HLA alleles predisposing to autoimmunity are linked to impaired immunoregulation in patients with juvenile autoimmune liver disease and in their first-degree relatives

• Published in: Journal of autoimmunity Vol. 154; p. 103436
• Main Authors: Wang, Pengyun, Yuksel, Muhammed, Gabeta, Stella, Graham, Jonathon, Hussain, Munther, Blackmore, Laura Jayne, Huang, Xiaohong, Hadzic, Dino, Samyn, Marianne, Grammatikopoulos, Tassos, Heneghan, Michael, Liberal, Rodrigo, Longhi, Maria Serena, Mieli-Vergani, Giorgina, Vergani, Diego, Ma, Yun
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.06.2025
• Subjects: Adolescent; Adult; Alleles; Autoimmunity; Autoimmunity - genetics; Child; Child, Preschool; Cholangitis, Sclerosing - genetics; Cholangitis, Sclerosing - immunology; Cytokines - metabolism; Family; Female; Genetic Predisposition to Disease; Genotype; Hepatitis; Hepatitis, Autoimmune - genetics; Hepatitis, Autoimmune - immunology; HLA Antigens - genetics; Human study; Humans; Immunogenetics; Immunophenotyping; Male; Programmed Cell Death 1 Receptor - metabolism; Regulatory T cells; Sclerosing cholangitis; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Autoimmunity; AIH; PSC; AST; SMA; Treg; ALT; Regulatory T cells; Hepatitis; ASC; CYP2D6/FTCD; Immunogenetics; ANA; Teff; CTLA-4; Sclerosing cholangitis; Human study; PD-1; AILD
• ISSN: 0896-8411; 1095-9157; 1095-9157
• DOI: 10.1016/j.jaut.2025.103436

Juvenile autoimmune liver disease (JAILD) comprises autoimmune hepatitis and autoimmune sclerosing cholangitis. JAILD-predisposing genes include HLA-DR3,DR7, DR13 and haplotype A1-B8-DR3. Mechanisms leading to liver autoimmunity remain elusive, though JAILD patients have aberrated immunoregulation. We investigated the influence of HLA genes on immune cells, focusing on T-cells and frequency and function of T regulatory cells (Tregs) in JAILD patients, their first-degree-relatives (FDRs) and healthy controls (HCs). HLA class I and II genotypes were defined by PCR and peripheral blood mononuclear cells were immunophenotyped by FACS in 82 patients, 72 FDRs, 50 HCs. Treg function was tested by inhibition of CD4posCD25neg T-cell proliferation. Links between HLA genes, Treg frequency/function, pro-inflammatory/immunoregulatory cytokines, soluble and membrane-bound programmed cell death-1 (PD-1) were investigated. Proportion of subjects carrying HLA DR3/DR7/DR13 was 88 %, 92 %, 64 % in patients, FDRs and HCs. Circulating Treg frequency was lower in patients and FDRs than HCs. Inhibitory capacity of Tregs was lower in patients but similar in FDRs compared to HCs. FDRs possessing HLA DR3/DR7/DR13 genes had Treg frequencies lower than those without. PD-1 posCD4pos T-cells were fewer in patients than HCs; PD-1posCD8pos T-cells were fewer in patients and FDRs than HCs. Patient plasma levels of IFN-γ were higher, and ratios of IFN-γ/IL-10 and IFN-γ/IL-2 lower than in HCs. All nine FDRs with autoimmune disorders had HLA DR3/DR7/DR13 genes and lower Treg frequency than those without autoimmune disorders and HCs. We show a link between HLA disease-predisposing genes and defective immunoregulation not only in JAILD patients, but also in their FDRs, who are prone to autoimmune disorders. •Regulatory T cell abundance depends on human leukocyte antigen alleles.•Also first degree relatives of index patients have similarly immune dysregulation.•Ratio of plasma IFN-γ and IL-10 is aberrated in patients/relatives compared to controls.•Level of soluble PD-1 in plasma depends on cytokine level and not on genetic make-up.•Type of autoimmune liver disease does not affect immune phenotype.