Review article: chemokines as orchestrators of autoimmune hepatitis and potential therapeutic targets

Abstract

Summary Background Chemokines contribute to the pathogenesis of autoimmune hepatitis by directing the migration and positioning of inflammatory and immune cells within the liver. Aim Describe the liver‐infiltrating effector cell populations in autoimmune hepatitis, indicate the chemokines that influence their migration, describe the role of chemokines in hepatic fibrosis and identify chemokine‐directed treatment opportunities. Methods Studies cited in Pub Med from 1972 to 2014 for autoimmune hepatitis, chemokines in liver disease, pathogenesis of autoimmune hepatitis and chemokine therapy were selected. Results T helper type 17 lymphocytes expressing CXCR3 and CCR6 are attracted to the liver by the secretion of CXCL9, CXCL10 and CXCL11. These cells recruit pro‐inflammatory T helper type 1 lymphocytes expressing CXCR3 and CCR5 by secreting CXCL10. Resident natural killer T cells expressing CXCR6 migrate in response to the local secretion of CXCL16, and they modulate the inflammatory response. T helper type 2 lymphocytes expressing CCR4 are attracted by CCL17 and CCL22, and they dampen the expansion of pro‐inflammatory cells. Regulatory T cells expressing CXCR3 are attracted by the secretion of CXCL9, and they help dampen the pro‐inflammatory responses. CCL2, CCL3, CCL5, CXCL4, CXCL10 and CXCL16 promote fibrosis by activating or attracting hepatic stellate cells, and CX3CL1 may prevent fibrosis by affecting the apoptosis of monocytes. Conclusions Chemokines are requisites for mobilising, directing and positioning the effector cells in immune‐mediated liver disease. They are feasible therapeutic targets in autoimmune hepatitis, and the evaluation of monoclonal antibodies that neutralise the pro‐inflammatory ligands or designer peptides that block receptor activity are investigational opportunities.

Galectin-3 in autoimmunity and autoimmune diseases

“…120 Gal-3 is an interesting molecule due to its ability to induce hepatocyte apoptosis 121 and liver fibrosis, 122 both orchestrating the activation and differentiation of hepatic stellate cells (HSCs) into myofibroblasts. 123 Concanavalin-A (Con A)-induced hepatitis is an experimental model that mimics pathological changes observed in AiH patients. 124 The induction of hepatitis by Con A in gal-3 À/À mice resulted in a weak liver injury, marked by low levels of pro-inflammatory cytokines secreted by hypoactive lymphocytes and DCs and a high number of annexin V þ propidium-idodide þ later apoptotic cells.…”

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

“…Characterization of the mimicking epitopes may unmask exogenous triggers and improve risk management strategies. Molecular mimicry more effective than molecular identity to overcome tolerance [183] Epitope mapping of principal autoantigen can identify homologies with possible exogenous triggers [118] Epitope spread Reactivity against dominant epitope early [182] Reactivity spreads to neighboring and remote epitopes later [182] May sustain or extend the autoreactive response [182,184] May exacerbate indolent disease [184] Clarification of chemokine milieu CXCL9, CXCL10, and eotaxin-3 increased in serum [215,221,222,228] CXCL11, CCL11, CCL20, CXCL12, CXCL1 implicated in other immune liver diseases [215] May indicate severity and activity [222] Patterns may support diagnosis [228] May implicate key effector cells [228] Possible therapeutic targets [215] Identification of key cell mediators…”

“…The migration of inflammatory and immune cells to sites of tissue injury is orchestrated by chemokines [214][215][216]. These small proteins are produced by stressed cells within the liver and by cells comprising the innate and adaptive immune responses.…”

“…These small proteins are produced by stressed cells within the liver and by cells comprising the innate and adaptive immune responses. They function as ligands that attract cells expressing complementary ligand receptors [217], and they initiate a reparative response that involves lymphocytes, natural killer (NK) cells, dendritic cells, natural killer T (NKT) cells, and hepatic stellate cells [215]. The attracted immune and inflammatory cells contribute to a positive feedback loop in which more ligands are produced and more effector cells are recruited [218].…”

“…The attracted immune and inflammatory cells contribute to a positive feedback loop in which more ligands are produced and more effector cells are recruited [218]. Chemokines lack disease specificity and organ specificity, but they have emerged as key regulators of the inflammatory and immune responses to liver injury [214][215][216]. The number of cysteine (C) residues that are conserved at the amino terminus of the molecule and the number of variable amino acids (X) that separate the conserved motifs determine one of the four designations that are applied to the chemokines (C, CC, CXC, and CX3C) [215,219,220].…”