A new model for Hendra virus encephalitis in the mouse

Hendra virus (HeV) infection in humans is characterized by an influenza like illness, which may progress to pneumonia or encephalitis and lead to death. The pathogenesis of HeV infection is poorly understood, and the lack of a mouse model has limited the opportunities for pathogenetic research. In this project we reassessed the role of mice as an animal model for HeV infection and found that mice are susceptible to HeV infection after intranasal exposure, with aged mice reliably developing encephalitic disease. We propose an anterograde route of neuroinvasion to the brain, possibly along olfactory nerves. This is supported by evidence for the development of encephalitis in the absence of viremia and the sequential distribution of viral antigen along pathways of olfaction in the brain of intranasally challenged animals. In our studies mice developed transient lower respiratory tract infection without progressing to viremia and systemic vasculitis that is common to other animal models. These studies report a new animal model of HeV encephalitis that will allow more detailed studies of the neuropathogenesis of HeV infection, particularly the mode of viral spread and possible sequestration within the central nervous system; investigation of mechanisms that moderate the development of viremia and systemic disease; and inform the development of improved treatment options for human patients.     

Role of neutrophils in systemic autoimmune diseases

Neutrophils have emerged as important regulators of innate and adaptive immune responses. Recent evidence indicates that neutrophils display marked abnormalities in phenotype and function in various systemic autoimmune diseases, and may play a central role in initiation and perpetuation of aberrant immune responses and organ damage in these conditions. This review discusses the putative roles that neutrophils and aberrant neutrophil cell death play in the pathogenesis of various systemic autoimmune diseases, including systemic lupus erythematosus, small vessel vasculitis and rheumatoid arthritis.     

Antineutrophil cytoplasmic autoantibody in renal disease

ANCA are an important marker for identifying pauci-immune necrotizing and crescentic glomerulonephritis and systemic vasculitis. Patients with ANCA-associated renal disease have a spectrum of illness ranging from renal-limited disease to widespread vasculitis, including the clinicopathologic syndromes of polyarteritis nodosa and Wegener's granulomatosis. ANCA may be directly involved in the pathogenesis of pauci-immune glomerulonephritis and necrotizing systemic vasculitis.     

Expression Profiling of PBMC-based Diagnostic Gene Markers Isolated from Vasculitis Patients

Vasculitis (angiitis) is a systemic autoimmune disease that often causes fatal symptoms. We aimed to isolate cDNA markers that would be useful for diagnosing not only vasculitis but also other autoimmune diseases. For this purpose, we used stepwise subtractive hybridization and cDNA microarray analyses to comprehensively isolate the genes whose expressions are augmented in peripheral blood mononuclear cells (PBMCs) pooled from vasculitis patients. Subsequently, we used quantitative real-time polymerase chain reaction (qRT–PCR) to examine the mRNA levels of each candidate gene in individual patients. These analyses indicated that seven genes exhibit remarkably augmented expression in many vasculitis patients. Of these genes, we analyzed G0/G1 switch gene 2 (G0S2) further because G0S2 expression is also enhanced in the PBMCs of patients with systemic lupus erythematodes (SLE). We generated G0S2 transgenic mice that ubiquitously overexpress human G0S2. Although we did not observe any obvious vasculitis-related histopathologic findings in these mice, these mice are unhealthy as they produce only few offspring and showed elevated serum levels of two autoimmunity-related antibodies, anti-nuclear antibody, and anti-double strand DNA antibody. Thus, our large-scale gene profiling study may help finding sensitive and specific DNA markers for diagnosing autoimmune diseases including vasculitis and SLE.Key words: vasculitis, angiitis, G0S2, EGR1, amphiregulin, hemoglobin delta     

