视盘血管炎——关于混合型的研讨

对６０例（６３眼）视盘血管炎的临床分型进行了探讨，结果表明，除分为Ⅰ、Ⅱ两型外，尚存在混合型，当视盘睫状血管炎性病变波及中央静脉，或两个血管系统同时受炎症侵犯时，即可再现混合型的临床表现，视盘明显水肿，视网膜静脉迂张，散在渗出，出血，动脉狭细。眼底荧光血管造影可见视盘荧光早期充盈明显迟缓，后期渗漏面积〉２．０ＰＤ，视网膜循环时间延长，混合型兼有Ⅰ，Ⅱ两型的临床特征，应作为一个独立类型存在，同时观察     

Nitric Oxide Modulates MCP-1 Expression in Endothelial Cells: Implications for the Pathogenesis of Pulmonary Granulomatous Vasculitis

Monocyte chemoattractant protein-1 (MCP-1) is a pivotal mediator of angiocentric granuloma formation in glucan-induced pulmonary granulomatous vasculitis. Based on the rationale that mononuclear phagocytes retrieved from granulomas are rich sources of nitric oxide (NO) and that the recruitment of mononuclear phagocytes into lesions abates as granuloma formation slows, we tested the hypothesis that MCP-1 gene expression is regulated by a NO-sensitive mechanism. Preexposure of endothelial cell (EC) monolayers to NO donor compounds markedly reduced cytokine-induced MCP-1 expression and cytosolic-to-nuclear translocation of nuclear factor-kappa B (NF-B), reversed fluctuations in endothelial reduced glutathione (GSH) pools but did not affect cGMP concentrations. The lungs of mice bearing targeted disruptions of the inducible nitric oxide synthase (iNOS) gene exhibited significantly higher concentrations of MCP-1 following glucan infusion than did those of wild-type mice. Cumulatively, these data suggest that NO suppresses MCP-1 expression by blunting the redox changes associated with cytokine-induced EC activation.     

A vascular smooth muscle-specific CD4+ T cell line that induces pulmonary vasculitis in MRL-+/+ mice

We established a T cell line, MV1, specific for rat vascular smooth muscle antigen from the regional lymph nodes of immunized MRL/Mp-+/+ mice. Adoptive transfer of MV1 T cells induced vasculitis lesions in the lungs of the syngeneic recipient mice pre-treated with cyclophosphamide. Flow cytometric analysis showed that MV1 was a CD4⁺ T cell line. The T cells proliferated in the presence of the vascular smooth muscle antigen and mitomycin C-treated syngeneic spleen cells. The cross experiments using an ovalbumin-specific T cell line demonstrated that MV1 was specific for vascular smooth muscle antigen. The antigen-specific proliferation of MV1 was CD4-dependent, which was consistent with the flow cytometric analysis. In addition, MV1 T cells, upon activation with anti-CD3 antibody or antigen-specific activation, killed A20.2J mouse B lymphoma cells. MV1 T cells also killed a CD95 (Fas)-transfected T lymphoma line, but not its parental Fas-negative cell line. These findings indicate that MV1 T cells killed target cells via a Fas ligand (FasL)/Fas pathway. The cytotoxicity of MV1 T cells may play an important role in the development of vasculitis in this model. Although the antigenic epitopes of MV1 and the lung specificity of vasculitis remain to be clarified, MV1-induced vasculitis should serve as an experimental model of human pulmonary vasculitis.     

Soluble cell adhesion molecules and von Willebrand factor in children with Kawasaki disease.

Fifty-nine children with acute Kawasaki disease (KD), a childhood vasculitis, were compared with 35 children with fever due to infection and 48 healthy children. Levels of soluble E-selectin (sE-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) in the healthy children were double those found in adults. All three soluble cell adhesion molecules and von Willebrand factor (vWF) were higher in the children with KD than in the healthy children, but only sE-selectin, a marker for activated endothelial cells, and sICAM-1 were higher than in the febrile children. The high levels of vWF in KD appear to reflect the prominent acute-phase reaction. This information can help us to understand further the complex interactions between cytokines, circulating inflammatory cells and the vascular endothelium, and may lead to new therapeutic avenues in KD and other inflammatory diseases and vasculitides.     

