Home About us Contact
|
Home About us Contact | ||
|
|
||
Immune Complex Deposition (immune + complex_deposition)
Selected AbstractsSystemic autoimmune disease induced by dendritic cells that have captured necrotic but not apoptotic cells in susceptible mouse strainsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 11 2005Liang Ma Abstract Systemic lupus erythematosus (SLE) is an autoimmune disorder of a largely unknown etiology. Anti-double-stranded (ds) DNA antibodies are a classic hallmark of the disease, although the mechanism underlying their induction remains unclear. We demonstrate here that, in both lupus-prone and normal mouse strains, strong anti-dsDNA antibody responses can be induced by dendritic cells (DC) that have ingested syngeneic necrotic (DC/nec), but not apoptotic (DC/apo), cells. Clinical manifestations of lupus were evident, however, only in susceptible mouse strains, which correlate with the ability of DC/nec to release IFN-, and to induce the pathogenic IgG2a anti-dsDNA antibodies. Injection of DC/nec not only accelerated disease progression in the MRL/MpJ- lpr/lpr lupus-prone mice but also induced a lupus-like disease in the MRL/MpJ-+/+ wild-type control strain. Immune complex deposition was readily detectable in the kidneys, and the mice developed proteinuria. Strikingly, female MRL/MpJ-+/+ mice that had received DC/nec, but not DC/apo, developed a ,butterfly' facial lesion resembling a cardinal feature of human SLE. Our study therefore demonstrates that DC/nec inducing a Th1 type of responses, which are otherwise tightly regulated in a normal immune system, may play a pivotal role in SLE pathogenesis. [source] Gene expression profile of transgenic mouse kidney reveals pathogenesis of hepatitis B virus associated nephropathy,JOURNAL OF MEDICAL VIROLOGY, Issue 5 2006J. Ren Abstract Hepatitis B virus (HBV)-associated nephritis has been reported worldwide. Immune complex deposition has been accepted as its pathogenesis, although the association between the presence of local HBV DNA and viral antigen and the development of nephritis remains controversial. To understand better the roles played by HBV protein expression in the kidney, the global gene expression profile was studied in the kidney tissue of a lineage of HBV transgenic mouse (#59). The mice expressed HBsAg in serum, and HBsAg and HBcAg in liver and kidney, but without virus replication. Full-length HBV genome (adr subtype, C genotype) isolated from a chronic HBV carrier was used to establish the transgenic mice #59. Similarly manipulated mice that did not express HBV viral antigens served as controls. Southern blotting, hybridization with HBV probe, and immuno-histochemical staining were used to study HBV gene expression. mRNA extracted from the kidney tissue was analyzed using Affymetrix microarrays. HBsAg and HBcAg were located mainly in the cytoplasm of tubular epithelium. Altogether 520 genes were "up-regulated" more than twofold and 76 genes "down-regulated" more than twofold in the kidney. The complement activation, blood coagulation, and acute-phase response genes were markedly "up-regulated". Compared to the controls, the level of serum C3 protein was decreased in #59 mice, while the level of C3 protein from kidney extract was increased. Results indicate that expression of HBsAg and HBcAg in tubular epithelial cells of the kidney per se can up-regulate complement-mediated inflammatory gene pathways, in addition to immune complex formation. J. Med. Virol. 78:551,560, 2006. © 2006 Wiley-Liss, Inc. [source] Selective blockade of BAFF for the prevention and treatment of systemic lupus erythematosus nephritis in NZM2410 miceARTHRITIS & RHEUMATISM, Issue 5 2010Meera Ramanujam Objective To determine whether BAFF or combined BAFF/APRIL blockade is effective in a mouse model of systemic lupus erythematosus (SLE) nephritis characterized by rapidly progressive glomerulosclerosis. Methods NZM2410 mice at early and late stages of SLE nephritis were treated with a short course of BAFF-R-Ig or TACI-Ig fusion protein. Proteinuria and serologic profile were evaluated every 2 weeks. Immunohistochemical, flow cytometric, and enzyme-linked immunospot analyses of the spleen, kidney, and bone marrow were performed after 8 weeks and after 33 weeks. Results A short course of selective blockade of BAFF alone was sufficient to prevent and treat SLE nephritis in NZM2410 mice, despite the formation of pathogenic autoantibodies. Decreases in spleen size and B cell depletion persisted for more than 33 weeks after treatment and resulted in secondary decreases in CD4 memory T cell formation and activation of splenic and peripheral monocytes. Immune complex deposition in the kidneys was dissociated from renal damage and from activation of renal endothelial and resident dendritic cells. Conclusion Selective blockade of BAFF alone, which resulted in B cell depletion and splenic collapse, was sufficient to prevent and treat the disease in this model of noninflammatory SLE nephritis. This shows that the inflammatory microenvironment may be a determinant of the outcome of B cell modulation strategies. [source] Systemic IFN-, drives kidney nephritis in B6.Sle123 miceEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 7 2008Anna-Marie Fairhurst Abstract The impact of IFN-, secretion on disease progression was assessed by comparing phenotypic changes in the lupus-prone B6.Sle1Sle2Sle3 (B6.Sle123) strain and the parental C57BL/6 (B6) congenic partner using an adenovirus (ADV) expression vector containing a recombinant IFN-, gene cassette (IFN-ADV). A comprehensive comparison of cell lineage composition and activation in young B6 and B6.Sle123 mice revealed a variety of cellular alterations in the presence and absence of systemic IFN-,. Most IFN-,-induced phenotypes were similar in B6 and B6.Sle123 mice; however, B6.Sle123 mice uniquely exhibited increased B1 and plasma cells after IFN-, exposure, although both strains had an overall loss of mature B cells in the bone marrow, spleen and periphery. Although most of the cellular effects of IFN-, were identical in both strains, severe glomerulonephritis occurred