https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(07)61864-9.pdf

A wearable haemodialysis device for patients with end-stage renal failure: a pilot study

IFNγR signaling mediates alloreactive T-cell trafficking and GVHD.

Cytokine gene polymorphisms and cytokine levels in pulmonary tuberculosis

Type I and II interferons (IFNs αβ and γ) have opposing effects on immune resistance to certain pathogenic bacteria. While IFNγ generally plays a protective role, IFNαβ exacerbates Listeria monocytogenes and Mycobacterium tuberculosis infections. Our findings provided evidence that this increased susceptibility reflects a novel antagonistic cross talk between IFNαβ and IFNγ. Macrophages infected with L. monocytogenes strains that induce IFNαβ production responded poorly to IFNγ, as measured by reduced phosphorylation of STAT1 and reduced IFNγ-dependent gene expression. The impaired responsiveness to IFNγ correlated with reduced expression of its receptor, IFNGR, by both infected and bystander macrophages. Down regulation of IFNGR was dependent on responsiveness to IFNγ and mimicked by recombinant IFNβ. Mice lacking responsiveness to IFNαβ (IFNAR1 (-/-)) retained high IFNGR expression, developed higher expression of MHC-II on macrophages and DCs, and were more resistant to systemic L. monocytogenes infection--but only in the presence of IFNγ. Thus, the ability of IFNαβ to down regulate IFNGR provides an explanation for its ability to reduce responsiveness to IFNγ and to increase host susceptibility to bacterial infection. It remains to be determined whether and how such antagonistic interferon crosstalk benefits the host.

Antagonistic crosstalk between type I and II interferons and increased host susceptibility to bacterial infections.

Genetic susceptibility to tuberculosis includes several unknown yet different loci each contributing to a small extent. Intronic polymorphisms within the interferon- g (IFN-g) gene IFNG Tþ 874A and IFNG Gþ 2109A correlate with the IFN-g production in vitro, and the frequency of potential high IFN-g producers was previously reported by others to be lower in patients than in controls from Sicily. The aim of this study was to determine whether there is an association between polymorphisms in the IFN-g gene and predisposition to tuberculosis. We analysed two IFNG SNPs (Tþ 874A and Gþ 2109A) in patients (n¼ 253) hospitalized in Rijeka (Croatia) and controls (n¼ 519) from the same area. One fifth of the controls were healthy contacts of the diseased, and the rest were blood donors. IFNG alleles, their predicted haplotypes or genotypes were not associated with disease susceptibility. Thus, we could not reproduce results from Sicilian case-control study. However, T/Tþ 874 (possible high IFN-g producer) and þ 874A/A (putative low producer) genotypes were associated with microscopically positive– negative forms of disease. Haplotypes (Tþ 874A and Gþ 2109A) based on a prediction by software PHASE and subsequent genotype analysis corroborated these findings. Patients had significantly higher frequency of genotypes without T at þ 874 (AA/AA ; AA/AG and AG/AG) in microscopy or bacterial culture-positive groups compared with their negative counterparts.These data suggest an association with disease severity rather than susceptibility to tuberculosis in Croatian Caucasian population.

Interferon-γ Gene (T874A and G2109A) Polymorphisms Are Associated With Microscopy-positive Tuberculosis

We analysed frequencies of two single-nucleotide polymorphisms (SNP) in the interferon-γ (IFN-γ) receptor-1 (IFNGR1) gene promoter (G-611A, T-56C) in tuberculosis patients (n = 244) and compared them with controls (n = 521). These frequencies were not significantly different, whether analysed independently or as haplotypes. Because these SNP affect transcription, the results suggest that the expression of the IFNGR1 gene does not confer susceptibility to disease in patients from Croatia. Further analysis revealed a significant association between the protective (CA)n polymorphism (22 repeats, 192 FA1), located in the fifth intron of the IFNGR1 gene (+16682), and GT promoter haplotype (−611; −56) that showed the strongest expression capacity. In addition to this cis relationship, the (CA)22 allele was correlated in trans with an IFN-γ SNP (IFNG G + 2109A), which might affect the transcription of the IFNG gene. These results suggest that a particular combination of IFNG and IFNGR1 SNP might offer a better protection against tuberculosis in this population.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-3083.2005.01694.x

Zlata Beg-Zec

Papers

Interferon‐γ Receptor‐1 Gene Promoter Polymorphisms (G‐611A; T‐56C) and Susceptibility to Tuberculosis