Table 2 All papers, which have so far been published concerning BA and immunology in both, human and experimental BA

T-regs

[123]

Circulating and local T-regs in lymph nodes of the porta hepatis are reduced in CMV positive patients with BA, compared to age matched controls with other cholestatic liver diseases

CD4 + −T-Cells

Osteopontin

[43]

[124]

Osteopontin mRNA expression was shown in liver biopsies of BA patients and also in experimental BA

Cholangiocytes

TLRs

[125]

TLRs 2 and 8 mRNA expression was higher in early states of BA-patients and significantly elevated to age matched controls

CD4 + −T-Cells

Th₂/IL-13

[106]

[106]

STAT1–/–mice infected with RRV exhibit a Th₂ dominated inflammation, evidence can be found in humans, too, also mediating experimental biliary atresia if not accompanied by IL-13 blockade

CD4 + −T-Cells

[41]

DNA-Hypomethylation throughout the genome of CD4 + −T-Cells is negatively correlated with IFN-ɣ mRNA-levels compared to healthy controls

Dendritic Cells

[86]

[86]

RRV-primed DC, also present in human livers, boost lymphocyte expansion and mediate epithelial injury whereas depletion of DC or blocking IL-15 reduced NK-Cell activation

Macrophages

Mip2/Cxcl2

[100]

RRV-infected Macrophages influence neutrophil chemotaxis

iNOS

[44]

Liver samples show a strong correlation between NF-κB -activation and iNOS hyperexpression

T-regs

[114, 126]

Activated T-regs reduce inflammatory cytokine production and suppress NK-cell activation in vitro and in vivo

Cholangiocytes

[101]

Release of CXC–and CC-Chemokines by cholangiocytes markedly increase upon onset of disease

Cholangiocytes

[97]

In the setting of RRV-infection and Th₁ inflammation cholangiocytes produce inflammatory cytokines and chemokines but do not function as APC despite expressing all necessary surface markers

NK-Cells

[127]

[115]

NK-Cells populate the liver of mice, and humans, and their depletion or blocking Nkg2d prevents cholangiocyte lysis in vitro and in vivo

IFN-ɣ /TNF-α

[109]

Inhibition of caspases reduces apoptosis induced by synergism of IFN-ɣ and TNF- α

CD8 + −T-Cells

[49]

Primarily CD8 + −T-Cells of the lymphocyte infiltrate suffer from maternal micochimerism

NF-κB gene products

[55]

Intrahepatic Biliary Epithelium reacts with NF-κB activation if treated with a viral-dsRNA-analogon

TNF-α

[103]

Although highly elevated in experimental biliary atresia blocking TNF- α exerts no effect

T-Cells

[45]

CD4+ and CD8 + −T-Cells show oligoclonal expansion of TCR Vβ with Vβ20 dominating in the latter

NF-κB gene products

[117]

Biliary Epithelium reacts similar to a viral infection if treated with a viral-dsRNA-analogon

CD8 + −T-Cells

[110]

Depletion of RRV-primed CD8 + −T-Cells reduces disease incidence and mediate the epithelial injury

IL-12

[105]

Loss of IL-12 in mice does not prevent experimental biliary atresia but shifts the Th₁-phenotype of inflammation towards neutrophils

CD4 + −T-Cells

IFN-ɣ

[116]

Although not being able to elicit experimental biliary atresia in SCID mice RRV-primed CD4 + −T-Cells are the source of IFN-ɣ

IFN-ɣ

[107]

IFN-ɣ-RII is without influence on development of experimental biliary atresia

CD8 + −T-Cells

[46]

Elevated numbers of CD8 + −T-Cells populate the portal tract in biliary atresia

T-Cells

[47]

T-Cells within the livers of diseased express more CXCR3 than controls

IFN-ɣ

[128]

RRV-challenge of mice upregulates Interferoninducers followed by the IFN-ɣ network genes with onset of disease in the biliary transcriptome

CD4 + −T-Cells Macrophages

Th₁ TNF-α

[113]

With RRV present one week p.i. the portal tract infiltrate is predominated by CD4 + −T-Cells producing IFN-ɣ and Macrophages producing TNF-α, whereas both effectors produce TNF-α after virus clearance

Macrophages

[129]

Increased infiltration of Macrophages in the liver after Kasai is associated with a favourable outcome

IFN-ɣ

[99]

IFN-ɣ depletion prevents bile duct obstruction while administering IFN-ɣ to IFN-ɣ–/–induces experimental biliary atresia after RRV-injection

CD4 + −T-Cells

Th₁

[33]

The portal tract inflammatory response is dominated by CD4 + −T-Cells with a Th1-cytokine response and an increased number of Kupffer cells

CD4 + −T-Cells

[130]

The reduced number of naïve-CD4 + −T-Cells in patients persists after transplantation

Costimulatory factors

[35]

Costimulatory factors of APC are highy expressed on bile duct epithelium

Lymphocytes

[36]

Leukocyte infiltration of livers often do not include immunocompetent lymphocytes

Th₁

[43]

Within the transcriptome of pooled mRNA genes pointing towards a Th₁-profile are often upregulated

Lymphocytes

[40]

Activated and proliferating lymphocytes populate the liver

CD8 + −T-Cells

[48]

CD8+ T-Cell infiltrate of the proliferating bile ducts after Kasai operation lack the phenotype of activated cytoxic lymphocytes

CD4 + −T-Cells

[42]

A decreased number of naïve-CD4 + −T-Cells is accompanied by reduced receptor density

Mast cells

[37]

The number of intrahepatic mast cells negatively correlates with liver function

Macrophages

IL-18

[38]

Proliferation of Kupffer-Cells is found in the liver accompanied of elevated IL-18 levels in serum

IFN-α

[121]

IFN-α prevents experimental biliary atresia

Macrophages

[58]

Increased infiltration of Macrophages in the liver after Kasai is correlated with a bad prognosis

Macrophages

[57]

Macrophages coexpress CD68 and CD14 in biliary atresia

Lymphocytes

[34]

Lymphocyte infiltration into biliary epithelium is quite similar to GVHD

Mononuclear cells

[131]

Mononuclear infiltrate in BA is more similar to normal livers than to those suffering from chronic infection or autoimmunity

T-regs

[114, 126, 132]

The RRV-induced murine model of BA is associated with defects in the production and function of T-regs, probably suppressing DC-dependent activation of naive NK cells