- de Jong R,
- Altare F,
- Haagen I-A,
- et al.
Purpose of the Studies
Bacille Calmette-Guérin (BCG) and nontuberculous mycobacteria (NTM) are poorly virulent mycobacteria that sometimes cause disseminated disease in children. It was recently discovered that complete interferon gamma (IFN-γ) receptor deficiency causes a predisposition for this type of infection, and lack of mature granulomas; partial deficiency leads to a milder course of infection with mature granuloma formation. Some patients with disseminated NTM infections, however, do not have this defect. Because interleukin-12 (IL-12) is a potent inducer of IFN-γ, this study evaluated the possibility that IL-12 receptor abnormalities were responsible for disseminated BCG or NTM in the patients without any other immunodeficiency or defect in the IFN-γ receptor.
A total of 7 unrelated patients were reported (4 in the first, 3 in the second paper). All experienced disseminated NTM infections and 5/7 had also experienced disseminated Salmonella infections. There were no other significant infections (viral, bacterial, fungal). None had a recognizable immunodeficiency (primary or secondary) and all had normal numbers of T, B, and NK cells.
A variety of molecular biologic and immunologic techniques were used to define the role of IL-12 receptor deficiency in this immunodeficiency phenotype.
DNA sequence and immunologic analyses excluded defects in IFN-γ receptor and IL-12. Specific mutations in genes encoding the IL-12 receptor β1 chain were identified (distinct mutations for each patient including missense, nonsense, and frameshift). Addition of recombinant IL-12 in NK cytotoxicity assays did not result in increased activity in patients versus controls. Affected patient's T cells had reduced IFN-γ production after stimulation with a variety of mitogens and antigens but cells did have normal surface expression of IFN-γ receptor expression and normal expression of IL-12. There was no detectable surface expression of IL-12 receptor β1. Adding exogenous IL-12 did not increase IFN-γ production by T cells nor did adding antibody to IL-12 cause a decrease in the low constitutive expression of IFN-γ. Tuberculin-specific, delayed type hypersensitivity reactions were normal. Like patients with partial deficiency if the IFN-γ receptor, these patients had well-circumscribed granuloma formation in affected organs.
The lack of IL-12 receptor β1 results in human immunodeficiency characterized by unusual susceptibility to mycobacterial and Salmonella infections. IL-12 dependent IFN-γ secretion is the unifying pathophysiologic cause for this immunodeficiency that is phenotypically identical to partial IFN-γ receptor deficiency. Although more patients must be evaluated, it appears that this pathway is essential for immune responses to these intracellular organisms but is dispensable (redundant pathways exist) for other infectious organisms.
It is very exciting that the molecular mechanisms responsible for the primary immunodeficiencies are being unraveled at a remarkable pace. As evidenced by this work, unusual manifestations of immunodeficiency are being elucidated and provide fundamental insights into immune system mechanisms. These findings already provide clues to better therapies (1 patient was treated successfully with recombinant IFN-γ) and because IL-12 receptor signaling is involved in other conditions such as cancer, there are many diagnostic and therapeutic ramifications from these studies.