Th2 dominance in nasal mucosa in patients with Wegener's granulomatosis

Wegener's granulomatosis initially affects upper respiratory tract organs including the nasal mucosa in more than 90% of patients. The inflammation is typically granulomatous with associated vasculitis. T lymphocytes are usually a prominent component of the leucocyte infiltrate. Previous studies using peripheral blood T cells have implicated IFN-gamma rich Th1-type responses. This study addressed the cytokine milieu in nasal mucosa from 10 patients with active Wegener's granulomatosis using immunohistochemistry. Increased levels of CD3+ T cells and eosinophils were present compared with normal and disease controls. There was increased expression of IL-4, down-regulation of IL-2 and no detectable IFN-gamma. There was increased expression of the chemokine receptor CCR3 by infiltrating cells, consistent with an IL-4 dominant, Th2-biased response. In contrast, renal biopsy tissue from 10 patients with active Wegener's granulomatosis showed expression of IL-2 and IL-4. The Th2-type environment within nasal mucosa, often the initial site of disease activity in Wegener's, is consistent with a local allergic response in these patients.     

Alpha 1-antitrypsin deficiency and anti-proteinase 3 antibodies in anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis.

alpha 1-antitrypsin (alpha 1-AT) is a naturally occurring inhibitor of proteinase 3 (PR3) and elastase, two of the target antigens of anti-neutrophil cytoplasmic antibodies (ANCA). An increased incidence of alpha 1-AT phenotypes associated with dysfunctional alpha 1-AT or low serum levels has been reported in patients with anti-PR3 antibodies. We have studied the relationship between ANCA, and phenotypes and serum levels of alpha 1-AT. Phenotypes usually associated with a moderate or severe reduction in alpha 1-AT serum levels or in dysfunctional activity were found more often in individuals with anti-PR3 antibodies than in the general population: four of the 31 patients (13%) with anti-PR3 antibodies had phenotypes MZ (n = 2), S (n = 1) or Z (n = 1) (P < 0.05). However, the corresponding alpha 1-AT serum levels were normal (n = 3) or elevated (n = 1). None of the 31 sera with anti-PR3 antibodies had low levels of alpha 1-AT. No abnormal alpha 1-AT phenotype was demonstrated in seven patients with anti-elastase antibodies, despite a low level of alpha 1-AT in one serum. Anti-myeloperoxidase antibodies are common in patients with ANCA, but no abnormal phenotype or low serum alpha 1-AT level was demonstrated in any of 29 sera containing these antibodies. Finally anti-glomerular basement membrane (GBM) antibodies occur occasionally in patients with ANCA-associated diseases, but again none of 10 sera had an abnormal alpha 1-AT phenotype or low serum level. ANCA were not demonstrated by indirect immunofluorescence in any serum from 73 patients with abnormal alpha 1-AT phenotypes. These results confirm that patients with anti-PR3 antibodies often have alpha 1-AT phenotypes that are usually associated with low serum levels of alpha 1-AT or with dysfunctional protein. Nevertheless, the incidence of anti-PR3 antibodies in patients with abnormal alpha 1-AT phenotypes is very low. This probably reflects the rarity of Wegener's granulomatosis, the major disease associated with anti-PR3 antibodies, and the relative frequency of abnormal alpha 1-AT phenotypes. The mechanism for the development of anti-PR3 antibodies in patients with abnormal alpha 1-AT phenotypes is not clear, but may relate to the increased propensity of unbound and uninhibited PR3 to stimulate autoantibody production.     

Lack of association between the Met196Arg polymorphism in the TNFR2 gene and autoimmune diseases accompanied by vasculitis including SLE in Japanese

A polymorphism in high-affinity receptor of TNF (TNFR2) gene, Met196Arg, was reported to be associated with systemic lupus erythematosus (SLE) in Japanese, whereas the association could not be found in Europeans at all and this represents an apparent discrepancy. The association, then, should be tested in other populations to clarify the possible involvement, if any, of the TNFR2 polymorphism in SLE or other related autoimmune diseases. The purposes of this study were to examine the TNFR2 polymorphism in Japanese patients with SLE and to investigate its association with other autoimmune diseases accompanied by vasculitis, mixed connective tissue disease, Buerger's disease, and Takayasu's arteritis. We found no association at all between the TNFR2 polymorphism and any autoimmune diseases including SLE in Japanese.     

