Hepatitis: Role Of KIR 2DS4-HLA Interaction

A. PODHORZER; N. PALADINO; M. CUARTEROLO; H. FAINBOIM; S. PAZ; G. THEILER; M. CAPUCCHIO; S. LÓPEZ; A. MACHICOTE; L. FAINBOIM

Conferencia; EASL Monothematic Conference: "Autoimmune Hepatitis?; 2015

Introduction: We previously reported a strong association between HLA-DRB1*1301 andtype 1 paediatric autoimmune hepatitis (PAH); and HLA-DR*0405 with Adult autoimmunehepatitis (AAH). We postulated that PAH and AAH may represent two different clinicalentities. More recently autoimmune diseases susceptibility have been also associated toHuman killer cell immunoglobulin-like receptors (KIRs)Aims: We want to establish the combined role of HLA and KIR genes in autoimmunehepatitis. In addition, we want to analyse the differentiation stage of T cell subsets todetermine if the mechanisms involved in the development of PAH and AAH are differentiallydictated by innate or adaptive immunityMaterial and Methods: A total of 144 PAH patients and 86 AAH patients were comparedwith 273 controls. KIR and HLA-A, B, and C typing was performed by polymerase chainreaction-sequence-specific oligonucleotide probing. By flow cytometry T cell differentiationstages were compared in PAH and AAH patients with paediatric and adult controlsResults: In PAH, the genomic analysis revealed a decreased frequency of KIR2DL2 and anincreased frequency of the full length KIR2DS4 (KIR2DS4-FL). In PAH-KIR2DS4FL+subjects we detected an increased frequency of their putative HLA-C*02, 04 and 06 ligands.In addition, PAH-KIR2DL2+ patients showed a decreased frequency of the HLA-C1 ligand.Furthermore, C2/C2 frequency within KIR2DS4FL+ homozygous/ KIR2DL2+ individualswas also increased, thus a high frequency of these individuals had no inhibition throughKIR2DL2. The combined analysis of KIR2DS4-FL and HLA-DRB1*1301 demonstrateda strong synergistic effect (OR: 36.5). In AAH, we detected a weaker increased frequencyof KIR2DS4-FL, HLA association with HLA-DRB1*0405, and lack of any synergisticeffect. In contrast with PAH, AAH patients showed an expansion of the more differentiatedeffector T cellsConclusions: KIR2DS4-FL acting synergistically with HLA-DRB1*1301 and a diminishedinhibitory effect through KIR2DL2 appears to be involved in PAH development. In contrastAAH showed a less predominant role of KIR2DS4-FL, a lack of any synergistic effect withHLA-class II antigens, but an increased population of highly differentiated effector T cells,which in contrast with PAH seems to endow the adaptive immunity with a predominant rolein AAH pathogenesis