Potential roles of NLRP3 inflammasome in the pathogenesis of Kawasaki disease

There is a heterogeneous group of rare illnesses that fall into the vasculitis category and are characterized mostly by blood vessel inflammation. Ischemia and disrupted blood flow will cause harm to the organs whose blood arteries become inflamed. Kawasaki disease (KD) is the most prevalent kind of vasculitis in children aged 5 years or younger. Because KD's cardiovascular problems might persist into adulthood, it is no longer thought of as a self-limiting disease. KD is a systemic vasculitis with unknown initiating factors. Numerous factors, such as genetic predisposition and infectious pathogens, are implicated in the etiology of KD. As endothelial cell damage and inflammation can lead to coronary endothelial dysfunction in KD, some studies hypothesized the crucial role of pyroptosis in the pathogenesis of KD. Additionally, pyroptosis-related proteins like caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC), proinflammatory cytokines like IL-1 and IL-18, lactic dehydrogenase, and Gasdermin D (GSDMD) have been found to be overexpressed in KD patients when compared to healthy controls. These occurrences may point to an involvement of inflammasomes and pyroptotic cell death in the etiology of KD and suggest potential treatment targets. Based on these shreds of evidence, in this review, we aim to focus on one of the well-defined inflammasomes, NLRP3, and its role in the pathophysiology of KD.     

What you should know about PR3-ANCA: Evidence for the role of T cells in the pathogenesis of systemic vasculitis

The pathogenesis of systemic vasculitis is complex and is likely to involve many mechanisms. There is a growing body of evidence that T cells may contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Predominantly, T cells and monocytes are found in inflammatory infiltrates in patients with Wegener's granulomatosis (WG). The production of ANCA appears to be T-cell-dependent. T lymphocytes from the peripheral blood of patients with ANCA-associated vasculitis have been shown to proliferate in response to proteinase 3 (PR3). These and other findings outlined in this review indicate T-cell involvement, although further studies are still needed to elucidate the exact contribution of T cells to the pathogenesis of systemic vasculitis.     

What you should know about PR3-ANCA. Evidence for the role of T cells in the pathogenesis of systemic vasculitis

The pathogenesis of systemic vasculitis is complex and is likely to involve many mechanisms. There is a growing body of evidence that T cells may contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Predominantly, T cells and monocytes are found in inflammatory infiltrates in patients with Wegener's granulomatosis (WG). The production of ANCA appears to be T-cell-dependent. T lymphocytes from the peripheral blood of patients with ANCA-associated vasculitis have been shown to proliferate in response to proteinase 3 (PR3). These and other findings outlined in this review indicate T-cell involvement, although further studies are still needed to elucidate the exact contribution of T cells to the pathogenesis of systemic vasculitis.     

Allergic Complications of Meningococcal Disease I—Clinical Aspects

Out of 717 patients with meningococcal disease 53 showed one or more of the three allergic complications: 47 (6·6%) developed arthritis, 12 (1·7%) developed cutaneous vasculitis, and 6 developed episcleritis. These complications, which were often multiple, occurred six to nine days after the beginning of the illness and three to six days after the start of successful antibiotic therapy. Those patients with severe systemic disease were prone to the complications.Histological and bacteriological study of the arthritis and vasculitis showed that these lesions were probably not due to persisting infection and suggested that they might be due to immune complex disease.     

Correlations between plasma levels of a fibronectin isoform subpopulation and C-reactive protein in patients with systemic inflammatory disease

Surrogate markers to detect vasculitic processes prior to organ compromise are lacking. To determine if specific populations among the fibronectin (FN) family of alternatively spliced proteins correlate with parameters of vasculitis in at-risk patients, we retrospectively evaluated the association of plasma levels of total FN (TFN) and FN bearing the alternatively spliced EIIIA segment (A⁺FN) with clinical vasculitis status and with levels of two putative vasculitis markers (C-reactive protein (CRP) and von Willebrand factor) in a previously studied cohort of 27 patients with systemic inflammatory disease. We found that the percentage of TFN composed by A⁺FN (%A⁺) and A⁺FN, but not TFN, correlated with plasma levels of CRP, the prototypic inflammation biomarker used to detect vasculitis. These findings suggest that different FNs may confer distinct clinical information, and that their simultaneous measurement merits further investigation in our efforts to identify soluble biomarker systems to detect vasculitis.     

