Hepatic overexpression of MHC Class II antigens and macrophage-associated antigens (CD68) in patients with biliary atresia of poor prognosis

doi:10.1016/S0022-3468(97)90714-4

Journal of Pediatric Surgery

Volume 32, Issue 4, April 1997, Pages 590-593

https://doi.org/10.1016/S0022-3468(97)90714-4 Get rights and content

Abstract

The pathogenesis of biliary atresia (BA) is still unknown. Progression to cirrhosis despite restoration of bile flow by successful portoenterostomy suggests that it is a progressive disease of the liver and biliary tree. Whether immunologic factors play any role in the development of this disease remains uncertain. Aberrant expression of major histocompatibility complex (MHC) Class II antigens of HLA-DR on hepatocytes and biliary epithelium is regarded as important in the progression of hepatocellular and biliary damage mediated by cytotoxic T cells. This study was undertaken to evaluate expression of MHC Class II antigen and macrophage-associated antigens (CD68) in liver of patients with biliary atresia to determine their prognostic usefulness and possible role in the pathogenesis of the disease. Liver biopsy specimens from infants with BA (n = 15), neonatal hepatitis (n = 3), and normal livers (n = 6) were studied using an indirect immunoperoxidase staining using antibodies against MHC Class II antigen and macrophage-associated antigens (CD68) as well as routine H&E and Masson's trichome stain. In patients with biliary atresia, the liver biopsy specimen was obtained at the time of Kasai portoenterostomy. Expression of HLA-DR antigens and CD68 antigens was either absent or minimal in normal liver biopsy specimens. There were a few HLA-DR antigens and a few CD68-positive cells around portal tracts in all patients with neonatal hepatitis and five of the seven biliary atresia patients with successful Kasai portoenterostomy. In contrast, there was strong expression of HLA-DR antigen in bile ductules, inflammatory cells, and adjacent damaged hepatocytes and marked CD68-positive macrophage infiltrate in the portal tracts as well as hepatic lobules in two patients with good prognosis and in all eight patients with bad prognosis. Hepatic expression of MHC Class II antigen and CD68 antigens correlated well with the severity of clinical course in patients with BA and may act as a prognostic factor in these patients.

