Enhanced natural but diminished antibody-mediated cytotoxicity in the lungs of MRLlpr/lpr mice

Abstract

SUMMARYHuman systemic lupus erythematosus (SLE) patients, as well as MRLlpr/lpr mice which develop a SLElike disease, have decreased numbers and functional activity of systemic natural killer (NK) cells. In contrast, it has been found that among lymphocytes recovered from the bronchoalveolar lavage fluid of SLE patients, NK cells were increased in number, correlating with the severity of the lung engagement. The present study was undertaken to assay the capacity for natural killing in the lung compartment of MRLlpr/lpr mice compared with healthy congenic MRL / and heterozygous MRL /lpr mice. 51 Crlabelled YAC-1 cells were injected intravenously to settle in the lungs where they were targeted for lysis by NK cells. YAC-1 cell killing inversely correlated with radioactivity remaining in the lungs after the assay, and was inhibited by antibody to the asialo-GM1 antigen expressed on NK cells. To analyse the capacity in the lung for cytolysis of non-NK cell-sensitive target cells, a similar in vivo 51 Cr-release assay was set up for antibody-mediated allospecific cytotoxicity. We demonstrate that MRLlpr/lpr mice throughout their lifespan display significantly increased natural cytotoxic activity in the lungs compared with MRL / and MRL /lpr mice, as demonstrated by more efficient killing of YAC-1 cells. In contrast, antibody-mediated allospecific cytotoxicity in the lungs was significantly less effective in the MRLlpr/lpr strain.

NKG2D ligand overexpression in lupus nephritis correlates with increased NK cell activity and differentiation in kidneys but not in the periphery

“…The phenotypic and functional aspects of NK cells in SLE target organs have not been studied extensively. To date, only 3 studies have been published, 2 of which reported a more cytotoxic phenotype for liver and lung NK cells from diseased MRL/lpr mice than from prediseased MRL/MpJ or MRL/lpr mice [45,46]. In a 3rd study, PMA/ionomycin-stimulated NK cells from diseased MRL/lpr mice produced more cytotoxic granules than prediseased MRL/lpr or MRL/MpJ mice [10].…”

The progressive state, in contrast to the stable or regressive state of alopecia areata, is reflected in peripheral blood mononuclear cells

“…It has been hypothesized that NK cells may be regulators of the disease state (37) and functional defects in the NK‐cell population have been identified concomitantly with defects in CD4 + CD25 + T reg from patients with insulin‐dependent diabetes mellitus (38). In contrast, NK cells in some animal models of autoimmunity may exacerbate the disease state (39–41). The contribution of CD16 + cells to the follicular infiltrate in AA has not previously been explored, and whether NK cells are systemic functional regulators or promoters of inflammation in AA is unknown.…”

Recent findings on the role of natural killer cells in the pathogenesis of systemic lupus erythematosus

“…NK cells from liver and lungs of diseased MRL/MpJ lpr mice have enhanced natural cytotoxicity compared with healthy controls [79,80]. Long-term NK cell depletion delays glomerulonephritis onset in NZBxNZW(F1) mice [81], which suggests a local role for these cells.…”