Animal models of systemic vasculitis

Necrotizing leucocytoclastic vasclitis in the histopathological hallmark of the small vessel systemic vasculitides (SV), a group of human diseases commonly associated with anti-neutrophil cytoplasm autoantibodies (ANCA). Necrotizing vasculitis is seen in a number of experimental systems, but none of these provide an ideal animal model for human SV. Vasculitis occurs in serum sickness reactions; in murine models of systemic lupus erythematosus; in association with infection, particularly chronic viral infections; and after treatment with certain drugs or inflammatory mediators. 'Spontaneous' vasculitis has been reported in specific mouse strains, especially with ageing, and in some larger species. The size of vessel involved and the type of inflammatory cells predominating are variable in these experimental situations, and none of these models feature antibodies analogous to ANCA. We have recently reported that Brown Norway rats treated with mercuric chloride (HgCl2) develop necrotizing leucocytoclastic vasculitis, especially in the gut, and also develop antibodies to myeloperoxidase (MPO) which recognize smilar determinants on MPO to those bound by a subset of ANCA. Transfer of serum from HgCl2-treated rats to naive animals does not induce tissue injury. Preliminary experiments using pooled immunoglobulin or an anti-CD4 monoclonal antibody did not show useful therapeutic benefit from these treatments. HgCl2-induced vasculitis has weaknesses as an animal model of human SV, but is the only experimental model in which anti-MPO autoantibodies have so far been demonstrated, and therefore may be of particular relevance to ANCA-associated SV.link_to_subscribed_fulltex

Osmotic stress and mortality in elderly patients with kidney failure: a retrospective study

Caroline Grangeon-Chapon,1 Manuella Dodoi,2 Vincent LM Esnault,2,3 Guillaume Favre2,3 1Departments of Nuclear Medicine and Pharmacy, University Côte d’Azur, University Hospital of Nice, Nice, France; 2Department of Nephrology, University Côte d’Azur, University Hospital of Nice, Nice, France; 3Department of Nephrology, University Côte d’Azur, Institute for Research on Cancer and Aging of Nice (IRCAN), “Aging and Diabetes” Team, University Hospital of Nice, Nice, France Purpose: Water balance disorders are associated with a high risk of death in elderly patients. The role of osmotic stress intensity and its direction toward hypo- or hypernatremia is a matter of controversy regarding patients’ survival. The aims of this study were, first, to measure the frequency of cellular hydration disorders in patients over 75 years old hospitalized in nephrology department for reversible acute renal failure, and second, to compare the impact of hyperhydration and hypohydration on the risk of death at 6 months. Patients and methods: We retrospectively studied the data of 279 patients with chronic kidney disease (CKD), aged 75 years or older, with pre-renal azotemia who experienced dysnatremia. We classified them according to natremia levels and compared their outcome in univariate and multivariate analysis. Results: The patients were on average 83.2±5.4 years old. Among them, 128 were normonatremic, 82 were hyponatremic and 69 were hypernatremic. Osmotic stress intensity appreciated by the variation rate of natremia did not differ significantly between hyper- and hyponatremic patients. Patients had CKD stage 3B and 4 with acute kidney injury (AKI) of different severities. We observed that only hypernatremia was linked to death in the first 6 months following hospital discharge. Conclusion: Hypernatremia is a strong predictor of fatal outcome in elderly patients suffering from chronic kidney impairment and referred for pre-renal azotemia. Keywords: acute kidney injury, aging, chronic kidney failure, hypernatremia, osmoregulatio

Autoantibodies to myeloperoxidase in Brown Norway rats treated with mercuric chloride

BACKGROUND: Mercuric chloride (HgCl2) induces an autoimmune syndrome in Brown Norway (BN) rats characterized by the presence of a number of autoantibodies, including antibodies to glomerular basement membrane. Tissue injury has previously been reported to be rare in this model, but in the accompanying paper we describe changes in a number of organs including a necrotizing leucocytoclastic vasculitis in the gut. Myeloperoxidase (MPO) is one of the target antigens for anti-neutrophil cytoplasm antibodies, that are present in the majority of patients with the human autoimmune disease systemic vasculitis and have been implicated in pathogenesis. There is at present, no animal model for anti-neutrophil cytoplasm antibody positive systemic vasculitis. EXPERIMENTAL DESIGN: Ten BN rats were given five injections of HgCl2, each of 1 mg/kg, over 10 days. Sequential serum samples were tested for autoantibodies to MPO using solid phase assays, indirect immunofluorescence on normal rat neutrophils, and Western blot analysis. The specificity of these antibodies in the solid phase assay was confirmed by inhibition studies with purified antigen, and by testing binding to uncoated plates. Sera from control animals treated with saline were also tested. RESULTS: BN rats given HgCl2 developed antibodies to MPO, which in Western blots bound to similar determinants to those bound by human anti-MPO antibodies. The anti-MPO antibodies resolved spontaneously, with a time course similar to that of the anti-glomerular basement membrane antibodies, but there was no correlation between the two antibody responses in individual animals. There was no anti-MPO activity in sera taken before HgCl2 was given, nor in sera from saline-treated controls. CONCLUSIONS: BN rats treated with HgCl2 develop anti-MPO antibodies. Together with the description in the accompanying paper of necrotizing vasculitis in these animals, these observations suggest that HgCl2-induced autoimmunity in the BN rat may provide a useful model of anti-neutrophil cytoplasm antibody positive systemic vasculitis.link_to_subscribed_fulltex

