Linked help from bacterial proteins drives autoantibody production in small vessel vasculitis.

The small vessel vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis are associated with autoantibodies to neutrophil cytoplasm antigens (ANCA), principally proteinase-3 (PR3) and myeloperoxidase (MPO). There is an association between GPA and nasal carriage of Staphylococcus aureus. The recent finding that S. aureus produces proteins that bind tightly to and block the function of both PR3 and MPO suggests a mechanism for ANCA formation. The bacterial protein-autoantigen conjugate is recognised by B cells with ANCA specificity, internalised, and the bacterial protein processed and presented to T cells with specificity for bacterial peptides. The T cell can then provide help to the B cell, allowing class switching, affinity maturation and the production of pathogenic ANCA. This mechanism predicts that T cells with this specificity will be found in patients, and that the bacterial protein-autoantigen conjugate will be particularly efficient at eliciting ANCA production.

Blockade of OX40-ligand after initial triggering of the T helper 2 response inhibits mercuric chloride-induced autoimmunity.

Mercuric chloride (HgCl2)-induced autoimmunity in Brown Norway rats is a spontaneously resolving autoimmune response driven by the activation of T helper type 2 lymphocytes (Th2 cells). Treatment with antibody to OX40-ligand (OX40-L) from the time of the first HgCl2 injection for 12 days had little effect. Delayed treatment commenced 8 days after the first HgCl2 injection significantly suppressed immunoglobulin E production, splenomegaly, weight loss and mortality. This makes OX40/OX40-L signalling an attractive therapeutic target for Th2-driven autoimmune diseases. Intravenous administration of the murine antibody to OX-40-L elicited a vigorous anti-mouse immunoglobulin antibody response that was significantly enhanced compared to the response to control immunoglobulin. It is likely that this response significantly reduced the plasma half-life of the anti-OX40-L antibody and this observation has clear implications for the interpretation of data from experiments where anti-OX40-L is used in vivo.

The role of N-acetylcysteine in the prevention of contrast-induced nephrotoxicity.

PURPOSE: To determine the role of prophylactic N-acetylcysteine in the prevention of contrast-induced nephrotoxicity. METHODS: One hundred and sixteen patients undergoing noncoronary angiography, with or without pre-existing renal impairment, were randomly assigned to receive prophylactic oral N-acetylcysteine or no treatment. Serum creatinine (sCr) was measured prior to angiography and 48 hr after the procedure. Urine samples were collected before and after the examination for measurement of malondialdehyde (MDA) concentration. Contrast-induced nephrotoxicity (CIN) was defined as a rise in serum creatinine of 0.5 mg/dl (44 mmol/l) at 48 hr. RESULTS: Complete data were available on 106 patients, 53 of whom had received N-acetylcysteine. There were no significant differences between the two groups in baseline characteristics, type of angiogram, or volume and concentration of contrast used. Three patients (2.8%), all of whom had received N-acetylcysteine, developed CIN. In the N-acetylcysteine group, the mean serum creatinine in patients with renal impairment was 151.0 +/- 44.2 micromol/l prior to the procedure and 155.6 +/- 48.6 micromol/l (p = 0.49) after the procedure. Respective values for those without renal impairment were 79.6 +/- 15.1 micromol/l and 81.2 +/- 20.0 micromol/l (p = 0.65). In the group that had not received N-acetylcysteine, the mean serum creatinine levels before and after the procedure were 150.0 +/- 58.1 and 141.4 +/- 48.0 micromol/l (p = 0.17) in patients with renal impairment and 79.7 +/- 14.2 and 81.4 +/- 15.4 micromol/l (p = 0.34) in those without renal impairment. In both groups, no significant change in urinary MDA concentration was observed. CONCLUSION: There is no benefit to the prophylactic administration of N-acetylcysteine in patients undergoing peripheral angiography using current contrast media.

A central role for the mast cell in early phase vasculitis in the Brown Norway rat model of vasculitis: a histological study.

Administration of mercuric chloride (HgCl(2)) to Brown Norway rats causes Th2-dominated autoimmunity with raised immunoglobulin E concentrations and gut vasculitis, both of which are T-cell dependent, peak at 14 days after starting HgCl(2) and then spontaneously resolve. If animals are re-challenged with HgCl(2) 6 weeks after initial exposure, they are resistant to autoimmunity, developing only attenuated disease. Recently, a separate phase of early caecal vasculitis was described beginning 24 h after initiating HgCl(2) and prior to caecal entry of T cells. Previous work suggested this early vasculitis was alpha beta T-cell independent and implied a role for mast cells. We further tested this hypothesis by performing a histological study during the first 93 h following HgCl(2) challenge defining the precise relationship between gut mast cell degranulation and appearing caecal vasculitis. We also studied whether early caecal vasculitis enters a resistant phase upon re-challenge with HgCl(2). We show a direct correlation between mast cell degranulation and early caecal vasculitis following initial HgCl(2) challenge. We demonstrate resistance to re-challenge in this phase of injury, with results at re-challenge also showing a correlation between mast cell degranulation and early caecal injury.

Antioxidants inhibit mercuric chloride-induced early vasculitis.

In the Brown Norway (BN) rat, mercuric chloride (HgCl(2)) induces a T(h)2-dominated autoimmune syndrome which includes an early phase of mast cell-dependent vasculitis. We have shown in vitro that oxidative stress up-regulates IL-4 in mast cells and predisposes to degranulation. The aim of this study was to determine whether administration of antioxidants inhibits HgCl(2)-induced early vasculitis in vivo, and, if so, to examine whether modulation of the oxidative/antioxidative balance influences IgE and IL-4 expression by mast cells in situ. Groups of rats were given HgCl(2) + saline, HgCl(2) + N-acetyl-L-cysteine (NAC), saline + saline or saline + NAC respectively and blood was taken and animals killed 48 h later. NAC significantly reduced both HgCl2-induced early vasculitis and HgCl(2)-enhanced IgE expression on mast cells with a trend to a decrease in HgCl(2)-enhanced IL-4 expression in these cells. In addition, there was an increased rat mast cell protease (RMCP) II concentration in the serum after HgCl(2) injection and the elevated levels of RMCP II stimulated by HgCl(2) were totally abolished by the administration NAC in the HgCl(2) + NAC group. However, there was no significant change in serum total IgE concentrations between the HgCl(2) + saline group and the HgCl(2) + NAC group. The non-sulphydryl-containing antioxidants desferrioxamine and pyruvate demonstrated a similar effect in inhibiting HgCl(2)-induced early vasculitis. Our data show that administration of an antioxidant to BN rats reduces HgCl(2)-induced early vasculitis, suggesting that oxidative stress plays a role in the pathogenesis of HgCl(2)-induced early vasculitis. This finding may have implications for the understanding of the initiation in this experimental model of T(h)2 cell-driven autoimmunity and possibly of analogous human diseases.