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Published on: November 16, 2016
What We Have Here Is a Failure to Communicate: Interleukin-12 / Interferon-gamma Axis Defects and Mendelian
Alicia Μ Johnston1, Nicholas L Rider2, Alexandra F Freeman3
1Division of Infectious Diseases, Boston Children's Hospital, Harvard Medical School, Boston, Mass.
Abstract:
Mendelian susceptibility to mycobacterial disease (MSMD) is a rare group of immunodeficiencies with high mortality characterized by a failure of communication between phagocytic cells and their regulatory/support networks. The objective of this article was to review key aspects of MSMD management. A defective IL-12/IFN-γ circuit can result in overwhelming intracellular infection, leading to lymphadenopathy, organomegaly, and sepsis. In the setting of unexplained lymphadenopathy, early tissue and blood culture, with special attention to mycobacteria, is essential. If MSMD is suspected, genetic testing to assess for pathogenic variants affecting the IFN-γ/IL-12 signaling pathway is available. To date, at least 19 genes with hundreds of unique mutations have been identified; thus, genetic testing is essential to determine the specific defect and direct therapy. Multiple antibiotics, cytokine therapy in selected cases, and bone marrow transplantation should be considered.
Insights
Mendelian Susceptibility to Mycobacterial Disease (MSMD) management involves understanding immune system communication failures. Early diagnosis through genetic testing and tailored treatments like antibiotics or bone marrow transplant are crucial for high-mortality cases.
Area of Science:
- Immunology
- Genetics
- Infectious Diseases
Background:
- Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a rare, high-mortality immunodeficiency.
- It stems from impaired communication between phagocytic cells and regulatory networks.
- Defects in the interleukin-12 (IL-12) / interferon-gamma (IFN-γ) circuit cause severe intracellular infections.
Purpose of the Study:
- To review key management strategies for Mendelian Susceptibility to Mycobacterial Disease (MSMD).
- To highlight the importance of early diagnosis and genetic assessment in MSMD.
- To discuss current and potential therapeutic interventions for MSMD patients.
Main Methods:
- Review of existing literature on MSMD management.
- Emphasis on diagnostic approaches including cultures and genetic testing.
- Discussion of therapeutic options such as antibiotics, cytokine therapy, and transplantation.
Main Results:
- Identification of at least 19 genes associated with MSMD, with numerous mutations.
- Genetic testing is essential for pinpointing specific defects in the IFN-γ/IL-12 pathway.
- Effective management requires a multi-faceted approach tailored to the genetic defect.
Conclusions:
- Early recognition of MSMD, particularly with unexplained lymphadenopathy, is critical.
- Genetic testing is indispensable for accurate diagnosis and guiding therapy in MSMD.
- Treatment options include antibiotics, cytokine therapy, and potentially bone marrow transplantation.
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