Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0153470 (Spleen)
 4,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anti-histone antibodies have been demonstrated in the sera of patients with both idiopathic and drug-induced lupus. We measured anti-histone antibodies in female NZB/NZW (F1) mice, which are considered to be a model of human SLE. Using a sensitive and quantitative enzyme-linked immunosorbent assay (ELISA), we detected minimal serum antibody activity in NZB/NZW mice younger than 4 mo of age and in nonautoimmune mice at all ages tested. Serum anti-histone antibodies progressively increased in NZB/NZW mice from 4 to 8 mo of age and showed an age-related maturation from IgM to IgG. The predominant antibody activity in the older mice was to the individual histones H2B and H3, and the pattern of reactivity to the histone proteins was similar to that seen in human SLE. We also studied the spontaneous in vitro production of anti-histone antibodies using spleen cells from NZB/NZW mice of different ages. Culture supernatants were analyzed for antibody activity by an ELISA with total histones as the antigen. Spleen cells from older NZB/NZW mice, with elevated serum levels, produced 10-fold higher levels of antibody activity compared to age-matched nonautoimmune mice. Antibody production was maximal at 4 days of culture and was inhibited by the addition of puromycin to the culture. Surprisingly, spleen cells from 1 to 3-mo-old NZB/NZW mice, with normal serum levels, also demonstrated significantly elevated production. The antibodies produced by these young mice were mostly IgM, whereas spleen cells from older mice produced mostly IgG anti-histone antibodies. The present results provide the basis for using the anti-histone antibody system to study further the immune abnormalities that allow for autoantibody production.
 ...
PMID:In vivo and in vitro production of anti-histone antibodies in NZB/NZW mice. 686 18

Although multiple studies suggest a potential role for angiotensin II in inflammation, most were performed either in vitro or in animals with non-immune-complex-mediated diseases. Extrapolation of these findings to humans, particularly patients with lupus, which involves multiple immunoregulatory pathways, is unclear. In autoimmune-prone MRL/lpr mice, angiotensin-converting-enzyme (ACE) inhibition improved survival although to a lesser degree than cyclophosphamide and diminished the glomerular histopathologic damage, proteinuria, lymphoid hyperplasia, dermatitis, and hypergammaglobulinemia, with a reduction in TGF-beta1 and beta 2 expression in the kidneys and renal chemokine mRNA expression. Spleen levels of IL-4 and IL-10 were also reduced. Uncontrolled studies in patients with treatment-refractory lupus nephritis showed a significant reduction in proteinuria with ACE-inhibitors and Angiotensin receptor blockers treatment. The 'masking' effect of ACE-inhibitors should be taken into consideration, as an exacerbation of lupus nephritis may be missed when estimated by the magnitude of proteinuria, which is decreased by these treatments. No single ACE genotype was consistently associated with subsets of SLE patients. In retrospective analyses, ACE-inhibitor use predicted a favourable outcome in 94 cases of pauci-immune vasculitis. The attenuating effect of angiotensin II inhibitors on the progression of chronic renal disease is well recognized. The data on the role of this intervention in lupus is limited.
 ...
PMID:The renin-angiotensin system in lupus: physiology, genes and practice, in animals and humans. 1683 Aug 77

Murine models of lupus, both spontaneous and inducible, are valuable instruments to study SLE pathogenesis. Accelerants such as Type I IFN are often used to trigger earlier disease onset. We used a topical TLR7 agonist, previously reported to induce lupus-like disease in WT mice within weeks, to validate this data in C57BL/6j mice, and to test TLR7 agonism as an accelerant in lupus-prone NZM2410 mice. We found that TLR7-stimulated B6 and NZM2410 mice had significantly reduced survival and exhibited profound splenomegaly with significantly reduced B cells (4 vs. 40%), and T cells (8 vs. 31%). Spleen pathology and IHC revealed massive expansion of F4/80+ cells in TLR7-treated mice consistent with histiocytosis. While resiqimod treatment caused mild autoimmunity in B6 mice and accelerated autoimmunity in NZM2410 mice, it did not cause significant nephritis or proteinuria in either strain (renal function intact at death). Given the macrophage expansion, cytopenias, and disruption of normal splenic lymphoid follicle architecture, histiocytic sarcoma is favored as the cause of death. An alternative etiology is a macrophage activation syndrome (MAS)-like syndrome, since the mice also had a transaminitis and histologic hemophagocytosis in the setting of their rapid mortality. For investigators who are focused on murine models of lupus nephritis, this model is not ideal when utilizing B6 mice, however topical resiqimod may prove useful to accelerate autoimmunity and nephritis in NZM2410 mice, or potentially to investigate secondary complications of lupus such as histiocytic diseases or macrophage activation like syndromes.
 ...
PMID:TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice. 3199 21