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

Littera, Roberto;CHESSA, LUCHINO;ONALI, SIMONA;FIGORILLI, FRANCESCO;Lai, Sara;Secci, Luca;LA NASA, GIORGIO;CAOCCI, GIOVANNI;Arras, Marcella;Melis, Maurizio;Cappellini, Sara;Balestrieri, Cinzia;Serra, Giancarlo;Conti, Maria;Zolfino, Teresa;CASALE, MICHELE;CASU, STEFANIA;Pasetto, Maria Cristina;BARCA, LUCIA;Salustro, Claudia;MATTA, LAURA;SCIOSCIA, ROSETTA;Zamboni, Fausto;FAA, GAVINO;ORRU, SANDRO;CARCASSI, CARLO

2016-01-01

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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.