Retinal vasculitis: a diagnostic dilemma

Inflammation of the retinal vasculature, retinal vasculitis, is a poorly understood category of ocular pathology. Patients may or may not be symptomatic. Retinal vasculitis, classified as arteritis or phlebitis, can present as a sole clinical feature or can be accompanied by an anterior uveitis, vitritis, retinal hemorrhages and/or retinal ischemia, thereby making diagnosis difficult. There is evidence that most causes of vasculitis involve an autoimmune response to specific antigens. This disorder may occur in association with infectious disease, systemic inflammatory disorders, primary ocular conditions or as an idiopathic syndrome. Differential diagnosis includes eliminating these etiologies as well as non-inflammatory disorders which can mimic true retinal vasculitis. Proper identification along with timely treatment is crucial in the management of this potentially visually devastating entity. This article provides a current, general guide to the etiology and differential diagnosis of retinal vasculitis. The clinical presentation will be illustrated through four case presentations. The practitioner will also be provided with a tailored approach to management.     

Trafficking of QD-conjugated MPO-ANCA in murine systemic vasculitis and glomerulonephritis model mice

In systemic vasculitis, the serum level of myeloperoxidase (MPO)-specific anti-neutrophil cytoplasmic autoantibodies (MPO-ANCA) is significantly elevated with the progression of disease. We have established a model of murine systemic vasculitis by administration of MPO-ANCA and fungal mannoprotein to C57BL/6 mice. We examined the role of MPO and MPO-ANCA in the pathogenesis of glomerulonephritis and systemic vasculitis in this model using quantum dots (QDs). We demonstrated that QD-conjugated MPO-ANCA (ANCA-QD) visualized the translocation of MPO on the neutrophil membrane surface after stimulation with proinflammatory cytokines. We also observed that MPO translocation on neutrophils in both patients with rapid progressive glomerulonephritis and these model mice without any stimulation, suggesting that MPO translocation is certain to contribute to the development of glomerular lesion. In addition, blood flow on the kidney surface vessel was significantly decelerated in both SCG/Kj mice and this model, suggesting that ANCA induces the damage of blood vessel. These results indicate that MPO-ANCA and surface-translocated MPO on the activated neutrophils coordinately plays essential roles in the initial steps of the glomerulonephritis.     

Subclinical brain injury caused by H5N1 influenza virus infection

Although H5N1 influenza A viruses can cause systemic infection, their neurotropism and long-term effects on the central nervous system (CNS) are not fully understood. We assessed H5N1viral invasion of the CNS and its long-term effects in a ferret model. An H5N1 virus caused nonsuppurative encephalitis, which lasted for 3 months without neurologic signs. Further, another H5N1 virus caused nonsuppurative vasculitis with brain hemorrhage. Three-dimensional analysis of viral distribution in the brain identified the olfactory system as a major route for brain invasion. The efficient growth of virus in the upper respiratory tract may thus facilitate viral brain invasion.     

Protective effects of Helicobacter pylori against gastroesophageal reflux disease may be due to a neuroimmunological anti-inflammatory mechanism

There is some evidence that Helicobacter pylori infection has a protective effect against gastroesophageal reflux disease (GORD) and its complications such as Barrett's oesophagus and oesophageal adenocarcinoma. In this paper, we propose that a neuroimmunological mechanism is responsible for the protective effect of H. pylori on GORD. H. pylori infection of the gastric mucosa induces a T helper1-like immune response and production of pro-inflammatory cytokines. These cytokines can inhibit local sympathetic tone, whereas they increase systemic sympathetic tone. Increased sympathetic tone can induce an anti-inflammatory milieu, which in turn can inhibit inflammation in the oesophagus and lower oesophageal sphincter (LOS). Furthermore, H. pylori infection may stimulate the cholinergic anti-inflammatory pathway. It has been suggested that reflux-induced oesophageal inflammation plays an important role in the pathogenesis of reflux oesophagitis. Reduction of oesophageal inflammation by increased systemic sympathetic tone and vagal activity may lead to a decrease in reflux-induced oesophageal injury and LOS dysfunction in GORD.     