Induction of biologically active antineutrophil cytoplasmic antibodies by immunization with human apoptotic polymorphonuclear leukocytes

Translocation of intracellular components to the cell surface during the priming or apoptosis of polymorphonuclear leukocytes (PMN) is an important mechanism for interaction of antineutrophil cytoplasmic antibodies (ANCA) with these antigens. To test the capacity of apoptotic PMN to trigger production of ANCA, six groups of mice were immunized with either live or apoptotic lymphocytes, or with live, apoptotic, formalin-fixed, or lysed PMN. Mice immunized with both live and apoptotic neutrophils developed high titers of antibodies which gave a granular cytoplasmic immunofluorescent pattern. These antibodies were specific for lactoferrin and myeloperoxidase. Following a second intravenous infusion of apoptotic PMNs, mice developed anti-PR3 antibodies. Vasculitis lesions were not found in mice which developed ANCA. The ANCA-containing IgG fraction induced superoxide production by human PMNs. These results support the hypothesis that neutrophil-specific antigens presented on the cell membranes of apoptotic PMN may induce ANCA in the proper conditions.     

Neutrophil and endothelial cell activation in the vasa vasorum in vasculo-Behçet disease

AIM: The aim of this study was to analyse the immunopathological mechanisms of vasculo-Beh?et disease, which were also compared to cases of Takayasu's arteritis and inflammatory aneurysm to evaluate differences in inflammatory mechanisms. METHOD AND RESULTS: We reviewed six cases of vasculo-Beh?et disease, four of Takayasu's arteritis and seven inflammatory aneurysms which underwent surgical repair. Immunohistochemical studies were performed on paraffin-embedded tissue using a labelled streptavidin-biotin method, as was in-situ hybridization for Epstein-Barr virus. Microscopically, neutrophils and lymphocytes accumulated around the vasa vasorum. Neutrophils were prominent as compared to Takayasu's arteritis and inflammatory aneurysm. Elastic fibres were not severely destroyed. Endothelial cells (ECs) of most vasa vasorum expressed HLA-DR. The number of vasa vasorum around which inflammatory infiltrating cells were observed in vasculo-Beh?et disease was significantly greater than in inflammatory aneurysms and Takayasu's arteritis (P < 0.001). The cytokines IL-1alpha, TNF-beta and IFN-gamma were expressed in neutrophils and lymphocytes which were distributed around vasa vasorum, as well as neutrophils adherent to HLA-DR positive ECs. CONCLUSION: Our results suggest that vasculo-Beh?et disease should be classified as a neutrophilic vasculitis targeting the vasa vasorum. Aneurysm formation may be related to degeneration of arterial wall caused by inflammation of the vasa vasorum.     

Genetic dissection of the complex pathological manifestations of collagen disease in MRL/lpr mice

An MRL strain of mice bearing a Fas-deletion mutant gene, lpr, MRL/MpJ-lpr/lpr (MRL/lpr) develops collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjögren’s syndrome, respectively. Development of such lesions seems dependent on host genetic background since the congenic C3H/HeJ-lpr/lpr (C3H/lpr) mice rarely develop them. To identify the gene loci affecting each lesion, a genetic dissection of these complex pathological manifestations was carried out. First, histopathological features in MRL/lpr, C3H/lpr, (MRL/lpr × C3H/lpr) F1 intercross, and MRL/lpr × (MRL/lpr × C3H/lpr) F1 backcross mice were analyzed. Genomic DNA of the backcross mice were subjected to association studies by Chi-squared analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. As a result, gene loci recessively associated with each lesion were mapped on different chromosomal positions. We concluded that each of these lesions in MRL/lpr mice is under the control of a different set of genes, suggesting that the complex pathological manifestations of collagen disease result from polygenic inheritance.