only in B6.Sle123 mice. Mice injected with IFN-ADV showed an increase in immune complex deposition in the kidney, together with an unexpected decrease in serum anti-nuclear antibody levels. In summary, the predominant impact of systemic IFN-, in this murine model is an exacerbation of mechanisms mediating end organ damage. [source] Hepatitis C virus-related extra-hepatic disease , aetiopathogenesis and managementALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 2 2004J. Medina Summary Hepatitis C virus infection is often associated with extra-hepatic manifestations, secondary to the elicitation of autoimmune reactions, generalized deposition of immune complexes and lymphoproliferative disorders. The most clearly established associations are those linking chronic hepatitis C with mixed cryoglobulinaemia (and the related glomerulonephritis and cutaneous vasculitis), as well as with the presence of autoantibodies. Less well-documented disorders include non-Hodgkin's lymphoma, thrombocytopenia, sialadenitis, thyroid disease, lichen planus, porphyria cutanea tarda, rheumatoid disorders and neurological disorders. Extra-hepatic manifestations are most frequent in patients of female sex, advanced age, long-lasting infection and cirrhosis. Optimal treatment strategies should be based on the predominant manifestation of the disease. In the case of autoimmune disorders not clearly attributable to the viral infection, corticosteroids may be the most effective option. Interferon-, alone or in combination with ribavirin may be indicated for those disorders related to immune complex deposition, such as mixed cryoglobulinaemia, although relapses of extra-hepatic signs often occur on discontinuation of treatment. In some cases, interferon-, may induce or exacerbate some extra-hepatic manifestations. [source] Rituximab-induced accelerated cryoprecipitation in hepatitis C virus,associated mixed cryoglobulinemia has parallels with intravenous immunoglobulin,induced immune complex deposition in mixed cryoglobulinemia: Comment on the article by Sène et alARTHRITIS & RHEUMATISM, Issue 10 2010FRCPath, Siraj A. Misbah FRCP No abstract is available for this article. [source] Interferon-,,dependent inhibition of B cell activation by bone marrow,derived mesenchymal stem cells in a murine model of systemic lupus erythematosusARTHRITIS & RHEUMATISM, Issue 9 2010Francesca Schena Objective Bone marrow,derived mesenchymal stem cells (BM-MSCs) are multipotent cells characterized by immunomodulatory properties and are therefore considered a promising tool for the treatment of immune-mediated diseases. This study was undertaken to assess the influence of murine BM-MSCs on the activation of B cells in (NZB × NZW)F1 mice as an animal model of systemic lupus erythematosus (SLE). Methods We evaluated the in vitro effects of BM-MSCs on the proliferation and differentiation to plasma cells of splenic mature B cell subsets, namely follicular and marginal zone B cells isolated from (NZB × NZW)F1 mice. Lupus mice were also treated with BM-MSCs, and serum autoantibodies, proteinuria, histologic changes in the kidney, and survival rates were monitored. Results BM-MSCs inhibited antigen-dependent proliferation and differentiation to plasma cells of follicular and marginal zone B cells in vitro. This inhibitory effect was dependent on interferon-, (IFN,) and was mediated by cell-to-cell contact, involving the programmed death 1 (PD-1)/PD ligand pathway. In vivo treatment with BM-MSCs did not affect the levels of anti,double-stranded DNA antibodies or proteinuria. However, a reduction in glomerular immune complex deposition, lymphocytic infiltration, and glomerular proliferation was observed. Conclusion Our findings indicate that BM-MSCs affect B cell receptor,dependent activation of both follicular and marginal zone B cells from lupus mice. This inhibitory effect is IFN,-dependent and cell contact,dependent. MSCs in vivo do not affect the production of autoantibodies, the level of proteinuria, or the mortality rates. Nonetheless, the significant improvement in histologic findings in the kidney supports the potential role of MSCs in the prevention of glomerular damage. [source] Distinct mechanisms of action of anti-CD154 in early versus late treatment of murine lupus nephritisARTHRITIS & RHEUMATISM, Issue 9 2003Sergio A. Quezada Objective Treatment with anti-CD154 antibody is known to ameliorate murine lupus nephritis when given early in the disease. The aims of this study were to identify the mechanism of this early effect, to determine whether late anti-CD154 treatment could halt established nephritis, and, if so, to examine potential mechanisms of late efficacy. Methods We studied the effects of anti-CD154 treatment on autoantibody production and immune complex deposition, renal pathology, survival, and renal cytokine and chemokine messenger RNA (mRNA) expression both in (NZB × NZW)F1 mice (BW mice) and in NZM.2410 mice. Results Early treatment with anti-CD154 produced long-term survival in BW mice, with abrogation of renal immune complex deposition for months after treatment was stopped. Late anti-CD154 treatment, started after development of nephritis, could halt disease in ,40% of mice. In some mice, proteinuria could be reversed repeatedly with sequential courses of anti-CD154 antibody. The remissions induced by late treatment with anti-CD154 occurred despite ongoing renal immune complex deposition. In preliminary studies, responding mice had rapid reductions in renal mRNA for transforming growth factor ,, interleukin-10, and tumor necrosis factor ,. Conclusion Amelioration of murine lupus by anti-CD154 therapy is mediated by distinct mechanisms in early versus late intervention. We postulate that anti-CD154 therapy prevents autoantibody production and renal immune complex deposition in the early, induction phase and limits secondary tissue damage in situ in the late, effector phase. These data demonstrate that CD40,CD154 interactions are critical for the maintenance of autoimmunity and suggest a potential role for anti-CD154 as a therapeutic agent in established human lupus. [source] | ||||||||||