Parvovirus B19 and immune disorders

Parvovirus B19 (PVB19) is the causative agent of erythema infectiosum and sometimes the infection is correlated with severe haematological complications, or in pregnancy to fetalis hydrops. Moreover some authors suggest an infection involvement in some autoimmune diseases. To this purpose we evaluated seroprevalence for PVB19 in following the autoimmune or dysreactive pathologies: systemic lupus erythematosus (SLE), cryoglobulinemia, idiopathic systemic--ANCA associated vasculitis, rheumatoid arthritis (RA). In the case of LES, 31/42 patients were positive for PVB19 versus 21/42 of blood donors, as controls subjects (73.8% vs. 50%; significant difference for p < 0.05), moreover a significant difference for p < 0.001 was detected comparing mean titre values of IgGs against PVB19 of two groups (UI 1.94 +/- 0.90 vs. 1.24 +/- 0.80). In contrast no significant differences were found in the case of percent seropositivity of cryoglobulinemic subjects (37/57 = 64.9%, the majority of whom were HCV+) in comparison with the control group (50%). However mean units index (UI) was 1.63 +/- 0.81; p = 0.019 versus the control group. Similar result, with regard to the percentage of seropositivity, was found for vasculitis (9/17 = 52.9%). The data reported here can confirm a possible correlation between PVB19 prior infection and LES and also suggest possible implications in the case of cryoglobulinemia. In fact, most of our patients were affected by a nephropathic or systemic form of HCV+ cryoglobulinemia and the presence of other infective cofactors could be suggestive in the evolution of this clinical situation.     

Analysis of risk epitopes of anti-neutrophil antibody MPO-ANCA in vasculitis in Japanese population

Autoantibodies to myeloperoxidase (MPO) are a subset of anti-neutrophil cytoplasmic antibody (ANCA, MPO-ANCA) detected in the sera of some patients with primary systemic vasculitis. The titer of MPO-ANCA does not always reflect disease activity and this inconsistency may be attributable to differences in epitopic specificity by MPO-ANCA among various patients with vasculitis. Epitope analysis may also explain the occurrence of MPO-ANCA in different vasculitic syndromes. We screened the sera of 148 MPO-ANCA positive patients from six vasculitic syndromes: rapidly progressive gromerulonephritis (RPGN), microscopic polyangiitis (MPA), idiopathic crescentic glomerulonephritis (I-CrGN), classic polyangiitis nodosa (cPAN), Churg-Strauss syndrome (CSS), Kawasaki disease (KD); and from patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The sera were collected by the Intractable Vasculitis Research Project Group in Japan. No serum showed epitopes La and Lb of light chain of MPO, and sera with 68.6% of patients showed a positive reaction to one or more epitopes in heavy chain of MPO. Analysis of binding level showed that RPGN, I-CrGN and MPA sera mainly reacted to the Ha epitope at the N-termimus of the MPO heavy chain, CSS sera reacted to Ha and the Hf epitope close to the C-terminus of the MPO heavy chain, KD reacted mainly to Hf, while SLE and RA sera reacted to all epitopes. These results suggest that MPO-ANCA recognizing specific regions of the N-terminus of the MPO H-chain confer an increased risk of vasculitis RPGN, I-CrGN, MPA and CSS. Furthermore, the epitopic specificity of MPO-ANCA differentiates vasculitic from non-vasculitic syndromes associated with MPO-ANCA positivity and differentiates in the cirtain type of vasculitis from various vasculitic syndromes. In particular, vasculitic syndromes associated with kidney involvement had similar epitopic reactivity which suggests that this pattern confers an increased risk of vasculitis.     

