What is the correlation between unfavorable (non-CC) IL28B (interleukin 28B) alleles and depressed Natural Killer (NK) cell and innate immune function?

Correlation Between Unfavorable IL28B Alleles and NK Cell/Innate Immune Function

Non-CC IL28B genotypes (CT/TT) are strongly associated with depressed Natural Killer (NK) cell function, particularly through increased expression of inhibitory receptors that impair antiviral immune responses.

Relationship Between IL28B Genotypes and NK Cell Function

The IL28B gene (interleukin 28B) encodes interferon-lambda-3, which plays a crucial role in antiviral immune responses. The correlation between IL28B polymorphisms and NK cell function has been established through several key findings:

Inhibitory Receptor Expression

• Patients with unfavorable IL28B genotypes (CT/TT) demonstrate significantly higher expression of inhibitory NK cell receptors, including:

  • NKG2A
  • CD158b
  • CD158e 1

• These elevated inhibitory receptor levels directly correlate with:

  1. Poor viral decline during early treatment
  2. Higher rates of treatment failure
  3. Reduced sustained virological response (SVR) rates

Functional Impairment

• NKG2A-positive NK cells (associated with unfavorable IL28B genotypes) produce significantly lower levels of:

  • IFN-γ-inducible protein-10 (IP-10)
  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) 1

• This functional impairment reduces the NK cells' ability to clear HCV-infected hepatocytes

IFN-γ Production

• SVR patients show significantly higher IFN-γ production from NK cells compared to non-responders
• This difference in NK cell function appears to be independent of IL28B genotype, suggesting multiple pathways of immune dysfunction 2

Clinical Implications

The relationship between IL28B genotypes and NK cell function has significant clinical implications:

1. Treatment Response Prediction: A mathematical regression model incorporating NK cell inhibitory receptor expression (particularly NKG2A, CD158b, and CD158e) has shown high predictive value (AUC=0.88) for treatment response 1

2. Complementary to IL28B Testing: NK cell phenotyping provides additional predictive information beyond IL28B genotyping alone 1

3. Therapeutic Targeting: The identification of specific NK cell defects in patients with unfavorable IL28B genotypes may lead to targeted immunotherapeutic approaches

Mechanistic Understanding

The underlying mechanism connecting IL28B polymorphisms to NK cell dysfunction appears to involve:

• Altered cytokine production affecting NK cell development and maturation
• Dysregulation of inhibitory receptor expression
• Impaired NK cell activation in response to interferon stimulation
• Reduced capacity to produce antiviral cytokines and effector molecules

Pitfalls and Caveats

• The relationship between IL28B and NK cell function has primarily been studied in the context of HCV infection and treatment response
• Most studies have focused on pegylated interferon-based treatments rather than newer direct-acting antivirals
• The exact molecular pathway connecting IL28B polymorphisms to NK cell receptor expression remains incompletely understood
• Ethnic differences in IL28B allele distribution may affect the generalizability of findings across populations

In summary, unfavorable IL28B genotypes (CT/TT) are strongly associated with increased expression of inhibitory NK cell receptors, resulting in impaired NK cell function and reduced antiviral immune responses. This relationship provides a mechanistic explanation for the well-established association between IL28B polymorphisms and treatment outcomes in HCV infection.