Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis

PLoS One. 2016 Jan 8;11(1):e0146086. doi: 10.1371/journal.pone.0146086. eCollection 2016.

Abstract

Background: Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses.

Methods and findings: KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups.

Conclusions: The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Age of Onset
  • Aged
  • Biomarkers / blood
  • Case-Control Studies
  • Female
  • Gene Expression / immunology*
  • HLA-B Antigens / genetics
  • HLA-B Antigens / immunology
  • HLA-B18 Antigen / genetics
  • HLA-B18 Antigen / immunology
  • HLA-C Antigens / genetics
  • HLA-C Antigens / immunology
  • HLA-DR3 Antigen / genetics
  • HLA-DR3 Antigen / immunology
  • Haplotypes
  • Hepatitis, Autoimmune / diagnosis*
  • Hepatitis, Autoimmune / genetics
  • Hepatitis, Autoimmune / immunology*
  • Hepatitis, Autoimmune / pathology
  • Humans
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / pathology
  • Liver / immunology*
  • Liver / pathology
  • Male
  • Middle Aged
  • Outpatients
  • Receptors, KIR / genetics
  • Receptors, KIR / immunology*
  • Receptors, KIR2DL3 / genetics
  • Receptors, KIR2DL3 / immunology
  • Receptors, KIR3DL1 / genetics
  • Receptors, KIR3DL1 / immunology

Substances

  • Biomarkers
  • HLA-B Antigens
  • HLA-B18 Antigen
  • HLA-Bw4 antigen
  • HLA-C Antigens
  • HLA-C*05 antigen
  • HLA-DR3 Antigen
  • KIR2DL3 protein, human
  • KIR2DS1 protein, human
  • KIR3DL1 protein, human
  • Receptors, KIR
  • Receptors, KIR2DL3
  • Receptors, KIR3DL1

Grants and funding

The research performed in this report falls within the institutional responsibilities of the investigators of the participating centers, all of which pertain to the Italian National Public Health Service. Grant funding (2014-1861) for part of the reagents was received from the “Fondazione Banco di Sardegna”. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.