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1.  Signaling through the IL-12/IFN-gamma pathway is essential for the activation of phagocytes to control mycobacteria and salmonella infections. Macrophages infected with mycobacteria produce IL-12 which stimulates Th1 T cells and NK cells to produce IFN-gamma.  IFN-gamma then binds to the IFN-gamma receptor on macrophages to induce killing of mycobacteria and salmonella (this signal transduction occurs through STAT 1). 


2.  A number of molecular defects in this signaling pathway have been described to cause Mendelian Susceptibility to Mycobacterial Diseases (MSMD). These diseases are characterized by increased susceptibility to mycobacteria (BCG vaccine, tuberculosis, atypical mycobacteria) and salmonella.  




-Both autosomal recessive (AR) and autosomal dominant (AD) forms of IFN-gamma receptor 1 and 2 deficiency have been described.  


-Autosomal Recessive (complete IFN-gamma receptor deficiency) - Patients present in infancy or childhood with mycobacterial disease and fail to form well-circumscribed mycobacterial granulomas.  Administration of BCG typically results in disseminated infection.  Severe salmonella infections are also common.  


-The mutations involve the extracellular domain of the IFN-gamma receptor and result in a complete absence of cell surface receptor expression.  


-The diagnosis is suggested by the absence of IFN-gamma receptor on the surface of lymphocytes as well as impaired STAT1 phosphorylation in response to IFN-gamma signaling.  Genetic testing for IFNGR1 and IFNGR2 is commercially available.  


-The cornerstone of therapy remains aggressive treatment with antimycobacterial antibiotics.  Given the absence of cell surface receptors, IFN gamma cytokine replacement therapy is not beneficial.  


-Given the severe nature of the disease, stem cell transplantation has been performed in some patients with variable success  fatal infectious complications and GVHD have been reported.  The current data suggest that myeloablative conditioning with a matched donor (sibling or unrelated) may yield the best results.  


-Rare AR partial defects in IFN-R1 and IFN-R2 due to missense mutations have been reported  signal transduction is impaired but not abolished.    


-Autosomal Dominant (partial IFN gamma receptor deficiency) - This milder form of disease is caused by heterozygous truncations of the cytoplasmic domain of the IFN-gamma R1.  This results in an accumulation of non-functional receptor molecules at the cell surface which are unable to transduce signals.  Dominant heterozygous mutations in IFN-gamma R2 have also been reported.  


-Clinically, patients present later in childhood or adolescence with disseminated or localized BCG, pulmonary nontuberculous mycobacteria (NTM), histoplasmosis, or salmonellosis.  Multifocal NTM osteomyelitis is particularly common among these patients and is considered a disease hallmark (79% of patients in one study).  Unlike patients with AR disease, these patients are able to form mycobacterial granulomas.  


-The diagnosis is suggested by a 3-5 fold increase in IFN-gamma R1 expression on monocytes.  Despite the increased number of surface receptors, STAT1 phosphorylation following IFN-gamma stimulation is minimal or undetectable.  Sequencing of the IFN-gamma R1 gene can confirm the diagnosis. 


-Infections should be treated aggressively with antimycobacterial antibiotics.  Unlike patients with AR IFN-R deficiency, patients with AD disease are able to respond to higher doses of IFN-gamma therapy.  




-Autosomal recessive mutations in the IL-12 receptor beta 1 have been identified in patients with disseminated NTM and Salmonella infections.  Patients also develop disseminated infection following BCG vaccination.  Granulomas are well-contained and well-organized.  


-Mutations occur in the extracellular domain of the IL-12R1 leading to premature stop codons and absent cell surface expression of this protein.  Without IL-12 signaling, IFN-gamma secretion from T cells and NK cells is greatly impaired.  


-Useful diagnostic clues include the absence of IL-12R1 on T cells and defective STAT4 phosphorylation in response to IL-12 stimulation. 


-Patients respond well to antibiotics typically used to treat mycobacteria.  Because the IFN-gamma receptor and downstream signaling is intact, IFN-gamma therapy may be beneficial for patients who fail antimycobacterial therapy alone.  




-IL-12 is comprised of two subunits, p35 and p40, encoded for by the IL-12A and IL-12B genes respectively.  The p40 subunit is also included in the structure of IL-23.    Patients with autosomal recessive mutations in the IL-12B gene have undetectable IL-12 p40 subunits.


-The infectious complications are similar to patients with IL-12R1 deficiency (BCG infection, NTM infections and Salmonella sepsis).  


-The clinical spectrum can be quite variable, ranging from fatal NTM mutations early in life to individuals presenting late in life with localized mycobacterial infection.


-The diagnosis is suggested by a lack of detectable IL-12 p40 secretion.


