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

被引：0

作者：

Wang, Pengyun ^{[1
]}

Yuksel, Muhammed ^{[1
,2
]}

Gabeta, Stella ^{[1
,3
,4
]}

Graham, Jonathon ^{[1
]}

Hussain, Munther ^{[1
]}

Blackmore, Laura Jayne ^{[1
,6
]}

Huang, Xiaohong ^{[1
]}

Hadzic, Dino ^{[7
]}

Samyn, Marianne ^{[7
]}

Grammatikopoulos, Tassos ^{[7
]}

Heneghan, Michael ^{[1
]}

Liberal, Rodrigo ^{[1
,8
]}

Longhi, Maria Serena ^{[1
,5
]}

Mieli-Vergani, Giorgina ^{[1
,7
]}

Vergani, Diego ^{[1
]}

Ma, Yun ^{[1
]}

机构：

[1] Kings Coll London, Inst Liver Studies, Fac Liver Sci & Med, Sch Immunol & Microbial Sci,Dept Inflammat Biol, London, England

[2] Univ Westminster, Coll Liberal Arts & Sci, Sch Life Sci, London, England

[3] Univ Thessaly, Dept Med, Larisa, Greece

[4] Univ Thessaly, Sch Med, Res Lab Internal Med, Larisa, Greece

[5] Harvard Med Sch, Beth Israel Deaconess Med Ctr, Dept Anesthesia, 330 Brookline Ave, Boston, MA 02215 USA

[6] Kings Coll Hosp Fdn Trust, Univ Hosp Lewisham, London SE13 6LH, England

[7] Kings Coll Hosp London, GI & Nutr Ctr, Paediat Liver, Denmark Hill, London, England

[8] Univ Porto, Ctr Hosp Sao Joao, Gastroenterol Dept, Fac Med, Porto, Portugal

来源：

JOURNAL OF AUTOIMMUNITY | 2025年 / 154卷

基金：

美国国家卫生研究院; 英国医学研究理事会; 英国惠康基金;

关键词：

Immunogenetics; Autoimmunity; Hepatitis; Sclerosing cholangitis; Regulatory T cells; Human study; REGULATORY T-CELLS; SCLEROSING CHOLANGITIS; MOUSE MODEL; HEPATITIS; DIAGNOSIS; ASSOCIATION; PREVALENCE; MANAGEMENT; MICROBIOTA; CHILDREN;

D O I：

10.1016/j.jaut.2025.103436

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Background & aims: 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). Methods: 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. Results: 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-gamma were higher, and ratios of IFN-gamma/IL-10 and IFN-gamma/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. Conclusion: 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.

引用

页数：12

共 47 条

[1] Soluble programmed death-1 levels are associated with disease activity and treatment response in patients with autoimmune hepatitis [J].