Lipopolysaccharide from Gram-negative bacteria enhances polyclonal B cell activation and exacerbates nephritis in MRL/lpr mice

Abstract

Depletion of B cells in mice bearing the lymphoproliferation (lpr) gene reduces lymphoproliferation and polyclonal B cell activation (PBA) and attenuates mononuclear cell vasculitis. We sought to verify whether the obverse was true, i.e. whether enhancement of B cell activity might exacerbate the nephritis of MRL/lpr (MRL) mice, a lupus-prone strain. The experimental approach was designed to address three questions: whether naturally occurring PBA in MRL mice could be further enhanced; whether enhanced PBA would exacerbate nephritis; and whether the mechanism of nephritis exacerbation involved interference with mononuclear phagocyte system (MPS) function. To enhance B cell activity, we injected MRL mice with lipopolysaccharide (LPS) from Gram-negative bacteria, a potent B cell activator. To determine whether nephritis was exacerbated, we performed immunopathologic studies and tests of renal function. To verify whether nephritis exacerbation involved impairment of MPS function, we probed the kinetics of immune complex removal from the circulation, their uptake by the liver and spleen, and their localization in kidney tissue. The results indicate that in MRL mice: (i) spontaneous PBA can be enhanced by LPS; (ii) enhancement of PBA by LPS exacerbates nephritis; and (iii) the MPS is already saturated, presumably due to excessive production of endogenous immune complexes. Thus, further increase in immune complex formation due to enhanced PBA by LPS results in increased localization of immune complexes in kidneys and exacerbated nephritis.