Natural killer cells and estrogen in experimental rheumatic diseases

Abstract

MRLlpr/lpr mice constitute a model for systemic lupus erythematosus (SLE). These mice spontaneously develop polyclonal activation of B cells with hypergammaglobulinemia and production of anti-DNA antibodies, which deposit in the form of immune complexes in glomeruli causing glomerulonephritis. Additionally, inflammatory infiltrates dominated by CD4+ T cells form around blood vessels (vasculitis) and in salivary glands (sialadenitis). To investigate the influence of estrogen on pathogenesis, castrated MRLlpr/lpr mice were administered a physiological dose of 17b-estradiol or olive oil (controls). 17b-estradiol enhanced deposition of immunoglobulins in glomeruli, but at the same time ameliorated kidney vasculitis and sialadenitis. 17b-estradiol increased serum levels of immunoglobulins in MRLlpr/lpr mice as well as in the healthy, congeneic MRL+/+ mice, and to a variable degree also in other mouse strains tested. The impact of 17b-estradiol on the cytotoxic activity of mouse natural killer (NK) cells in vivo was studied. It was found that a pharmacological dose of 17b-estradiol significantly suppressed NK cell activity, although to a variable degree in different mouse strains. Spleen cells from MRL+/+ mice depleted of NK cells were tested for in vitro immunoglobulin production by the ELISPOT method. Lack of NK cells significantly increased the number of IgG producing B cells. NK cell activity of MRLlpr/lpr mice was compared to that of MRL+/+ mice. It was found that the MRLlpr/lpr mice had higher in vivo cytotoxic capacity than both MRL+/+ and the heterozygous MRL+/lpr mice. In contrast, the MRLlpr/lpr mice had a reduced capacity for antibody-mediated lysis of allogeneic spleen cells, assayed in vivo and in vitro. In non-infected C57BL/6 mice, it was shown that depletion of NK cells increased the level of antibodies to oxazolone after booster immunization, whereas the magnitude of the T cell dependent DTH reaction to oxazolone was not affected. C57BL/6 mice were injected i.v. with Staphylococcus aureus 2x107 colony forming units per mouse. Starting before and continuing during the development of septic arthritis, half of the mice were depleted of NK cells by use of mAb PK136 directed against the NK1.1 antigen. NK cell depleted mice showed increased frequency and severity of arthritis. The mechanism for this finding remains to be elucidated, as there was no difference in the number of positive joint cultures and no NK cells could be found in joint sections. In conclusion, we show that 17b-estradiol enhances immune complex mediated glomerulonephritis in MRLlpr/lpr mice, at the same time as it reduces T cell infiltrates. Estradiol suppresses NK cell activity. NK cells downregulate polyclonal and antigen-specific antibody production. Surprisingly, MRLlpr/lpr mice have a high in vivo NK activity. NK cells down-regulate inflammation in Staphylococcus aureus mediated septic arthritis.