The Role of Chemokines in the Recruitment of Lymphocytes to the Liver

Abstract

Chemokines direct leukocyte trafficking and positioning within tissues, thus playing critical roles in regulating immune responses and inflammation. The chemokine system is complex, involving interactions between multiple chemokines and their receptors that operate in combinatorial cascades with adhesion molecules. The involvement of multiple chemokines and chemokine receptors in these processes brings flexibility and specificity to recruitment. The hepatic vascular bed is a unique low-flow environment through which leukocytes are recruited to the liver during homeostatic immune surveillance and in response to infection or injury. The rate of leukocyte recruitment and the nature of cells recruited through the sinusoids in response to inflammatory signals will shape the severity of disease. At one end of the spectrum, fulminant liver failure results from a rapid recruitment of leukocytes that leads to hepatocyte destruction and liver failure; at the other end, diseases such as chronic hepatitis C infection may progress over many years from hepatitis to fibrosis and cirrhosis. Chronic hepatitis is characterized by a T lymphocyte-rich infiltrate and the nature and outcome of hepatitis will depend on the T cell subsets recruited, their activation and function within the liver. Different subsets of effector T cells have been described based on their secretion of cytokines and specific functions. These include Th1 and Th2 cells, and more recently Th17 and Th9 cells, which are associated with different types of immune response and which express distinct patterns of chemokine receptors that promote their recruitment under particular conditions. The effector function of these cells is balanced by the recruitment of regulatory T cells that are able to suppress antigen-specific effectors to allow resolution of immune responses and restoration of immune homeostasis. Understanding the signals that are responsible for recruiting different lymphocyte subsets to the liver will elucidate disease pathogenesis and open up new therapeutic approaches to modulate recruitment in favor of resolution rather than injury.

Cxcr3 Chemokine Receptor Expression on Peripheral Blood B-Cell Subsets in Patients With Chronic Hepatitis C

“…Во время хронической вирусной инфекции постоянная антигенная стимуляция В-клеток может привести к их истощению, что проявляется в дефекте функций клеток и повы-шенной экспрессии ингибиторных и хемокино-вых рецепторов, включая CXCR3 [2,6,15]. Этот ре-цептор необходим для миграции активированных лейкоцитов в очаг воспаления, что способствует развитию иммунной реакции, как считается, пре-имущественно опосредованной цитотоксически-ми лимфоцитами [17]. Однако в печени больных ХВГС обнаруживается повышенное содержа-ние В-лимфоцитов, несущих CXCR3 [13].…”

Experimental evidence on the immunopathogenesis of primary biliary cirrhosis

“…We are convinced that these should not be regarded as mutually exclusive from any causative factor, such as susceptible genes, but rather as terminal mechanisms of the pathway leading to the clinical manifestations, possibly mediated by a specific cytokine pattern. 99 One major hypothesis for the selective destruction of biliary epithelial cells implies that the immunodominant autoantigen PDC-E2 should be aberrantly exposed on the cholangiocyte cell surface, where it may be recognized by AMA and/or antigen-specific T cells. Studies based on in situ hybridization of PDC-E2 mRNA failed to demonstrate significant differences in its amount in PBC liver compared with other liver diseases.…”

Gene Expression Profiles of T Cells from Hepatitis E Virus Infected Patients in Acute and Resolving Phase

“…Being HEV self resolving, the phenotypic expression of memory makers on the recruited effector T cells were not studied. This process is mainly guided by the expression of specific chemokine receptors (18). Thus, it would be important to address the activation status and expression of chemokine receptors of T cells from patients at different phases of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 …”