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. 1999 Jun;154(6):1711-20.
doi: 10.1016/S0002-9440(10)65427-2.

Enhanced expression of CD80 (B7-1), CD86 (B7-2), and CD40 and their ligands CD28 and CD154 in fulminant hepatic failure

L Leifeld  1 , C Trautwein, F L Dumoulin, M P Manns, T Sauerbruch, U Spengler
Affiliations

Enhanced expression of CD80 (B7-1), CD86 (B7-2), and CD40 and their ligands CD28 and CD154 in fulminant hepatic failure

L Leifeld et al. Am J Pathol. 1999 Jun.

Abstract

To define a possible role for changes in the regulation of antigen presentation in fulminant hepatic failure (FHF), we studied the expression of co-stimulatory molecules CD80 (B7-1), CD86 (B7-2), and CD40 along with their ligands CD28 and CD154. We analyzed the liver tissue from patients with FHF (n = 18), chronic liver disease (n = 30), and acute hepatitis (n = 3) and from normal controls (n = 9) by immunohistochemistry and examined the temporal relationship between CD80/CD86 and CD40 expression and disease in the mouse models of galactosamine-lipopolysaccharide and galactosamine-tumor-necrosis-factor-induced FHF. In human controls, faint CD80/CD86 immunoreactivity was restricted to Kupffer cells, and CD40 expression was expressed on bile ducts, macrophages, and sinusoidal endothelial cells (SECs). In FHF, immunoreactivity for CD80 and CD86 was observed on significantly higher numbers of cells, including SECs. Increased CD80/CD86 expression corresponded to increased numbers of CD28-positive lymphocytes. The expression of CD40 was also clearly elevated on virtually all cell types in FHF. In both murine models, CD40 and CD80/CD86 expression was up-regulated before tissue damage could be detected. Our data suggest that up-regulated expression of co-stimulatory molecules might lead to an excessive antigen presentation in FHF as an early step in the pathogenesis before the onset of tissue damage.

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Figures

Figure 1.
Figure 1.
A and B: Hepatic CD86 expression in a patient with fulminant HBV (patient 2, MAb Fun-1). Cell types with typical morphological characteristics of macrophages (B, thin arrows) and of sinusoidal endothelial cells (thick arrows) are positive for CD86. Magnification, ×40 (A) and ×400 (B). C: Hepatic CD86 expression in a patient with toxic FHF (patient 9, MAb Fun-1). Islets of surviving hepatocytes showed absence of infiltrating cells and a normal expression of co-stimulatory molecules, exclusively on Kupffer cells, within the islets. The islets are surrounded by a dense wall of CD86-positive macrophages. In areas of liver necrosis outside the islets, macrophages and SECs, are CD86 positive. An identical pattern could be demonstrated for CD80 expression (not shown). Magnification, ×200.
Figure 2.
Figure 2.
Assignment of CD86 expression to macrophages and SEC (patient 1). Serial sections were stained for CD86 (A, MAb Fun-1), CD68 (B, MAb JC/70A), and CD31 (C, MAb PGM1). As shown by the (thin arrows), expression of CD86 can be allocated to macrophages (CD86+, CD68+, CD31−) and as shown by the thick arrows also to SECs (CD86+, CD68−, CD31+). Double stainings with CD31-FITC (D) and CD86 (E) demonstrate CD86-positive (thick arrows) and CD86-negative (thin arrows) SECs. Magnification, ×400 (A to C) and ×1000 (D and E).
Figure 3.
Figure 3.
CD86 expression in a normal control (A, MAb Fun-1) and in a patient with chronic HBV infection (B). Only macrophages are CD86 positive in both normal controls and chronic liver disease. The number of positive Kupffer cells is higher and staining is stronger in chronic HBV compared with normal controls. Magnification, ×400.
Figure 4.
Figure 4.
CD40 expression in a liver specimen of a patient with chronic HBV (MAb 5C3). Hepatocytes, Kupffer cells, SECs, and bile duct epithelia stain strongly positive for CD40 in the patient with chronic HBV. Magnification, ×400.
Figure 5.
Figure 5.
CD86 (A to D, MAb GL1) and CD40 (E to H, MAb 3/23) expression in mice without (A and E) and 4 (B and F), 8 (C and G) and 12 (D and H) hours after treatment with GalN/TNF. Sinusoidal CD40 and CD86 expression is induced 8 hours after treatment with GalN/TNF. Similar expression could be observed in the GalN/LPS model (not shown).
Figure 6.
Figure 6.
Correlation between the number of CD40-positive cells to CD8- and CD28- as well as CD86- to CD28-positive cells.
Figure 7.
Figure 7.
Number of CD86- and CD40-expressing cells after treatment with GalN/TNF or GalN/LPS.
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