunity [81]. Pacis et al. showed that the *Mycobacterium tuberculosis* infection of dendritic cells induces rapid loss of DNA methylation at distal enhancers that activate master immune transcription factors (including nuclear factor-kB and members of the Interferon Regulatory Factor family), suggesting an important role for DNA methylation in regulating innate immune responses [82,83].
