Renal-limited vasculitis in children: a single-center retrospective long-term follow-up analysis.

Pauci-immune renal limited vasculitis (RLV) is a rare and aggressive autoimmune disease. We retrospectively analyzed the renal outcome of 6 children with biopsy proven RLV. Median age at diagnosis was 10.6 years (range 7.1 - 14.5) and the median follow-up was 4.4 years (range 2.3 - 6.6). At diagnosis, 5 patients were given induction therapy (methylprednisolone + cyclophosphamide pulses) followed by maintenance treatment (prednisolone + azathioprine) while 1 patient received maintenance treatment only. After induction, 4 patients either retained or recovered normal renal function, and 1 patient, in whom short-term plasma exchange was prescribed to try to rescue her renal function, became free from dialysis. Repeated biopsy showed no disease activity; however, renal scarring was evident in all renal specimens. At last follow-up, 2 patients had normal renal function, 3 patients had mild renal insufficiency, and 1 patient had advanced renal failure. In addition, 5 patients were treated for hypertension. Our case series suggests that an initial favorable response to immunosuppressive therapy might not necessarily prevent the occurrence of renal scarring and highlights the importance of regular follow-up.

A CD26-controlled cell surface cascade for regulation of T cell motility and chemokine signals.

Chemokines are key regulators of cell trafficking, and dipeptidyl peptidase IV/CD26 (CD26) inactivates chemokines. Here we show that the CD26-processed chemokines SDF1alpha/CXCL12 and RANTES/CCL5, in contrast to a control chemokine not processed by CD26, are potent inducers of cell surface expression of thrombospondin-1 (TSP-1) in T lymphocytes through a CD26-controlled mechanism and that TSP-1 stimulates expression of lipoprotein receptor related protein/CD91. Accordingly, intact TSP-1 and a peptide mimetic of a sequence in TSP-1 were sufficient to stimulate CD91 expression. The chemokine-induced expression of TSP-1 and CD91 was mimicked by inhibitors of CD26 and CXCL12 and CCL5 as well as inhibitors of CD26 stimulated polarized cytoplasmic spreading and migration through TSP-1. Silencing of CD26 using small interfering RNA or Ab-induced modulation of CD26 also increased TSP-1 expression and enhanced cytoplasmic spreading and T cell migration markedly. These results indicate that CD26 is an endogenous inhibitor of T cell motility through inhibition of TSP-1 expression and that chemokines stimulate cell polarity and migration through abrogation of the CD26-dependent inhibition. This suggests that T cell motility is regulated by a cascade of interacting cell surface molecules.

Generalized Wegener's granulomatosis in an immunocompetent adult after cytomegalovirus mononucleosis and bacterial urinary tract infection.

Human cytomegalovirus (HCMV) is frequently detected in autoimmune diseases, but its role in such disorders is poorly understood. Herein we describe the case of a young woman who developed generalized Wegener's granulomatosis (WG) after HCMV mononucleosis and urinary tract infection. During mononucleosis, the patient had extraordinarily high plasma levels of proinflammatory cytokines such as interleukin-5 and lymphotoxin alpha, autoantibodies, and a higher blood level of viral DNA than were found in other immunocompetent patients infected with HCMV or healthy controls. Active HCMV replication was detected after the onset of vasculitis, and HCMV genomes or antigens were found in blood, urine, and inflammatory lesions on the kidney. Thus, HCMV may have triggered or exacerbated inflammation and autoimmunity in this case of WG.

Anti endothelial cell autoantibodies selectively activate SAPK/JNK signalling in Wegener's granulomatosis.

The pathogenic role of anti-endothelial cell antibodies (AECA) in vascular injury is debated. It was previously shown that many patients with Wegener's granulomatosis (WG) have AECA that react with human kidney microvascular endothelial cells (EC). In addition, during active disease, renal endothelium strongly expresses the inflammatory molecules vascular adhesion protein-1 (VAP-1) and MHC class I-related antigen A (MICA). This study sought to determine whether AECA mediates this upregulation of VAP-1 and MICA and to define better the signaling pathways that are activated by these autoantibodies upon binding to EC in the kidney. Stimulation of human kidney microvascular EC with AECA IgG upregulated surface expression of MICA and VAP-1, elicited a rapid Ca2+ flux, induced high levels of the chemokines monocyte chemoattractant protein-1 and granulocyte chemotactic protein-2, induced specific phosphorylation of stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) and the transcription factors c-Jun and activating transcription factor-2, and activated NF-kappaB. Specific inhibitors of SAPK/JNK significantly reduced AECA-induced chemokine production and phosphorylation of c-Jun and activating transcription factor-2 and abrogated protein expression of MICA but not VAP-1. In kidney sections from patients with WG, infiltrating cells that expressed the ligand for MICA (NKG2D+) were identified, as were CD8+ and 32 gamma delta+ T cells. In conclusion, AECA may be involved in the pathogenesis of WG, and the SAPK/JNK pathway and the endothelial inflammatory protein VAP-1 may be novel therapeutic targets for vasculitis.

