Immunohistochemical characterization of inflammatory cells and immunologic activation markers in muscle and nerve biopsy specimens from patients with systemic polyarteritis nodosa

Mc, Cid; Grau, Josep M.; Casademont, Jordi; Campo, Elı́as; Coll-Vinent, Blanca; López‐Soto, Alfons; Ingelmo, M; Urbano-Márquez, Á

doi:10.1002/art.1780370711

Cited by 66 publications

(32 citation statements)

References 30 publications

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“…The vascular pathology in chronically T. cruzi-infected mice has some features that resemble human polyarteritis nodosa (PAN) with regard to multiorgan involvement of medium-sized to small arteries (21), fibrinoid necrosis, mixed cellular infiltrates including pathogen-specific CD8 ϩ T cells and macrophages (22), lack of immune complex deposition in lesions, and involvement of muscles, skin, and nerves (23)(24)(25)(26). The most notable and interesting differences between the mouse vasculitis we analyzed and PAN include an absence in the mouse of the eponymous skin vasculitic nodules found in human PAN, a lack of neutrophilic inflammation in the mouse, and the relative prominence of the extreme involvement of skeletal muscle in the mouse, which is associated with muscle weakness and paralysis.…”

Section: Discussionmentioning

confidence: 99%

“…It will also be interesting and important in future work to define (i) whether a persistent low level of parasites is required to maintain vasculitis lesions in the model, (ii) how innate and adaptive immune responses in the lesions are coordinated and regulated, (iii) why the immune response is localized mainly to arteries and arterioles, and (iv) the mechanism of fibrinoid necrosis. In PAN, the latter is thought to be the result of neutrophil degranulation, but specific molecular details are lacking (22). It is interesting to speculate that localization of the inflammation to arterioles may be the result of an incomplete chemoattractant relay from blood to tissue that is, on the one hand, sufficiently large to stage immune cells at vessels in infected tissue but, on the other hand, insufficient to trigger robust migration to infected microdomains.…”

Section: Discussionmentioning

confidence: 99%

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Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

et al. 2016

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dInfectious agents are often considered potential triggers of chronic inflammatory disease, including autoimmunity; however, direct evidence is usually lacking. Here we show that following control of acute infection of mice with the myotropic Colombiana strain of Trypanosoma cruzi, parasites persisted in tissue at low levels associated with development of systemic necrotizing vasculitis. Lesions occurred in many but not all organs and tissues, with skeletal muscle arteries being the most severely affected, and were associated with myositis, atrophy, paresis/paralysis, and death. Histopathology showed fibrinoid vascular necrosis, rare amastigote nests within skeletal muscle myocytes, and massive leukocyte infiltrates composed mainly of inflammatory monocytes, F4/80 ؉ macrophages, and T. cruzi tetramer-specific CD8 ؉ T lymphocytes capable of producing gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) but not interleukin-17 (IL-17). T. cruzi-specific IgG was detected in sera from infected mice, but antibody deposits and neutrophilic inflammation were not features of the lesions. Thus, T. cruzi infection of mice may be a specific infectious trigger of paralyzing systemic necrotizing vasculitis most severely affecting skeletal muscle, driven by pathogen-specific type I immune responses. Vasculitis is a general term for a spectrum of diseases involving leukocyte infiltration of the blood vessel wall. Many subtypes of vasculitis are recognized based on the types of blood vessels involved and the nature of the underlying immunopathology. In some cases, an association of vasculitis with specific infectious agents has been reported; for example, polyarteritis nodosa (PAN) has been associated with hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV infections (1). However, it has been difficult to establish either causality or pathogenetic mechanisms, in part because of the low prevalence of vasculitis and the lack of good animal models (2). In this regard, while studying the chronic phase of C57BL/6J mice infected with the myotropic Colombiana strain of Trypanosoma cruzi, the infectious cause of Chagas' disease in humans, we noticed that the majority of animals developed hind limb paralysis associated with severe systemic necrotizing vasculitis affecting arteries and arterioles in skeletal muscle. Lesions were also present in many other tissues. A review of the literature identified several studies from 1970 to 2000 that described perivascular inflammation and frank arteritis in chronically T. cruzi-infected mouse skeletal muscle, aorta, nerves, and heart (3-9); however, the underlying immunologic mechanisms of disease were not defined. Interestingly, Okumura et al. reported necrotizing arteritis in small arteries beneath the peritoneal lining of the bowel and, occasionally, of the aorta and coronary arteries of T. cruzi-infected mice, which was at that time interpreted as "allergic necrotizing angiitis" (10). Dias et al. reported obliterative changes of the small and medium-sized branches of coronary...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

et al. 2016

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“…25 We have proposed that angiogenesis may play a dual role in vasculitis which, in this regard, is unique among chronic inflammatory disorders. [13][14][15][16][17][18] Neovessels are the main site where endothelial cell adhesion molecules for leukocytes are expressed in medium-sized and large vessel vasculitis such as HUVECs differentiate into capillary-like structures on Matrigel. At low (2%) human serum concentration, tubes are incomplete and not well interconnected (A).…”

