Vigorous activation of monocytes in juvenile autoimmune liver disease escapes the control of regulatory T-cells.
Interface hepatitis, the histological lesion typical of autoimmune hepatitis (AIH), is composed of CD4 and CD8 T lymphocytes and of innate immunity cells, particularly monocytes. Studies in AIH have focused on autoreactive CD4 and CD8 T cells and impairment of CD4+CD25+ regulatory T cells (T-regs), whereas little is known about the role of monocytes and their relationship with T-regs. We have investigated 51 patients with autoimmune liver disease (AILD) and 27 healthy subjects, finding that monocytes were higher in number (P = 0.044), had a more vigorous spontaneous migration (P < 0.0005 in patients with inactive disease [ID], and P < 0.001 in those with active disease [AD]), displayed a higher tumor necrosis factor alpha (TNF-alpha) over interleukin (IL)-10 production (P = 0.07 in ID and P = 0.0005 in AD), and expressed higher levels of Toll-like receptor (TLR) 4 (P = 0.048 in ID and P = 0.03 in AD). Addition of conventional T-regs (cT-regs) in AILD enhanced monocyte migration (P = 0.05 in ID and P = 0.08 in AD), magnified TNF-alpha over IL-10 production (P = 0.0005 in ID and P = 0.006 in AD), and markedly increased TLR4 expression levels (P = 0.01 in ID and P = 0.004 in AD), whereas in normal subjects it either restrained or left unchanged monocyte function. Because a CD127-negative subpopulation within CD4+CD25+ T cells exerts the strongest regulatory activity, we performed additional experiments using purified CD4+CD25+CD127- T cells (true T-regs [tT-regs]). Addition of tT-regs to monocytes decreased monocyte migration (P = 0.03) and promoted IL-10 production (P = 0.009), leaving unchanged TLR4 expression in healthy subjects, whereas in patients with AILD it induced only a marginal increase in IL-10 production (P = 0.045 in ID and P = 0.13 in AD).


CONCLUSIONS
Monocyte overactivation and inability of cT-regs and tT-regs to restrain it may contribute to the loss of immune tolerance and perpetuation of the autoimmune attack in AILD.
Institute of Liver Studies, King's College London School of Medicine at King's College Hospital, London, UK.
Maria Serena
MS
Longhi
Ragai R
RR
Mitry
Marianne
M
Samyn
Astrid
A
Scalori
Munther J
MJ
Hussain
Alberto
A
Quaglia
Giorgina
G
Mieli-Vergani
Yun
Y
Ma
Diego
D
Vergani
D000293:Adolescent; D001327:Autoimmune Diseases / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D006801:Humans; D055633:Immune System Phenomena; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D008107:Liver Diseases / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*