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Biliary atresia (BA) is a cholestatic liver disease of children that progresses to hepatic fibrosis. BA is the main indication of pediatric liver transplantation (LTx). Histopathological markers in liver biopsies could be useful for predicting progression to end-stage disease.
To establish histopathological or immunohistochemical markers in liver biopsies of BA patients and correlate those markers with prognosis.
Histological analysis of biliary alterations and morphometric assessment of liver fibrosis were performed, in addition to indirect immunofluorescence assays (IF) for type I, III, IV and V collagens in initial and final liver biopsies of 36 patients with BA who underwent Kasai hepatoportoenterostomy (KPE) and LTx in the last 20 years at a single center.
Histopathological markers had no correlation with evolutive time until LTx. The perisinusoidal deposition of type III and V collagens was more prominent in the initial biopsies (p < 0.01), whereas deposition of type I and IV collagens indicated progression (p < 0.01). Patients with large amounts of perisinusoidal type I collagen in the initial biopsies had worse progression time curves until LTx (p = 0.04).
Morphometric assessment of perisinusoidal deposition of type I collagen by IF in the initial biopsy can correlate with progression time to LTx in post-surgical BA.
Troxis necrosis, a novel mechanism for drug-induced hepatitis secondary to immunomodulatory therapy
2015, Experimental and Molecular Pathology
Citation Excerpt :
The piecemeal necrosis is a novel mechanism of liver injury, hypothesized to be mediated by the MHC class II antigen presenting function of hepatocytes. Indeed, healthy hepatocytes normally do not express MHC class II molecules; however, in clinical hepatitis, viral or autoimmune, hepatocytes often exhibit aberrant MHC class II expression (Kobayashi et al., 1997; Herkel et al., 2003). Herein, the hepatocyte internalizes, metabolizes, and presents the antigenic derivative from the medication on the MHC class II molecule on its membrane surface.
A case of drug-induced hepatitis mediated by troxis necrosis, a form of autoimmune hepatitis, is described.
Clinical data, light and electron microscopy of an ultrasound-guided core needle liver biopsy specimen, were examined to investigate the cause of transaminitis in a 26 year old male patient on Cellcept and Plaquenil for the treatment of lupus erythematosus. A systematic PUBMED review of troxis necrosis as the underlying mechanism for drug-induced hepatitis was performed.
Liver function tests (LFTs) were significant for elevated AST (305) and ALT (174); the autoimmune workup was significant for anti-ANA positivity and α-SMA negativity. On light microscopy, the liver biopsy shows focal areas of lymphocytic infiltrates surrounding and forming immunologic synapses with lobular hepatocytes, indicating lobular hepatitis of autoimmune nature. Electron microscopy confirmed the presence of immunologic synapses. Upon cessation of the offending medications, the LFTs returned to baseline with no further intervention. Literature search yielded 7 previously reported cases of drug-induced hepatitis mediated by troxis necrosis.
Troxis necrosis is a novel mechanism for drug-induced hepatitis, including immunomodulatory medications including a monoclonal anti-TWEAK antibody and Cellcept and Plaquenil, two widely used immunosuppression/anti-rejection medications.
Th-17 cells infiltrate the liver in human biliary atresia and are related to surgical outcome
2015, Journal of Pediatric Surgery
Biliary atresia (BA), a cholangiopathy of unknown etiology is associated with intrahepatic mononuclear cell infiltrate. An abnormal reaction to viral exposure has been hypothesized in some cases. We aimed to investigate the nature of the CD4 + hepatic infiltrate in defined clinical variants of BA by quantification of inflammatory cell components.
Liver biopsies of infants obtained at Kasai portoenterostomy (KPE) were stained immunohistochemically using monoclonal antibodies to Tbet, GATA-3, FOXP3 and interleukin (IL) 17, identifying Th-1, Th-2, Tregs and Th-17 cells respectively. T cells were counted with the aid of a graticule. Data are reported as median (range) of cells per high-power-field (× 400) and compared using nonparametric statistical tests with P ≤ 0.05 regarded as significant.
Liver biopsies from BA (n = 37) and age-matched cholestatic controls (e.g. alpha-1-anti trypsin deficiency, Alagilles syndrome, n = 12) were investigated. BA infants were divided into three groups: cytomegalovirus IgM + ve (CMV; n = 9); BA splenic malformation (BASM; n = 9) and isolated BA (IBA; n = 19). All T-cell subsets were present in the portal tracts, with an overrepresentation of Th-1 (P < 0.001) and Th-17 (P < 0.03), but not Th-2 (P = 0.94) or Tregs (P = 0.15), compared to controls. Th-1 cells predominated in the CMV group; (18 [7–37] vs. 3 [0–14] [BASM] and vs. 5 [3–23] [IBA]; P < 0.01 both), while no subgroup differences were seen for Th-17 cells. The degree of Th-1 cell infiltrate inversely correlated with platelet count (r_S = − 0.49; P < 0.01). Th-17 cells were fewer (6 [2–11] vs. 11 [8–20]; P = 0.02) in infants who cleared their jaundice (n = 15, < 20 μmol/L) although this did not translate to improved native liver survival (P = 0.17).
Th-17 cells infiltrate the liver in BA and are associated with a worse surgical outcome; a Th-1 profile predominates in CMV-associated BA.
The inflammatory phenotype of the fibrous plate is distinct from the liver and correlates with clinical outcome in biliary atresia
2015, Pathology Research and Practice
Citation Excerpt :
Also, the percentage of CD163+ cells inversely correlated with the transplant-free interval in boys; in addition, patients with longer than average transplant-free intervals had lower percentages of CD163+ cells. This data is consistent, in part, with prior studies showing an inverse relationship between the number of macrophages and outcome [20,28]. The fact that some of the correlations were influenced by patient ethnicity or gender may be a consequence of immune system differences between members of different ethnic and gender groups.
Biliary atresia is an inflammatory cholangiopathy of still undetermined etiology. Correlations between histologic findings and clinical outcome in this disease have largely been based on evaluation of liver parenchyma. This study aimed to characterize the pattern of inflammation within the biliary remnant and identify associations between the type and degree of inflammation and clinical outcome as reflected by the transplant-free interval. The inflammation within the fibrous plates and livers of 41 patients with biliary atresia was characterized using immunohistochemical markers and the cell populations were digitally quantified. The type and quantity of cells within the infiltrate were then correlated with length of time from Kasai portoenterostomy until transplant. Histologic and immunohistochemical features of the biliary remnant allowed stratification of patients into “inflammatory plate” and “fibrotic plate” groups. Overall there was no significant difference in transplant-free interval between the two cohorts; however, there was a trend towards a longer time to transplant among patients in the “fibrotic plate” group. In addition, the composition of the inflammatory infiltrate in the fibrous plate was distinctly different from that present in the liver and only the characteristics of the inflammation in the fibrous plate, in particular the number of Foxp3+ T regulatory lymphocytes correlated with clinical outcome. The results of this study support the view of the extra-hepatic biliary tree as the primary site of injury in BA with the changes seen in the liver as secondary manifestations of outflow obstruction. The association between specific inflammatory cell subtypes within the fibrous plate and the length of transplant-free interval also supports the role of the immune system in the initial process of bile duct damage in biliary atresia.
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Hepatic overexpression of MHC Class II antigens and macrophage-associated antigens (CD68) in patients with biliary atresia of poor prognosis

Abstract

Gastroenterology

Consideration of the pathogenesis of neonatal hepatitis, biliary atresia and choledochal cyst—The concept of infantile obstructive cholangiopathy

Prog Pediatr Surg

Increased expression of intercellular adhesion molecules in biliary atresia

Am J Pathol

Recognition of major histocompatibility complex antigens on cultured human biliary epithelial cells by alloreactive lymphocytes

Hepatology