Section: Discussionmentioning

confidence: 99%

“…10,12 The role of angiogenesis in vasculitis has begun to be investigated. We have shown that angiogenesis is observed in vascular inflammatory lesions of patients with GCA, [13][14][15] polyarteritis nodosa, 16,17 and cryoglobulinemic vasculitis, 18 and that sera from patients with different types of vasculitis, including Wegener's granulomatosis, Takayasu's disease, and GCA, have angiogenic activity. 19 We have proposed that angiogenesis may have a dual role in vasculitis.…”

mentioning

confidence: 92%

Tissue and Serum Angiogenic Activity Is Associated With Low Prevalence of Ischemic Complications in Patients With Giant-Cell Arteritis

et al. 2002

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Background— Vascular inflammatory lesions from patients with giant-cell arteritis show a remarkable amount of neovascularization, but its clinical implications have never been investigated. Methods and Results— To assess the clinical relevance of neovascularization in giant-cell arteritis, angiogenesis was measured in temporal artery sections from 31 patients with biopsy-proven giant-cell arteritis by staining endothelial cells with Ulex europaeus lectin. Angiogenesis was highly variable among these patients. Patients without ischemic complications had higher tissue angiogenesis scores than patients with ischemic events (5.69±0.6 versus 2.91±0.6, P =0.003). Angiogenesis was also more prominent in patients with a strong acute phase response (score: 5.31±0.6) compared with those with a weak systemic inflammatory reaction (2.30±0.44; P =0.0007). Serum angiogenic activity was studied in an additional series of 38 biopsy-proven patients. Sera from patients without ischemic events tended to be more active in stimulating human umbilical vein endothelial cell growth (optical density ×1000, 270±15 versus 192±14, P =0.065) and differentiation into capillary-like structures (107±5 versus 84±8 relative units, P =0.0058) than patients with ischemic complications. Sera from patients without ischemic events had more in vivo full angiogenic activity tested in the chick chorioallantoic membrane than sera from patients with ischemic complications. Conclusion— Inflammation-induced angiogenic activity may play a compensatory role for ischemia in patients with giant-cell arteritis.

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“…Interleukin-2 receptor-α (IL-2Rα, CD25) is upregulated on macrophages and lymphocytes by cytokines, such as interferon-γ, interleukin-2 and interleukin-3 [19, 20], or by nonspecific stimulation of human monocytes with lipopolysaccharides [21]. Using antibodies against IL-2Rα as an indicator of inflammatory activation [22], we tested the hypothesis that u-PA colocalized more with activated inflammatory cells compared to the whole population of macrophages in atherosclerotic vessels.…”

Section: Introductionmentioning

confidence: 99%

Urokinase Plasminogen Activator Colocalizes with CD25+ Cells in Atherosclerotic Vessels

Falkenberg

Giglio²,

Björnheden³

et al. 1998

J Vasc Res

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Proteolytic activity in vascular tissue is necessary for cellular migration, remodelling of extracellular matrix and the development of atherosclerotic lesions. Inflammatory cells, mainly macrophages, are numerous in atherosclerotic plaques and may synthesize and secrete proteolytic enzymes. The principal activator of plasminogen in tissues is urokinase plasminogen activator (u-PA). To determine if an activated phenotype of inflammatory cells colocalizes with local expression of u-PA in atherosclerotic vessels, vascular biopsies from 15 patients with peripheral atherosclerotic disease were analyzed by immunohistochemistry on consecutive sections. Anti-CD68 antibodies were used as markers for macrophages and were positive in 14/15 specimens. Anti-CD25 (interleukin-2 receptor-α) antibodies were used to identify inflammatory cells with an activated phenotype and were positive in 9/14 CD68+ specimens. The same 9 specimens were positive for u-PA. A positive reaction for u-PA was found only in specimens with CD25+ cells. Specimens with positive reactions for all three antibodies were further analyzed with computer-assisted image analysis. The colocalization with u-PA was higher for CD25 compared to CD68 in all specimens. Mean percentage of the u-PA-positive area in regions positive for cellular markers was 52% (SEM 6%) for CD25 and 19% (SEM 5%) for CD68 (p < 0.01). The results indicated that the activation of macrophages in atherosclerotic vessels may modulate local proteolysis and be of importance in plaque development and stability.

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Immunohistochemical characterization of inflammatory cells and immunologic activation markers in muscle and nerve biopsy specimens from patients with systemic polyarteritis nodosa

Cited by 66 publications

References 30 publications

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

Trypanosoma cruzi Causes Paralyzing Systemic Necrotizing Vasculitis Driven by Pathogen-Specific Type I Immunity in Mice

Tissue and Serum Angiogenic Activity Is Associated With Low Prevalence of Ischemic Complications in Patients With Giant-Cell Arteritis

Urokinase Plasminogen Activator Colocalizes with CD25+ Cells in Atherosclerotic Vessels

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