Innate versus adaptive immunity in Candida albicans infection

Candida albicans is a common opportunistic pathogen, causing both superficial and systemic infection. Clinical observations indicate that mucocutaneous infections are commonly associated with defective cell-mediated immune responses, whereas systemic infection is more frequently seen in patients with deficiencies in neutrophil number or function. Analysis of mechanisms of host resistance against gastrointestinal and oral infection in mouse models has demonstrated an absolute dependence on CD4(+) T cells, although clearance also involves phagocytic cells. Both IL-12 and TNF-alpha appear to be important mediators, but mouse strain-dependent variations in susceptibility to infection may be related to T-cell enhancement of production of phagocytic cells by the bone marrow. In murine systemic infection, the role of innate and adaptive responses is less well defined. Studies in immunodeficient and T-cell-depleted mice suggest that clearance of the yeast may be predominantly a function of the innate response, whereas the adaptive response may either limit tissue damage or have the potential to cause immunopathology, depending on the host genetic context in which the infection takes place.     

Autoantibodies to peroxiredoxin I and IV in patients with systemic autoimmune diseases

Anti‐oxidative enzymes protect living bodies from various oxidative stresses. In the systemic autoimmune diseases, autoantibodies to oxidized molecules and to anti‐oxidative enzymes have been reported. To promote understanding of the relationships between autoimmunity and oxidative stress, we here investigate whether autoimmunity to the anti‐oxidative peroxiredoxin (Prxs) enzymes exists in patients with systemic autoimmune diseases. Specifically, we detected autoantibodies to recombinant Prx I and Prx IV respectively by ELISA and western blotting. Next, clinical parameters were compared between the anti‐Prx I or IV‐positive and ‐negative patients. We found that 33% of the 92 patients with autoimmune diseases tested possessed autoantibodies to Prx I (57% in systemic lupus erythematosus (SLE), 19% in rheumatoid arthritis (RA), 5% in Behçet disease, and 46% in primary vasculitis syndrome). In contrast, autoantibodies to Prx IV were detected in only 17% of the same patients. No significant correlation was found between occurrence of the two autoantibodies. Clinically, possession of anti‐Prx I autoantibodies correlated with lower serum levels of CH50, C3, and C4. Taken together, our data demonstrate the existence of autoantibodies to Prxs for the first time. The autoantibodies to Prx I may be involved in the pathophysiology of systemic autoimmune diseases such as SLE and vasculitis.     

Staphylococcus aureus and Wegener's granulomatosis

Wegener's granulomatosis (WG) is a form of systemic vasculitis. It is characterized by granulomatous inflammation in the upper and lower airways, vasculitis and necrotizing glomerulonephritis, and is strongly associated with antineutrophil cytoplasmic antibodies against proteinase 3. Since the etiology of the disease is not clear, treatment, consisting of corticosteroids and immunosuppressives, is nonspecific and associated with severe side effects. Pinpointing the trigger(s) of the disease would highly improve treatment. Clinical evidence shows that an infectious agent, the bacterium Staphylococcus aureus, is a risk factor for disease relapse, suggesting its involvement in the pathogenesis of WG. Here we review both clinical and experimental data that either indicate or support a role for S. aureus in WG.     

Experimental adenovirus hemorrhagic disease in white-tailed deer fawns

Infection with a newly described endotheliotropic adenovirus was the cause of a 1993 epizootic reminiscent of hemorrhagic disease in California mule deer (Odocoileus hemionus columbianus and O. hemionus hemionus). Pulmonary edema and intestinal luminal hemorrhage, or necrotizing stomatitis associated with systemic or localized vasculitis, respectively, were common lesions seen in animals that died during the epizootic. In order to determine if white-tailed deer (Odocoileus virginianus) also are susceptible to infection and fatal disease with the deer adenovirus, eight white-tailed deer fawns (4- to 6-mo-old) were inoculated with purified deer adenovirus. Four were inoculated intravenously and four were inoculated through the mucous membranes. Seven days post-inoculation, one of the fawns inoculated intravenously died. Pulmonary edema and hemorrhagic enteropathy were associated with pulmonary and intestinal vasculitis with systemic multiorgan distribution of endotheliotropic adenovirus as demonstrated by transmission electron microscopy and immunohistochemistry. Adenovirus was reisolated from lung homogenates of the fawn that died of adenovirus hemorrhagic disease.