-Patients respond well to antibiotics typically used to treat mycobacteria.  As with IL-12R1, because the IFN-gamma receptor is intact, IFN-gamma therapy may be beneficial for patients who fail antimycobacterial therapy alone.  



-STAT 1 is a key signal transducer for the Type II IFN pathway (IFN-gamma) and the Type I IFN (Interferon alpha/beta) pathway.     


-Heterozygous (dominant partial) STAT 1 Deficiency is marked by a relatively mild phenotype with increased susceptibility to mycobacterial infections (BCG, NTM) due to impaired IFN-gamma induced STAT1 homodimer formation and nuclear translocation.  In these patients, IFN-gamma signaling is defective but IFN alpha/beta mediated viral defense is intact.  Patients have survived mycobacterial infections early in life and have reached adulthood.  

-Homozygous (recessive complete) STAT 1 Deficiency causes a severe form of disease marked by life-threatening mycobacterial and viral (HSV) infections early in life.  Unlike heterozygous partial STAT1 deficiency, both the Type I and Type II interferon signaling pathways are markedly impaired.  This disease appears to be fatal in the first year of life and patients are candidates for stem cell transplantation. 






Step 1:  Initial Immune Evaluation


-Quantitative immunoglobulins (IgG, IgM, IgA) 
-Antibody titers to vaccine antigens   
-Lymphocyte flow cytometry for B-cell, T cell, and NK cell enumeration
-T cell proliferation to mitogens
-DHR assay
-Toll-like receptor assay


-IgG, IgM, IgA levels and antibody titers to protein (Tetanus, Diptheria) and polysaccharide (Pneumococcus) vaccine antigens are normal in patients with IFN-gamma receptor, IL-12 beta 1 receptor, IL-12 p40, and STAT 1 deficiency.  However, patients with NEMO deficiency have increased susceptibility to mycobacterial disease and can present with low IgG but elevated IgM and IgA.  Specific antibody responses can also be diminished in NEMO deficiency. 

-Patients will have normal lymphocyte subset values and proliferation to mitogens.  However, these should be performed to rule out SCID and other T cell defects, particularly when the presentation occurs during infancy.  

-A DHR assay should be performed to assess phagocyte oxidative burst.  Patients with chronic granulomatous disease can also develop atypical mycobacterial infections. 

-Toll-like receptor assays measure inflammatory cytokine production (TNF-alpha, IL-6 and IL-1β) following the stimulation of PBMCs with TLR ligands.   Inflammatory cytokine production is decreased in NEMO deficiency due to impaired NF-κB activation following TLR signaling.


Step 2:  Additional IL-12 / IFN-gamma pathway screening studies


-IFN-gamma receptor surface expression 
-IL-12 receptor surface expression
-STAT 1 phosphorylation following stimulation
-STAT 4 phosphorylation following stimulation


-These flow cytometry based studies are currently available commercially (see resource section). 

-Absent IFN-g receptor surface expression would be concerning for complete IFN-g receptor deficiency (AR).  Partial IFN-g receptor deficiency (AD) results in an increased accumulation of non-functional IFN-g receptor on the cell surface. 
-Absent IL-12 receptor surface expression is found in IL-12 receptor deficiency.
-Decreased STAT1 phosphorylation would be expected in complete and partial IFN-gamma receptor deficiency. 
-Decreased STAT4 phosphorylation would be expected in IL-12 p40 deficiency and IL-12 receptor deficiency. 


Step 3:  Gene Sequencing

-IFN gamma R1 (IFNGR1) 
-IFN gamma R2 (IFNGR2)


-IFN gamma R1 and R2 sequencing is commercially available through Correlagen Diagnostics (see resource section).





1. The cornerstone of therapy remains aggressive management with antimycobacterial antibiotics.


2. IFN-gamma therapy may be useful for some causes of MSMD.   It should be noted that for AR complete IFN-gamma receptor deficiency, this therapy is not effective.  There appears to be some effect for AD partial IFN-gamma receptor deficiency, IL-12 receptor beta 1 deficiency, and IL-12p40 deficiency.  


3. Patients with AR complete IFN-gamma receptor deficiency and complete STAT1 deficiency are candidates for HSCT given the high risk of mortality in infancy.  In patients with AR complete IFN-gamma receptor deficiency, HLA identical sibling grafts coupled with myeloablative conditioning have yielded the best results.  A high rate of graft rejection has been observed with reduced intensity conditioning.   








Literature Resources


1.   Dorman 2004 
      Clinical features of dominant and recessive IFN-g R1 Deficiencies

2.  Camcioglu 2004 
     HHV8 Kaposi Sarcoma in a patient with IFN-g R1 Deficiency

3.  Vinh 2009 
    Refractory disseminated Coccidiomycosis in IFN-gamma R1 Deficiency


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