IL28B gene
single nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 predict
treatment response in chronic hepatitis C (CH-C). Strong immune responses
control HCV infection. Little is known on the association between IL28B SNPs,
innate/adaptive immune responses in relation to Peg-IFN/ribavirin sustained
virologic response (SVR) in CH-C.
Aim: To
evaluate the relationship between rs12979860 and rs8099917, pre-treatment
frequency/phenotype of natural killer (NK) cells (innate immunity),
HCV-specific immune responses (adaptive immunity), and SVR.
Patients: 35 CH-C genotype
1 patients (23 males, median age 37y) treated with Peg-IFN/ribavirin were
divided in 2 groups: 18 responders (SVR), 17 non-SVR (9 non-responders and 8
relapsers).
Methods:
rs12979860 and rs8099917 were tested by direct sequencing. Baseline numbers of
NK-cells (CD3-CD56+), their subsets CD56dim/CD56bright,
CD3-CD56+/-CD16+/-, and expression
of NK-cells activation/inhibition (NKG2D/NKG2A) markers were investigated by
flowcytometry on peripheral blood mononuclear cells (PBMC). PBMC IFN-γ/IL-10
production after exposure to HCV antigens was evaluated by intracellular
cytokine staining. Results are presented as medians.
Results: rs12979860 genotype CC was more
frequent in SVR than non-SVR (85% vs.15%), while non-CC genotypes (CT/TT) were
present in 32% SVR vs.68% non-SVR; rs 8099917 genotype TT was present in
75% vs.25% non-SVR and non-TT genotypes (GT/GG) were more frequent in non-SVR
then SVR (80% vs.20%, all p< 0.05). Baseline number of NK-cells was similar in
all groups, but that of CD56bright cells was higher in SVR than
non-SVR (6.4%vs.2.9%,p=0.03). CD3-CD56-CD16+
cells were more frequent in non-SVR than SVR (11.4%vs.8.6%,p=0.05). The
proportion of CD56dim+/NKG2D+ cells was higher in SVR
than non-SVR (47.1%vs.36.3%,p=0.04). While number of HCV-specific IFN-γ
producing cells was similar in all groups, IL-10 producing cells were higher in
non-SVR than SVR for HCV core (CD4+/IL-10: 4.3%vs.1.8%,p=0.05).
Comparing patients according to rs12979860 CC vs. no CC genotypes, CC genotype
patients had more CD56bright cells (6.6%vs.3.1%,p=0.04), fewer CD3-CD56-CD16+
NK-cells (8.7%vs.11.1%,p=0.05) and HCV-core specific CD4+/IL-10+
cells (1.9%vs.4.2%,p=0.05). There were no associations between rs8099917
genotypes TT vs. no TT and immune responses.
Conclusions: High numbers
of CD56bright NK-cells, low numbers of unconventional CD3-CD56-CD16+
NK-cells, and low HCV-specific IL-10 production at baseline are associated with
IL28B gene SNP rs12979860 CC genotype and successful antiviral treatment of
CH-C genotype 1.
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