Proteinase 3 and dihydrolipoamide dehydrogenase (E3) are major autoantigens in hepatitis C virus (HCV) infection

Zhang, Zhaoying; Hsu, Tze-Fu; Chen, T.-Y.; Liu, T.-C.; Liu, G.-Y.; Lee, Y.-J.; Tsay, Gregory J.

doi:10.1046/j.1365-2249.2002.01827.x

Cited by 56 publications

(37 citation statements)

References 24 publications

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“…One study found two P-/MPO-ANCA-positive individuals among 22 individuals who were infected with hepatitis B virus (157). Similar reports have emerged regarding the presence of ANCA in patients with hepatitis C infection (158,159), including one study that found ANCA in as many as 56% of patients with a predominant anti-PR3 specificity (158). Although the high prevalence of ANCA in the setting of hepatitis is intriguing, evidence for a causal association between these viruses and ANCA-associated vasculitis remains poor.…”

Section: Viral Infectionsmentioning

confidence: 76%

Hypotheses on the Etiology of Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Wijngaarden¹,

Rijn²,

Hagen³

et al. 2008

Clinical Journal of the American Society of Nephrology

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The first description of what is now known as antineutrophil cytoplasmic autoantibody-associated necrotizing vasculitis appeared more than 140 yr ago. Since then, many aspects of the pathogenic pathway have been elucidated, indicating the involvement of antineutrophil cytoplasmic autoantibodies, but why antineutrophil cytoplasmic autoantibodies are produced in the first place remains unknown. Over the years, many hypotheses have emerged addressing the etiology of antineutrophil cytoplasmic antibody production, but no exclusive factor or set of factors can so far be held responsible. Herein is reviewed the most influential hypotheses regarding the causes of antineutrophil cytoplasmic antibody-associated vasculitis with the aim of placing in an epidemiologic background the different hypotheses that are centered on environmental and genetic influences.Clin J Am Soc Nephrol 3: 237-252, 2008237-252, . doi: 10.2215 A ntineutrophil cytoplasmic autoantibody (ANCA)-associated necrotizing vasculitis was probably first described in 1866 by Kussmaul and Maier (1) as "polyarteritis nodosa." It was not until the early 1930s when the first case of what was later named Wegener's granulomatosis (WG) was described (2). The disease was named after Friedrich Wegener, who described it as an entity in 1939 (3). In 1985, antibodies associated with the disease were detected and later became known as ANCA (4). WG is a systemic autoimmune disease that can cause damage in various organs. Later, microscopic polyangiitis (MPA) was distinguished as a separate ANCA-associated vasculitis. The disease-or its immunosuppressive treatment-can cause high levels of morbidity and death, especially in patients with renal involvement. Animal experiments have shown that ANCA directed against myeloperoxidase (MPO) can cause vasculitis that resembles human vasculitic disease (5,6); however, the cause of ANCA production remains unresolved.Theories have been developed to explain how ANCA could interact with neutrophils, along with monocytes and most probably T lymphocytes, to form the lesions that are characteristic of ANCA-associated vasculitis, such as fibrinoid necrosis and granulomas (7). A recent theory of interest has been postulated by Pendergraft et al. (8), stating that an antibody against the complementary peptide of proteinase-3 (PR3) in an idiotypic/anti-idiotypic network is essential to the development of ANCA and to the development of clinical vasculitis, but why and how these ANCA are produced in the first place remains unanswered. Nonetheless, many hypotheses have been developed about the initiating factor for ANCA production. Many factors, either directly or indirectly, have been considered important in the development of ANCA: Silica exposure (9); genetic predisposition (10); bacterial infection by Staphylococcus aureus (11); viral infection by, for instance, parvovirus B19 (12); and thyroid drugs (13) all have been correlated with and held to contribute to the incidence of ANCA-associated vasculitis. Some of these hypotheses are still th...

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Section: Viral Infectionsmentioning

confidence: 76%

Hypotheses on the Etiology of Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Wijngaarden¹,

Rijn²,

Hagen³

et al. 2008

Clinical Journal of the American Society of Nephrology

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“…In the present study, ANCA was present in 18 of the 136 patients (13.2%), with higher prevalence in cryoglobulin-positive than cryoglobulinnegative patients (25.5% vs 5.9%, OR 5.4, 95% CI 1.9-16.4). HCV patients with ANCA had a higher prevalence of skin involvement, anemia, abnormal liver function tests and elevated alpha feto-protein levels [75] . Anticardiolipin antibodies have been observed in 3.3% to 22% of HCV patients [77][78][79] .…”

Section: Discussionmentioning

confidence: 96%

“…Recent data suggests that the HCV core particles concentrated in the cryoprecipitate play a role in the interaction between the cryoglobulins, endothelial cells and neutrophil granulocytes [74] . The main antigens in HCV patients with a positive ANCA test are proteinase 3 and dihydrolipoamine dehydrogenase [75] . A positive ANCA has been found in 10% patients with HCV-associated mixed cryoglobulinemia [76] .…”

Section: Discussionmentioning

confidence: 99%

Chronic hepatitis C virus infection: Prevalence of extrahepatic manifestations and association with cryoglobulinemia in Bulgarian patients