Wegener's granulomatosis is associated with organ-specific antiendothelial cell antibodies.

BACKGROUND: Antiendothelial cell antibodies (AECA), usually detected using human umbilical vein endothelial cells (HUVEC), are frequently observed in systemic vasculitis, but their pathogenic role is unclear. Heterogeneity of endothelial cells necessitates use of clinically relevant endothelial cells for elucidation of the role of AECA in systemic vasculitis involving small blood vessels of specific organs. METHODS: Human endothelial cells were isolated from normal tissue specimens from the nose, kidney, lung, liver, and umbilical vein. Using flow cytometry, AECA were detected against both unstimulated and cytokine-stimulated [tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma)] endothelial cells. Functional capacity of AECA was determined by complement fixation assay. Sera from patients with Wegener's granulomatosis (16), limited Wegener's granulomatosis (8), renal limited disease (4), microscopic polyangiitis (MPA) (5), rheumatoid arthritis (10), and systemic lupus erythematosus (SLE) (9), and from healthy controls (20) were analyzed. RESULTS: Compared with controls (1) Wegener's granulomatosis is significantly associated with noncytotoxic AECA that selectively bind surface antigens on unstimulated nasal, kidney, and lung endothelial cells; (2) binding of Wegener's granulomatosis AECA to kidney and nasal endothelial cells in particular was lost upon treatment with IFN-gamma and TNF-alpha; (3) the two cytokines per se were cytotoxic (30%) to nasal and lung endothelial cells and lysis was further increased (60%) by addition of systemic vasculitis serum; and (4) Wegener's granulomatosis serum caused agglutination of cytokine-stimulated nasal endothelial cells. CONCLUSION: Based on these findings we suggest that AECA may be one factor involved in the initiation of Wegener's granulomatosis. Antigen identification and elucidation of the pathogenic roles of AECA and inflammatory cytokines in systemic vasculitis using these cells will be particularly important.

Serum sFAS levels are elevated in ANCA-positive vasculitis compared with other autoimmune diseases.

The role of the Fas/FasL system in ANCA-associated vasculitis is unclear. We therefore assessed levels of soluble Fas (sFas) in sera and Fas expression on mononuclear cells from patients with ANCA-positive vasculitis and compared the results with those found in other rheumatic diseases. Serum levels of sFas were determined by ELISA. The ANCA-positive vasculitis patients studied included 29 at onset, 17 in first remission while on therapy, and 12 in quiescence. For comparison, 10 patients with Sjogren's syndrome (SS), 14 patients with systemic lupus erythematosus (SLE), 29 patients with rheumatoid arthritis (RA), 7 patients on dialysis (DP), and 26 healthy controls (HC) were studied. In addition, Fas expression in mononuclear cells was examined at the mRNA level using reverse transcriptase (RT)-PCR in 6 vasculitis patients at onset and in first remission. The expression of CD95 on the surface of leukocytes was determined by flow cytometry in 6 vasculitis patients at onset of the disease, in 6 patients in clinical remission, and in 6 HC. Expression of Fas and FasL in renal biopsy specimens was studied using immunohistochemistry. Patients with vasculitis had high sFas levels irrespective of disease phase. Both vasculitis patients and patients with RA and SLE had significantly increased sFas levels compared with healthy controls. All patient groups had sFas levels, which correlated with raised serum creatinine values. However, the sFas levels in vasculitis patients in first remission and in quiescence were increased despite a lower serum creatinine compared with onset. Some of the vasculitis patients showed an increased mRNA expression of Fas in mononuclear cells after treatment, suggesting that Fas production fluctuates with the intensity of the disease. The expression of CD95 on leukocytes was slightly decreased in vasculitis patients compared to healthy controls. No alterations of Fas and FasL expression were seen in renal biopsy specimens. These results show that ANCA-positive vasculitis patients have high sFas levels and that the levels remain elevated even in clinical remission. The findings indicate that perturbations in the Fas/Fas ligand system may play a role in the disease process in ANCA vasculitis.