We have found a new spontaneous autosomal recessive mutation in mice that causes a systemic absence of lymph nodes and Peyer's patches. The name "alymphoplasia", with the gene symbol "aly", is proposed for this mutant. The spleen of aly/aly mice is devoid of well-defined lymphoid follicles, and the thymus does not show a clear cortical-medullary distinction. The mutant homozygotes are deficient in both humoral and cell-mediated immune functions, and are highly susceptible to infections. They have a reduced level of IgM and severely depressed levels of IgG and IgA in their sera, and do not reject allogeneic skin grafts. However, they have mature T and B cells as determined from their cell surface antigens. The results of bone marrow transplantation experiments suggest a mesenchymal disorder as a possible cause of the lack of lymph nodes and of immunodeficiency in the aly mouse. The aly mutant mouse may be a useful animal model of primary immunodeficiency, as are the nu (nude) and scid (severe combined immunodeficiency) mice.
Ligand-receptor internalization has been traditionally regarded as part of the cellular desensitization system. Low-density lipoprotein receptor-related protein (LRP) is a large endocytosis receptor with a diverse array of ligands. We recently showed that LRP binds heparin-binding growth factor midkine. Here we demonstrate that LRP mediates nuclear targeting by midkine and that the nuclear targeting is biologically important. Exogenous midkine reached the nucleus, where intact midkine was detected, within 20 min. Midkine was not internalized in LRP-deficient cells, whereas transfection of an LRP expression vector restored midkine internalization and subsequent nuclear translocation. Internalized midkine in the cytoplasm bound to nucleolin, a nucleocytoplasmic shuttle protein. The midkine-binding sites were mapped to acidic stretches in the N-terminal domain of nucleolin. When the nuclear localization signal located next to the acidic stretches was deleted, we found that the mutant nucleolin not only accumulated in the cytoplasm but also suppressed the nuclear translocation of midkine. By using cells that overexpressed the mutant nucleolin, we further demonstrated that the nuclear targeting was necessary for the full activity of midkine in the promotion of cell survival. This study therefore reveals a novel role of LRP in intracellular signaling by its ligand and the importance of nucleolin in this process.
There has recently been an increase in data indicating that autoimmune mechanisms are involved in the etiopathogenesis of idiopathic thrombocytopenic purpura (ITP) (1, 2). Although antibodies that react with platelets are found in most patients with ITP, the pathogenetic nature of the antibodies remains to be clarified . The discovery of an animal model for ITP has therefore been long-awaited. Here we have found that (NZW x BXSB)Fi (W/B Fi) mice, which develop lupus nephritis with myocardial infarction (3), show thrombocytopenia with age, and that this is due to the presence ofboth platelet-associated antibodies (PAA) and circulating antiplatelet antibodies.Recently, we have demonstrated that allogeneic bone marrow transplantation (ABMT) has curative effects on autoimmune diseases in (NZB x NZW)FI, BXSB, MRL/MP-lpr/lpr (MRL/lpr), and NOD mice (4-6) . These results prompted us to examine whether ABMT can be used to treat ITP. In the present study, we provide evidence that the transplantation of bone marrow from BALB/c mice to W/B F, mice does indeed have preventative and curative effects on ITP Materials and MethodsMice.Mice ofthe inbred strain BALB/c nu/nu, BALB/c, C57B/6, C3H/HeN, BXSB, NZW were raised under specific pathogen-free conditions in our animal facility. W/B F, males were obtained from the Nippon Shinyaku Research Laboratories, Kyoto, Japan.Staining Procedure andData Analysis.Platelet-rich plasma was obtained as described previously (7) . The platelets were suspended in 1% paraformaldehyde solution for 5 min. After
An outbred mouse strain known as ddY has been reported to spontaneously develop, late in life, mesangioproliferative glomerulonephritis with a severe glomerular immunoglobulin A (IgA) deposition that mimics human IgA nephropathy. However, the incidence of the disease in this strain is not very high, probably due to its heterogeneous genetic background. Therefore, we attempted to isolate a strain with a high incidence and an early onset of the disease through selection for high serum IgA from the outbred ddY mice. The selection procedure was successful in increasing the serum IgA level of the selected line and proved effective both in increasing the incidence and in accelerating the onset of the disease. We propose to designate this line of mice ‘HIGA’, denoting a line with high serum IgA levels. More than half of the mice from the HIGA strain showed a moderate to severe glomerular IgA deposition as early as 25 weeks of age. The severe deposition observed was comparable to that occasionally seen irt the original nonselected ddY strain after 40 weeks of age. Thus, we have succeeded in generating a mouse model of IgA nephropathy with a high incidence and an early onset of glomerular IgA deposition. Using light microscopy, progressive and marked mesangial matrix accumulation was shown to develop in HIGA mice. However, they showed only mild proteinuria (100-300 mg/dl) and did not show hematuria.
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