Familial atypical mycobacteriosis (FAM, MIM 209950) is a rare congenital condition characterized by familial inherited immunodeficiency to mycobacterial infection, which is more popularly known as Mendelian susceptibility to mycobacterial diseases (MSMD). Mutations causing MSMD have been identified in several genes. Because of the lethal effects of the MSMD mutations, the frequencies of these mutations are extremely rare (<1/million).7
The identification of these MSMD mutations not only enables precise diagnosis and guided treatment for MSMD, but also highlights the central molecular mechanisms of host immunity to mycobacterial infection, which is a superb paradigm for clarifying the molecular immune mechanisms of a disease by the genetics approach.
MSMD has simple Mendelian inheritance patterns, i.e., autosome dominant, autosome recessive, or X-linked inheritance. Clinically, MSMD is characterized by serious disseminated infection in early childhood of low virulence mycobacteria, most commonly BCG vaccine. The patients are resistant to infection with most other bacteria, fungi, and parasites. The Mendelian inheritance suggests the disease is controlled by a single mutation. Both patterns of autosome inheritance and X-linked inheritance suggest that a mutation causing MSMD can be from either an autosome gene or an X-chromosome gene. This selective susceptibility to mycobacterial infection demonstrates the critical roles of mutated genes in immunity against mycobacteria.
The BCG vaccine is comprised of virulence-attenuated M. bovis
sub-strains, and was first developed by Albert Calmette and Camille Guérin at the beginning of the twentieth century by culturing virulent M. bovis
on bile-containing medium for 230 serial passages. The attenuation of virulence results from the mutations involving M. bovis
proteins mediating its virulence, including ESX-1, PDIM/PGL, and PhoP.8
Live BCG bacilli induce the adaptive cellular immune responses by the cross-reactive antigens of MTB bacilli. The immunogenicity of BCG is mediated by M. bovis
proteins different from those mediating its virulence. BCG vaccination is a highly cost-effective intervention against severe childhood TB, and is significantly associated with a reduction in the incidence of pulmonary TB and extrapulmonary disease in early childhood, such as meningitis and miliary TB.3–6
The BCG vaccination is not efficacious in the prevention of pulmonary TB in adolescents and adults, as it does not prevent the establishment of primary infection or reactivation of latent MTB.5,9,10
The administration of BCG vaccination in neonates is relatively safe. However, in individuals with MSMD mutations, disseminated infection and bacteremia may develop.
Seven genes have been identified with MSMD mutations. Six of the seven genes are involved in the signaling of two cytokines, i.e., interferon-gamma (IFN-γ) and interleukin-12 (IL-12). The other gene, IKBKG, participates in the regulation of IL-12 and IFN-γ signaling, and other immune processes by the nuclear factor kappa B (NF-κB) pathway. The major components involved in the signaling of these two cytokines are listed in . Among these signaling components, the three Janus tyrosine kinases, JAK-1, JAK-2, and TYK-2, are involved in the signaling of a number of cytokines besides IFN-γ and IL-12. STAT1 mediates the signaling of both IFN-γ and IFN-α/β, and STAT4 mediates the signaling of both IL-12 and interleukin-23 (IL-23).
Genes involved in interferon-gamma (IFN-γ) and interleukin-12 (IL-12) signaling