Mendelian susceptibility to mycobacterial diseasesD84.8

MSMD, the "Mendelian susceptibility to mycobacterial disease" is a rare, autosomal dominant, autosomal recessive or X-linked (monogenic) immunodeficiency syndrome caused by molecular defects in the IL12 / IFNγ dependent signaling pathway. MSDM leads to an increased selective susceptibility to local or disseminated infections by only slightly virulent mycobacteria, such as the Bacillus Calmette-Guérin (BCG) vaccine and environmental mycobacteria (EM), or by typhoid and non-typhoid Salmonella. MSDM is characterized by severe, recurrent, disseminated or localized infections.

The prevalence is not known.

So far, 16 genes are known to be associated with MSMD. These show a considerable allelic heterogeneity, which leads to different genetic and pathogenetic diseases. Most MSMD deficiencies occur in isolation and become conspicuous as selective susceptibility to mycobacterial disease. The most important mutations affect the following genes:

• IFNGR1
• IFNGR2
• STAT1
• IL12B
• IL12RB1
• IRF8
• ISG15

2 Gene defects are inherited X-linked:

• IKBKG
• CYBB.

All mutations impair interleukin-12-dependent IFN-gamma signaling activity. The high allelic heterogeneity leads to several genetically well-defined and also pathogenetically distinct diseases.

The autosomal recessive (AR) inherited complete deficiency of the interferon-gamma receptors 1 (IFN-gammaR1) and 2 (IFN-gammaR2) leads to the most severe clinical pictures. These become manifest already in the first years of life. The infections caused by BCG and EM often appear as disseminated clinical pictures. They affect mainly the soft tissues, skin, lymph nodes and skeletal system as well as the lungs. Other infections, with typhoid and non-typhoid Salmonella spp, with Listeria monocytogenes have also been described.

X-linked recessive (XR) inherited mutations of MSMD, usually with less severe clinical course are caused by partial deficiency of IFN-gammaR1 and IFN-gammaR2. This results in complete deficiency of IL-12R-beta1, IL12B, and ISG15, and partial deficiency of STAT1 and IRF8. The disease does not manifest until after 3 years of age through adulthood. Patients are susceptible to Mycobacterium tuberculosis. A proportion of patients have severe infections due to non-typhoidal Salmonella, especially in IL-12R-beta1 and IL12B deficiency.

Diseases with non-tuberculous (atypical) mycobacteria are also particularly important for dermatology. Attention should be paid, for example, to"swimming pool granuloma", which has an unusual clinical course with resistance to therapy. But also infections by rapidly growing pathogens of the Mycobacterium fortuitum complex (M.fortuitum, M.chelonae, M.abscessus) may indicate this sepcial immunodeficiency.

BCG vaccination should be avoided in MSMD patients. Patients with IL-12B, IL-12R-beta1 or ISG15 deficiency and partial IFN-gammaR, IRF8 and STAT1 deficiency respond well to antibiotic therapy and can also be treated with IFN-gamma. Hematopoietic stem cell transplantation (HSCT) should be considered in patients with complete IFN-gammaR1 or IFN-gammaR2 deficiency. A high rate of rejection should be indicated (high IFN-gamma levels are measured in the serum of these patients).

1. Crow YJ (2011) Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 1238:91-98
2. Crow YJ et al (2015) Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol 15:429-440
3. Günther C et al (2016) Type I interferonopathies. Z Rheumatol 75: 134-140
4. Wang Li-Hui et al (2012) Impact of molecular diagnosis on treating Mendelian susceptibility to mycobacterial diseases. Journal of Microbiology, Immunology and Infection 45: 411-417
5. Zhang X et al (2015) Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation. Nature 517:89-93