ovalbumin and Lupus-Nephritis

Secreted IgA plays a pivotal role in the mucosal immunity to maintain the front line of body defense. We found that the level of fecal IgA was dramatically decreased in aged (NZB x NZW)F(1) (BWF(1)) mice developing lupus nephritis, whereas levels in similarly aged New Zealand Black (NZB) and New Zealand White (NZW) mice remained unchanged compared with young mice. The number of cells obtained from Peyer's patches was markedly decreased in aged BWF(1) mice. Aged BWF(1) mice showed increased susceptibility to pathogenic bacterial infection. Furthermore, oral administration of OVA failed to inhibit secondary IgG response induced by systemic immunization, suggesting defective oral tolerance in aged BWF(1) mice. A significant amount of orally administered OVA was incorporated directly into the intestinal lamina propria in aged BWF(1) mice whereas it was mainly localized in subepithelial domes and interfollicular region in Peyer's patches in young mice. T cells obtained from renal and pulmonary lymph nodes of aged BWF(1) mice that had been orally administered with OVA showed an Ag-specific T cell proliferation, whereas those from young BWF(1), aged NZB, and aged NZW mice did not. Interestingly, aerosol exposure to OVA of aged BWF(1) mice, which had been orally administered with the same Ag, provoked an eosinophil infiltration in the lung. These results demonstrate that mucosal immunity in the gut is impaired and oral Ags induce systemic sensitization instead of oral tolerance in the development of murine lupus.

Topics: Administration, Inhalation; Administration, Oral; Aging; Animals; Antigens; Cell Movement; Crosses, Genetic; Eosinophilia; Escherichia coli Infections; Female; Genetic Predisposition to Disease; Hydrazines; Immune Tolerance; Immunity, Mucosal; Immunoglobulin A; Intestinal Mucosa; Lupus Erythematosus, Systemic; Lupus Nephritis; Lymphocyte Activation; Mice; Mice, Inbred NZB; Ovalbumin

Inducible costimulator (ICOS)-B7 homologous protein (B7h) is a new member of the CD28-B7 family of costimulatory molecules that regulates T cell-dependent humoral immune responses. In this study, we examined the involvement of this costimulatory pathway in the development and progression of lupus in NZB/W F(1) mice. Expression of ICOS on T cells was enhanced with disease progression, whereas B7h expression on B cells was down-regulated. Administration of anti-B7h mAb before the onset of renal disease significantly delayed the onset of proteinuria and prolonged survival. Blockade of B7h effectively inhibited all subclasses of IgG autoantibody production and accumulation of both Th1 and Th2 cells. Hypercellularity and deposition of IgG and C3 in glomeruli were significantly reduced. B7h blockade after the onset of proteinuria prevented the disease progression and improved the renal pathology. Our results demonstrated the involvement of the ICOS-B7h costimulatory pathway in the pathogenesis of lupus nephritis, and the blockade of this pathway may be beneficial for the treatment of human systemic lupus erythematosus.

Topics: Adoptive Transfer; Animals; Antibodies, Antinuclear; Antibodies, Monoclonal; Antigens, Differentiation, T-Lymphocyte; Crosses, Genetic; Down-Regulation; Drug Administration Schedule; Female; Immunoglobulin G; Inducible T-Cell Co-Stimulator Ligand; Inducible T-Cell Co-Stimulator Protein; Injections, Intraperitoneal; Ligands; Lupus Nephritis; Lymphocyte Subsets; Mice; Mice, Inbred NZB; Mice, SCID; Mice, Transgenic; Ovalbumin; Protein Biosynthesis; Proteins; Signal Transduction; Spleen; T-Lymphocytes

(NZB x NZW)F1 (NZB / W) mice develop a disease similar to human systemic lupus erythematosus (SLE), including autoantibody production, hypergammaglobulinaemia and inflammation of the kidneys. It is known that large numbers of lymphocytes infiltrate the kidneys of these mice. Here, we compare the roles of bone marrow, spleen and inflamed kidneys of NZB / W mice in the activation of B cells and the persistence of antibody-secreting cells (ASC). ASC are present in the kidneys of NZB / W mice with full-blown disease, as many as in the spleen and bone marrow. The specificity of the ASC in the inflamed kidneys is not restricted to self-antigens. After immunization of NZB / W mice with ovalbumin (OVA) the OVA-specific ASC are found initially in the spleen. Weeks later, OVA-specific ASC are found in high numbers in the bone marrow and the kidneys of these mice, but no longer in the spleen. As determined by FACS, B cells with a germinal center phenotype (B220(+) / PNA(+)) are found only in very low numbers in the kidneys, but in high numbers in the spleen of NZB / W mice. Germinal centers could not be detected in the kidneys, but in the spleen, and plasma cells appear to be scattered over the tissue. These data suggest that in autoimmune NZB / W mice, plasma cells generated in immune reactions of secondary lymphoid organs, later accumulate and persist in the inflamed kidneys, were they enhance the local concentrations of Ab and immunocomplexes. These experiments identify the inflamed kidneys of NZB / W mice as a site of prime relevance for the homeostasis of plasma cells, irrespective of their specificity.

Topics: Animals; Bone Marrow; Germinal Center; Homeostasis; Kidney; Lupus Nephritis; Lymphocyte Count; Mice; Mice, Inbred NZB; Ovalbumin; Plasma Cells; Spleen

Polyclonal B cell activation is an early feature of autoimmune disease in humans and mice with systemic lupus erythematosus. The contribution of polyclonal activation to the progression of autoimmunity is unclear, however, since it precedes the development of end-organ damage by months or years. To examine this issue, 109 autoimmune-prone (NZB X NZW)F1 X NZB backcross mice were hemi-splenectomized at 10 wk and the number and antigenic specificity of their Ig-secreting B cells quantitated by ELISA spot assay. Of the 61 mice that had polyclonally increased numbers of Ig-secreting cells/spleen, 31 died by 6 mo. In contrast, 0/48 backcross mice with normal numbers of Ig-secreting B cells at 10 wk died over the same period (P less than 0.001). Polyclonally activated mice also developed proteinuria earlier and more frequently than littermates with normal numbers of Ig-secreting cells (P less than 0.001). As adults, backcross mice with proteinuria expressed repertoires skewed towards the production of anti-DNA antibodies. At 10 wk these same mice expressed repertoires marked by polyclonal activation rather than preferential anti-DNA production. These findings indicate that autoimmune disease in SLE is accompanied by the autoantigen-driven production of autoantibodies but is preceded and predicted by polyclonal B cell activation.

Topics: Animals; Autoantibodies; Autoimmune Diseases; B-Lymphocytes; DNA; Immunoglobulins; Lupus Nephritis; Lymphocyte Activation; Mice; Mice, Inbred Strains; Ovalbumin