Functional and genetic assessment of IFN-gamma receptor in patients with clinical tuberculosis.
OBJECTIVE
The molecular basis of the genetic vulnerability underlying the most common form of clinical tuberculosis (TB) remains largely unknown. We speculated that mild genetic defects in the interferon-gamma (IFN-gamma) signalling pathway caused a subtle functional impairment of IFN-gamma which would explain susceptibility to Mycobacterium tuberculosis in clinical TB.


METHODS
A case-control study.


RESULTS
We evaluated functional responsiveness to IFN-gamma in monocytes from patients with clinical TB (n = 10), and analysed the genetic sequences of the IFN-gamma receptor 1 (IFN-gammaR1) and STAT1 genes in patients with disseminated TB (n = 18). IFN-gamma stimulated an increase in the expression of HLA-DR and CD64 on monocytes of both controls and patients; the rate of increase in expression was the same in both groups. Treatment with IFN-gamma before lipopolysaccharide (LPS) stimulation further increased tumour necrosis factor-alpha (TNF-alpha) production as compared to TNF-alpha production with LPS stimulation alone; the rate of increase in TNF-alpha production was the same in both groups. The known mutations in the coding sequences of the IFN-gammaR1 and STAT1 genes were not found in the patients with disseminated tuberculosis.


CONCLUSIONS
These results suggest that impairment of the IFN-gamma signalling pathway did not account for cases of clinical TB in this study.
Park
G Y
GY
Department of Internal Medicine, Gachon Medical School, Gil Medical Centre, Incheon, South Korea. parkgy@gachon.md
Im
Y H
YH
Ahn
C H
CH
Park
J W
JW
Jeong
S W
SW
Ahn
J Y
JY
Hwang
Y J
YJ
D000328:Adult; D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics; D004198:Disease Susceptibility; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000276:immunology; D017452:Receptors, IgG / Q000032:analysis; D017471:Receptors, Interferon / Q000235:genetics*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics; D014376:Tuberculosis / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000096743:Interferon gamma Receptor
D004268:DNA-Binding Proteins; D006684:HLA-DR Antigens; D008070:Lipopolysaccharides; D017452:Receptors, IgG; D017471:Receptors, Interferon; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D000096743:Interferon gamma Receptor; C494079:STAT1 protein, human