Desferrioxamine modulates chemically induced T helper 2-mediated autoimmunity in the rat

A rise in interleukin (IL) 4-dependent immunoglobulin E (IgE) is a hallmark of the mercuric chloride (HgCl(2))-induced Th2-mediated autoimmune syndrome in the Brown Norway (BN) rat, and one of the mediators in allergic asthma in human. Oxidative stress, a potential factor related to the pathogenesis of allergy and asthma, has been shown to up-regulate IL-4 in mast cells and predispose to degranulation in vitro. However, it remains unknown whether oxidative/antioxidative imbalance plays a role in this Th2-driven model of autoimmunity in the rat. Here we show that administration of the non-sulphydryl-containing antioxidant desferrioxamine i.p. and s.c. to BN rats reduces HgCl(2)-enhanced IL-4 gene expression and inhibits HgCl(2)-induced Th2-mediated autoimmunity. Desferrioxamine treatment suppresses significantly IgE production and lymphoproliferation, and reduces tissue injury in the form of caecal vasculitis in the HgCl(2)-induced autoimmune syndrome. These results support a role for oxidative stress in the pathogenesis of the HgCl(2)-induced Th2-dominated autoimmune syndrome. This finding might have implications for understanding the mechanisms involved in Th2 cell responses as seen in allergy and asthma and thereby aid the development of new therapeutic strategies for these diseases

A role for αβ T cells in the resistant phase of the Brown Norway rat model of vasculitis

Administration of mercuric chloride (HgCl(2)) to Brown Norway rats causes Th2 dominated autoimmunity including a caecal vasculitis. Disease peaks 14 days after starting HgCl(2) after which animals immunoregulate spontaneously. In a third phase, if animals are rechallenged with HgCl(2) 6 weeks later they appear resistant, developing only attenuated disease. Previous studies suggested a role for CD8(+) cells as partial mediators of resistance but no groups had studied the role of αβ T cells, γδ T cells or natural killer (NK) cells in resistance. We used adoptive transfer and in vitro cell depletion to show that αβ T cells are also partially responsible for resistance. Donor animals were treated with HgCl(2) or saline and killed 21 days later. Cells from donor spleens were transferred into recipient animals which were challenged with HgCl(2) and killed 14 days later. Test recipients received spleen cells from HgCl(2)-treated donors after in vitro depletion of one subset of cells. Recipients receiving spleen cells from saline-treated donors remained susceptible to HgCl(2)-induced vasculitis; those receiving spleen cells from HgCl(2)-treated donors were resistant. Animals receiving αβ T-cell-depleted spleen cells from HgCl(2)-treated donors showed partial reversal of resistance. Our results suggest a role for αβ T cells in the resistant phase of the Brown Norway rat model of vasculitis

Anti-neutrophil cytoplasmic antibodies (ANCA) against bactericidal/permeability-increasing protein (BPI) and cystic fibrosis lung disease

Persistent infection with Pseudomonas aeruginosa and inflammatory mechanisms play an important role in cystic fibrosis (CF) lung disease. ANCA against BPI, a potent host defence protein with anti-bacterial and anti-endotoxin properties, have been described in CF. We have assessed the relationship of anti-BPI antibodies to pulmonary disease severity in 148 CF subjects. IgA and IgG anti-BPI antibodies were found in 55.4% and 70.3% of CF patients, respectively, and higher levels were strongly associated with colonization with P. aeruginosa (P = 0.001 and 0.039 for IgA and IgG antibodies, respectively). IgA and IgG anti-BPI antibodies were independently associated with more severe lung disease as assessed by chest radiograph score (P = 0.023) and a significantly lower forced expiratory volume in 1 s (FEV1)% (P = 0.01). The pathophysiological relevance of the autoantibodies was investigated further by determining their epitope specificity and their effect on bacterial phagocytosis in vitro. Both isotypes of anti-BPI antibodies were specific for the C-terminus of BPI shown recently to be important for BPI-mediated opsonization, and in vitro affinity-purified anti-BPI antibodies significantly reduced BPI-induced phagocytosis of Escherichia coli compared with controls. These data indicate that anti-BPI autoantibodies are associated with colonization with P. aeruginosa and worse lung disease in CF. The inhibition of bacterial phagocytosis suggests that these autoantibodies may contribute to the persistence of P. aeruginosa in the CF lung and so play a role in perpetuating CF lung damage