The Liver as a Lymphoid Organ

Crispe, Ian Nicholas

doi:10.1146/annurev.immunol.021908.132629

Cited by 832 publications

(747 citation statements)

References 96 publications

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“…Hence, the liver assumes the function of a scavenger organ by clearance of foreign Ags from the gut without inflammation, and therefore, it probably harbors organ-specific or dominant immunoregulatory mechanisms (19,20). Moreover, liver transplants are often not rejected despite MHC discrepancies and even in the absence of immunosuppression (21).…”

Section: Discussionmentioning

confidence: 99%

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Erhardt

Wegscheid

Claass

et al. 2011

The Journal of Immunology

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The chemokine receptor CXCR3 is preferentially expressed by Th1 cells and critically involved in their recruitment to inflamed tissue. In a mouse model of immune-mediated liver injury inducible by Con A, we investigated the role of CXCR3 in acute IFN-γ–mediated hepatitis as well as in tolerance induction, which has been shown to depend on IL-10–producing CD4+CD25+Foxp3+ regulatory T cells (Tregs). Induction of Con A hepatitis resulted in increased intrahepatic expression of the CXCR3 ligands CXCL9, CXCL10, and CXCL11. CXCR3−/− mice developed a more severe liver injury with higher plasma transaminase activities and a more pronounced Th1/Th17 response compared with wild-type (wt) animals upon Con A injection. Moreover, CXCR3−/− mice did not establish tolerance upon Con A restimulation, although Tregs from CXCR3−/− mice were still suppressive in an in vitro suppression assay. Instead, Tregs failed to accumulate in livers of CXCR3−/− mice upon Con A restimulation in contrast to those from wt animals. Con A-tolerant wt mice harbored significantly increased numbers of intrahepatic CXCR3+T-bet+ Tregs that produced IL-10 compared with nontolerant animals. IFN-γ deficiency or anti–IFN-γ Ab treatment demonstrated that conversion to CXCR3+T-bet+ Tregs depended on a Th1 response. Accordingly, in an immunotherapeutic approach, CD4+CD25+Foxp3+ Tregs from Con A-pretreated CXCR3-deficient mice failed to protect against Con A-induced hepatitis, whereas Tregs from Con A-tolerant wt mice allowed CXCR3-deficient mice to recover from Con A hepatitis. In summary, CXCR3+T-bet+IL-10+ Tregs are generated in the liver in dependence of IFN-γ, then disseminated into the organism and specifically migrate into the liver, where they limit immune-mediated liver damage.

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Section: Discussionmentioning

confidence: 99%

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Erhardt

Wegscheid

Claass

et al. 2011

The Journal of Immunology

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“…Macrophages involved in inflammatory responses to bacterial and viral infection are called M1 macrophages. M1 macrophages produce high amounts of proinflammatory cytokines, such as TNF, upon recognition of invading pathogens by a set of pattern-recognition receptors including TLRs, RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs) [6][7][8]. M1 macrophages are known to produce nitric oxide (NO) by expressing inducible NO synthase (iNOS) and are critical for clearing bacterial, viral and fungal infections.…”

Section: Conflict Ofmentioning

confidence: 99%

“…For instance, the PU.1 and C/EBP transcription factors are critical for the development of macrophages. M1 macrophage polarization by TLR ligands involves the activation of a set of transcription factors, such as NF-kB, AP-1, C/EBPb, PU.1 and IFN-regulatory factors (IRFs) [6,19]. On the other hand, transcription factors such as STAT6 and peroxisome proliferator-activated receptor (PPAR)-g are involved in the polarization of M2 macrophages [14,20].…”

Section: Conflict Ofmentioning

confidence: 99%

“…For example, alveolar macrophages are normally inhibited in their proinflammatory activity by means of repressive signals provided by lung epithelial cells to limit inflammation-mediated immunopathology in response to harmless aerial antigens [5]. Similarly, Küpffer cells (liver macrophages) show a tolerant phenotype as a result of constitutive exposure to low but significant levels of microbial components from the intestinal microflora [6]. These and other macrophage types (e.g.…”

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confidence: 99%

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Transcriptional control of macrophage diversity and specialization

Ostuni

Natoli

2011

Eur J Immunol

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The key driving force underlying cell identity is represented by the complex and dynamic interplay between cell‐intrinsic, lineage‐restricted developmental pathways on the one hand, and cell‐extrinsic, tissue‐specific microenvironmental signals on the other. In this context, macrophages are a paradigmatic cell population whose functional specialization in vivo reflects the impact of the local microenvironment on the intrinsic differentiation program, leading to a variety of specialized macrophage types in different tissues and conditions; however, how this is translated into a biological outcome is not appreciably understood. The kind of investigations described in this Viewpoint aim to explore the inner determinants of cell identity and functional diversification at a genomic level; mechanisms that permit plastic cell types, like macrophages, to adapt to different environments.

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“…The particular LSEC phenotype is adapted to the high metabolic and immuno-modulatory activity of the organ [16]. LSEC have open transcytoplasmic pores (fenestrations of 100 nm diameter; [17]) clustered into sieve plates, are devoid of a basement membrane and of tight junctions and form a discontinuous sinusoid lining.…”

Section: Cell Activation During Abscess Developmentmentioning

confidence: 99%

New insights into host-pathogen interactions duringEntamoeba histolyticaliver infection

Faust¹,

Markiewicz²,

Santi-Rocca³

et al. 2011

European Journal of Microbiology and Immunology

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Amoebiasis is the third worldwide disease due to a parasite. The causative agent of this disease, the unicellular eukaryote Entamoeba histolytica, causes dysentery and liver abscesses associated with inflammation and human cell death. During liver invasion, before entering the parenchyma, E. histolytica trophozoites are in contact with liver sinusoidal endothelial cells (LSEC). We present data characterizing human LSEC responses to interaction with E. histolytica and identifying amoebic factors involved in the process of cell death in this cell culture model potentially relevant for early steps of hepatic amoebiasis. E. histolytica interferes with host cell adhesion signalling and leads to diminished adhesion and target cell death. Contact with parasites induces disruption of actin stress fibers and focal adhesion complexes. We conclude that interference with LSEC signalling may result from amoeba-triggered changes in the mechanical forces in the vicinity of cells in contact with parasites, sensed and transmitted by focal adhesion complexes. The study highlights for the first time the potential role in the onset of hepatic amoebiasis of the loss of liver endothelium integrity by disturbance of focal adhesion function and adhesion signalling. Among the amoebic factors required for changed LSEC adherence properties we identified the Gal/GalNAC lectin, cysteine proteases and KERP1.

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The Liver as a Lymphoid Organ

Cited by 832 publications

References 96 publications

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

CXCR3 Deficiency Exacerbates Liver Disease and Abrogates Tolerance in a Mouse Model of Immune-Mediated Hepatitis

Transcriptional control of macrophage diversity and specialization

New insights into host-pathogen interactions duringEntamoeba histolyticaliver infection

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