Chemokine and chemokine receptors in autoimmunity: the case of primary biliary cholangitis

Abstract

Chemokines represent a major mediator of innate immunity and play a key role in the selective recruitment of cells during localized inflammatory responses. Beyond critical extracellular mediators of leukocyte trafficking, chemokines and their cognate receptors are expressed by a variety of resident and infiltrating cells (monocytes, lymphocytes, NK cells, mast cells, and NKT cells). Chemokines represent ideal candidates for mechanistic studies (particularly in murine models) to better understand the pathogenesis of chronic inflammation and possibly become biomarkers of disease. Nonetheless, therapeutic approaches targeting chemokines have led to unsatisfactory results in rheumatoid arthritis, while biologics against pro-inflammatory cytokines are being used worldwide with success. In this comprehensive review we will discuss the evidence supporting the involvement of chemokines and their specific receptors in mediating the effector cell response, utilizing the autoimmune/primary biliary cholangitis setting as a paradigm.

Keywords: Innate immunity; autoimmune cholangitis; biologics; chemokine receptor; monoclonal antibody; tolerance breakdown.

Figure 1

Chemokine receptors are classified according to the chemokine family they bind, followed by an R (for receptor) and a number that corresponds to the order of its discovery. Specific chemokine ligand-receptor interaction lead to directional cellular migration, activation, and various biological responses via different intracellular signaling pathways.

Figure 2

Gene mapping of the human chemokines (CC and CXC chemokine gene clusters) and chemokine receptors on chromosomes 3, 4, 17, and X.

Figure 3

Chemokines and chemokine receptors in the pathogenesis of primary biliary cirrhosis. Interaction of chemokines infiltrating immune cells, predominantly composed of Th1 cells, Th17 cells, NK cells, CD8+ T cells and monocytes, with their cognate chemokine receptors is found around the portal tract, eventually resulting in the immune-mediated destruction of small bile ducts.