Neutrophil gelatinase-associated lipocalin is instrumental in the pathogenesis of antibody-mediated nephritis in mice.

OBJECTIVE: The mechanism by which anti-DNA antibodies mediate lupus nephritis has yet to be conclusively determined. Previously, we found that treatment of mesangial cells with anti-DNA antibodies induced high expression of neutrophil gelatinase-associated lipocalin (NGAL), an iron-binding protein up-regulated in response to kidney injury. We undertook this study to determine whether NGAL is instrumental in the pathogenesis of nephritis, is induced as part of repair, or is irrelevant to damage/repair pathways. METHODS: To investigate the role of NGAL in antibody-mediated nephritis, we induced nephrotoxic nephritis by passive antibody transfer to 129/SyJ and C57BL/6 mice. To determine if NGAL up-regulation is instrumental, we compared the severity of renal damage in NGAL wild-type mice and NGAL-knockout mice following induction of nephrotoxic nephritis. RESULTS: We found that kidney NGAL expression, as well as urine NGAL levels, were significantly increased in mice with nephrotoxic nephritis as compared to control-injected mice. Tight correlations were observed between NGAL expression, renal histopathology, and urine NGAL excretion. NGAL-knockout mice had attenuated proteinuria and improved renal histopathology compared to wild-type mice. Similarly, following nephritis induction, NGAL injection significantly exacerbated nephritis and decreased survival. NGAL induced apoptosis via caspase 3 activation and up-regulated inflammatory gene expression in kidney cells in vitro and when injected in vivo. CONCLUSION: We conclude that kidney binding of pathogenic antibodies stimulates local expression of NGAL, which plays a crucial role in the pathogenesis of nephritis via promotion of inflammation and apoptosis. NGAL blockade may be a novel therapeutic approach for the treatment of nephritis mediated by pathogenic antibodies, including anti-glomerular basement membrane disease and lupus nephritis.

Diffuse calcifications of the spleen: a novel association with systemic lupus erythematosus.

OBJECTIVES: While anatomical and physiological changes in the spleen are reported in systemic lupus erythematosus (SLE), a complex autoimmune disease that can affect most organ systems, calcifications have not been described as a characteristic feature. We report 4 lupus patients with extensive splenic calcifications with no apparent cause except for their primary disease. The relevant literature on calcifications of the spleen in SLE is also reviewed. METHODS: Four lupus patients with extensive splenic calcifications are described, identified by radiologists at 2 large urban academic centers. In addition, the relevant literature was reviewed (PubMed search 1947 through May 2010) using the following terms: "lupus," "spleen," and "calcified," "calcification," "calcifications," or "microcalcifications." English-language case reports and series were selected. RESULTS: Four lupus patients were found to have a unique pattern of splenic calcifications. The age range was 36 to 73 years. Two of the patients were women, and 1 of these had SLE and limited systemic sclerosis. On reviewing the literature, 6 additional cases of lupus and splenic calcifications were found, 1 of which had pathologic assessment of the spleen on autopsy. The incidence of infection was apparently not increased in affected patients. CONCLUSIONS: A unique pattern of calcifications of the spleen may be found in lupus patients, which can suggest the diagnosis of the underlying connective tissue disease. Whether splenic calcification can predispose to hyposplenism remains to be determined. While the exact significance of diffuse splenic calcification is still unknown, this unique radiologic finding may be a result of the disease process itself.

Sex and autoantibody titers determine the development of neuropsychiatric manifestations in lupus-prone mice.

Emotional disturbances are among the most common neuropsychiatric manifestations of SLE, a systemic autoimmune disease with a strong female predominance. In this study, we evaluated young MRL/lpr mice, directly comparing males and females. MRL/lpr females exhibited significant depression as early as 5 weeks (at which time elevated levels of autoantibodies were already present), as compared to MRL/lpr males, where depression was noted only at 18 weeks. Depression was significantly correlated with autoantibodies against nuclear antigens, NMDA receptor, and ribosomal P. Our results are consistent with a primary role of autoantibodies in the pathogenesis of early neuropsychiatric deficits in this lupus model, which translate into gender-based differences in clinical phenotype.