Evaluation of Langerhans Cell Infiltrate by CD1a Immunostain in Liver Biopsy for the Diagnosis of Primary Biliary Cirrhosis

Abstract

Primary biliary cirrhosis (PBC) is characterized by chronic nonsuppurative destructive cholangitis, which is considered to be a cell-mediated immune reaction. Antigen-presenting cells, including Langerhans cells and dendritic cells, have been found in portal tracts and in bile duct epithelium and may play a role in the pathogenesis of PBC, but the importance of identifying these cells for diagnosing PBC has not been studied yet. In this study, we sought to evaluate the importance of identifying Langerhans cells using a CD1a immunostain in the diagnosis of PBC. Liver biopsies from adult patients diagnosed with PBC (n=60), primary sclerosing cholangitis (n=29), obstructive cholangitis (n=13), chronic viral hepatitis B or C (n=19), autoimmune hepatitis (AIH, n=15), acute cellular rejection (n=11), and chronic rejection (n=10) at our institution were retrospectively reviewed. An immunohistochemical stain for CD1a was used to detect Langerhans cells, and the distribution of CD1a-positive Langerhans cell infiltrate was recorded as lobular, portal with bile duct sparing, and intraepithelial. Intraepithelial Langerhans cells were identified in 58% of PBC including antimitochondrial antibody-negative PBC and PBC-AIH overlap cases, 14% of primary sclerosing cholangitis, 15% of obstructive cholangitis, 9% of acute cellular rejection, 6% of AIH, and no cases of chronic viral hepatitis or chronic rejection. The number of intraepithelial Langerhans cells was significantly higher in PBC than in other conditions, with the mean number of CD1a-positive intraepithelial Langerhans cells per bile duct in PBC calculated as 2.2 compared with <1 per duct for the other control cases. Thirty-three of 60 (55%) PBC cases showed at least one bile duct containing ≥2 CD1a-positive Langerhans cells. This was statistically significant (P<0.01) when compared with control groups. The overall sensitivity and specificity of using ≥2 CD1a-positive Langerhans cells per bile duct as the diagnostic criteria for PBC were 55% and 96%. Given the heterogenous nature of liver involvement by PBC, a review of cases with morphologic features of duct damage yielded an increased sensitivity (79%) with no reduction in specificity. In conclusion, the detection of a Langerhans cell infiltrate of ≥2 cells by CD1a in a given bile duct on needle biopsy may be a valuable tool in the diagnosis of PBC.

Immune system and cholangiocytes: A puzzling affair in primary biliary cholangitis

“…Langerhans cells (LCs) are immature mDCs that express high level of C‐type lectin Langerin and CD1a on their surface and are present in the damaged bile ducts of PBC 99,117,118 . Thus, the presence of LCs close to the bile ducts in PBC suggests their potential role in the establishment of the autoimmune response 119 . Moreover, LCs are found in close proximity of MIP3α‐expressing BECs, confirming BEC's role in the recruitment of innate immune cells at the site of inflammation in PBC 99 .…”

Frequent infiltration of S-100 protein+ CCR5+ immature dendritic cells in damaged bile ducts of primary biliary cirrhosis compared to cholangiocellular carcinoma

“…[12][13][14][15] These data suggest that DCs including Langerhans cells existing around or within biliary epithelial layers are important as periductal antigen presenting cells in PBC. Graham et al 16 proposed an attractive suggestion that chemokine receptors expressed on immature DCs (CCR1, CCR2, CCR5, CCR6, and CXCR4) are responsible for their recruitment to inflamed tissue. Thus, CCR5…”

“…[10][11][12][13][14][15] Moreover, several chemokines and chemokine receptors have recently been demonstrated to be expressed in certain liver diseases, including PBC. [14][15][16][17][18][19][20][21] However, information regarding the mechanisms underlying DC infiltration in PBC and an epithelial neoplasm, cholangiocellular carcinoma (CCC), arising from bile ducts and the pathological significance of this phenomenon is limited. The aim of the present study was therefore to investigate the histological distribution of DCs and the mechanisms by which immature DCs infiltrate the bile ducts in PBC, compared to CCC as a neoplastic condition, by immunohistochemistry, reverse transcription polymerase chain reaction (RT-PCR) amplification and in situ hybridization.…”

Conventional type 1 dendritic cells are essential for the development of primary biliary cholangitis

“…17 Furthermore, in 58% of PBC patients, CD1a-positive DC were found to be in the close vicinity of the damaged bile ducts, which is significantly higher than that in other chronic inflammatory liver conditions. 18 In mouse livers, there are two main subsets of classical DC (cDC):…”