Hepatic CD1d+ B cells reduce immune-mediated drug-induced hepatitis in male BALB/c mice and account for sex bias in hepatitis severity seen in this disease

Abstract

Abstract Sex modulates severity in autoimmune diseases. In susceptible individuals, drug metabolites induce hepatitis, autoimmunity and liver injury. Drug–induced hepatitis (DIH) is a leading cause of liver failure and is a common reason an approved medication is removed from the consumer market. We previously showed that estrogen and IL-6 promote sex bias by increasing hepatitis severity and by reducing IL-10 and Foxp3+ regulatory T cells in female BALB/c (WT) mice. We also found antibody-independent roles for sex bias via IL-10 and CD1d+B cells in male WT mice with reduced hepatitis. To directly assess the significance of CD1d+B cells in male WT mice with DIH, we induced hepatitis in male and female WT mice and treated them with anti-CD20 after 2 weeks at clinically relevant doses used for treating B cell-associated autoimmune diseases. Hepatitis was induced in female and male WT mice by immunizing them with cytochrome P4502E1 (CYP2E1) epitopes modified by drug metabolites. Splenic and hepatic B cells as well as hepatitis were assessed. Groups were analyzed using Mann-Whitney U. A p value < 0.05 was significant. We found reduced hepatitis in male when compared to female WT mice associated with elevated hepatic follicular CD21/CD35+IgM-B cells (p<0.01) and elevated hepatic and splenic CD1d+B cells (p<0.001) as well as reduced splenic marginal zone CD21/CD35+ IgD+ CD23− B cells in male mice (p<0.05). Anti-CD20 did not abolish sex bias in splenic CD1d+B cells (p<0.05) but reduced hepatic CD1d+B cells (p<0.01), abolished sex bias in the expression of splenic marginal zone B cells and increased DIH in male WT mice (p<0.05). We demonstrate protective roles for hepatic CD1d+B cells in sex bias and in the reduction of hepatitis in male WT mice.