"Lupoid hepatitis" in SLE patients and mice with experimental lupus

Abstract

The unusual subset of patients with severe hepatitis, hypergammaglobulinemia, arthritis, and LE cells in the blood reported by Henry Kunkel and others suggested to these investigators that "lupoid" hepatitis might share pathogenic mechanisms with SLE. More than half a century later, the etiology of autoimmune hepatitis remains unclear. The occurrence of autoimmune hepatitis in a small fraction (about 3%) of SLE patients in our lupus cohort and in two mouse models of SLE supports their conclusion that lupoid hepatitis may be share pathogenic mechanisms with SLE. The development of autoimmune hepatitis in mice with pristane-induced lupus provides an opportunity to further explore the potential link between these two autoimmune disorders.

Figure 1

Liver pathology of formalin-fixed tissue from a 29-year-old Black woman with SLE and autoimmune hepatitis. A, hematoxylin & eosin (H&E) stain showing bridging fibrosis (arrow); B, H&E stain showing plasma cell (arrow) and mononuclear cell infiltrates; C, periodic acid-Schiff (PAS) stain showing bile duct proliferation and disorganization; D, PAS stain showing liver cell necrosis, inflammatory cell infiltrates, and fibrosis; E, trichrome stain showing portal tract collagen fibrosis. F–H show double immunohistochemistry (IHC, peroxidase staining is shown in brown and alkaline phosphatase staining in red) after antigen recovery. F, double IHC for CD4⁺ (brown) and CD8⁺ (red) T cells; G, double IHC of plasma cells for intracellular for κ (brown) and λ (red) L-chain; H, double IHC of CD68⁺ liver macrophages (brown) and cleaved caspase-3⁺ dead cells (red).

Figure 2

Serum autoantibodies in SLE patients. A, levels of IgG anti-F-actin antibodies (AAA) (ELISA) in sera from patients with autoimmune hepatitis (AIH), in SLE patients with high, intermediate, or low levels of type I interferon (IFN), or in healthy controls (Con). High positive control O.D._{405 nm} = 2.24; low positive O.D._{405 nm} = 0.32; background O.D._{405 nm} = 0.08; B, correlation of IgG anti-F-actin autoantibody levels (ELISA) with interferon levels (monocyte CD64 expression, mean fluorescence intensity by flow cytometry).

Figure 3

Liver pathology in pristane-treated mice. B6 (A–D) and BALB/c (E–F) mice were treated with pristane and 10 months later, liver was formalin-fixed and stained with hematoxylin & eosin. Controls were untreated B6 mice (G–H). A, liver underlying a pristane-induced lipogranuloma (Lipo) showing coagulative necrosis (yellow arrowhead). Examination of the area within the red box at high power (B) showing coagulative necrosis and cell death (yellow arrowhead). C, bile stasis (yellow arrowhead). D, extensive bile duct proliferation (yellow arrowhead) and lymphoplasmacytic inflammatory infiltrates (white arrow). E (low power) and F (high power), lymphoplasmacytic infiltrates in a peri-portal distribution (yellow arrowheads) in liver tissue from a 10-month pristane-treated BALB/c mouse. Plasma cells are indicated by *. G (low power) and H (high power), absence of liver inflammation in tissue from an untreated B6 mouse.

Figure 4

Autoantibodies in 6-month pristane-treated B6 mouse sera. A, levels of IgG anti-F-actin autoantibodies (AAA) in sera from pristane-treated mice and untreated controls were determined by ELISA at a serum dilution of 1:100. B, levels of IgG anti-U1A (RNP) autoantibodies were determined by ELISA using recombinant human U1-A protein (1:100 serum dilution). C, correlation of the levels of IgG AAA and IgG anti-U1A autoantibodies in the sera.