Stefanova-Petrova¹,

Tzvetanska²,

Naumova³

et al. 2007

WJG

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AIM: To a s s e s s t h e p r e va l e n c e o f e x t ra h e p a t i c manifestations in Bulgarian patients with chronic hepatitis C virus (HCV) infection and identify the clinical and biological manifestations associated with cryoglobulinemia. METHODS:The medical records of 136 chronically infected HCV patients were reviewed to assess the prevalence of extrahepatic manifestations. Association between cryoglobulin-positivity and other manifestations were identified using χ 2 and Fisher's exact test. Risk factors for the presence of extrahepatic manifestations were assessed by logistic regression analysis. RESULTS:Seventy six percent (104/136) of the patients had at least one extrahepatic manifestation. Clinical manifestations included fatigue (59.6%), kidney impairment (25.0%), type 2 diabetes (22.8%), paresthesia (19.9%), arthralgia (18.4%), palpable purpura (17.6%), lymphadenopathy (16.2%), pulmonary fibrosis (15.4%), thyroid dysfunction (14.7%), Raynaud's phenomenon (11.8%), B-cell lymphoma (8.8%), sicca syndrome (6.6%), and lichen planus (5.9%). The biological manifestations included cryoglobulin production (37.5%), thrombocytopenia (31.6%), and autoantibodies: anti-nuclear (18.4%), anti-smooth muscle (16.9%), anti-neutrophil cytoplasm (13.2%) and anti-cardiolipin (8.8%). All extrahepatic manifestations showed an association with cryoglobulin-positivity, with the exception of thyroid dysfunction, sicca syndrome, and lichen planus. Risks factors for the presence of extrahepatic manifestations (univariate analysis) were: age ≥ 60 years, female gender, virus transmission by blood transfusions, longstanding infection (≥ 20 years), and extensive liver fibrosis. The most significant risks factors (multivariate analysis) were longstanding infection and extensive liver fibrosis. CONCLUSION:We observed a high prevalence of extrahepatic manifestations in patients with chronic HCV infection. Most of these manifestations were associated with impaired lymphoproliferation and cryoglobulin production. Longstanding infection and extensive liver fibrosis were significant risk factors for the presence of extrahepatic manifestations in HCV patients.

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“…Although PR3-ANCAs may occasionally occur in other inflammatory conditions including certain infections, [11][12][13][14] they are highly specific for WG. 15 Many in vitro experiments suggest a pathogenic role of PR3-specific autoantibodies; nevertheless, their in vivo relevance has been disputed since their discovery.…”

Section: Introductionmentioning

confidence: 99%

“…PR3-ANCAs have been reported to occur transiently in a variety of infections, but the development of systemic vasculitis in these patients remains an exception. [11][12][13] Cocaine abusers may also develop ANCAs, some of which react with PR3. 36 Although systemic vasculitis or glomerulonephritis was not observed in these patients, the clinical features prompting them to seek medical attention were their dramatic localized inflammatory tissue destruction.…”

mentioning

confidence: 99%

Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo

Pfister

Ollert

Fröhlich

et al. 2004

Blood

219

137

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Antineutrophil cytoplasmic autoantibodies (ANCAs) recognizing human proteinase 3 of neutrophil granules are a diagnostic hallmark of Wegener granulomatosis, an autoimmune systemic vasculitis with predilection for the respiratory tract and kidneys. In vitro experiments have implicated several mechanisms by which ANCAs may lead to tissue injury. However, little is known about the pathogenic significance of proteinase 3-specific antibodies in vivo. In vivo models for ANCAmediated proinflammatory effects have not been forthcoming, primarily because ANCA epitopes on human proteinase 3 are not shared by the murine homolog. In this study we generated ANCAs against recombinant murine proteinase 3 in proteinase 3/neutrophil elastase-deficient mice that recognized the murine antigen on the surface of neutrophils. Local inflammation induced by intradermal injection of tumor necrosis factor ␣ triggered a stronger subcutaneous panniculitis in the presence of passively transferred systemic proteinase 3-ANCAs than in the presence of mock immune serum. When we transferred mouse proteinase 3-ANCA serum to systemically lipopolysaccharideprimed wild-type mice, mice treated with proteinase 3-ANCAs did not develop significantly stronger signs of inflammation of the lungs or kidneys than the respective mock immune serum-treated animals. In conclusion, our in vivo study provides the first evidence for a pathogenic effect of proteinase 3-specific ANCAs at local sites of inflammation. IntroductionCirculating antineutrophil cytoplasmic autoantibodies (ANCAs), producing a granular cytoplasmic staining pattern on fixed neutrophils by binding to human proteinase 3 (PR3) of cytoplasmic granules, are well-accepted diagnostic markers for the idiopathic autoimmune vasculitis Wegener granulomatosis (WG). [1][2][3][4] In most patients levels of PR3-ANCAs correlate with activity and severity of the disease and decrease as the disease improves. [5][6][7] Persistently high titers or significant titer rises of PR3-ANCAs have repeatedly been reported to be positive predictors of clinical relapses. [8][9][10] Although increases in PR3-ANCAs are not necessarily followed by a clinical relapse, relapses have been rarely observed in the absence of PR3-ANCAs.Although PR3-ANCAs may occasionally occur in other inflammatory conditions including certain infections, 11-14 they are highly specific for WG. 15 Many in vitro experiments suggest a pathogenic role of PR3-specific autoantibodies; nevertheless, their in vivo relevance has been disputed since their discovery. 2,16 The prevailing view of PR3-ANCA pathogenicity at present is experimentally supported by a number of in vitro studies demonstrating a proinflammatory effect of PR3-ANCAs on neutrophils, monocytes, and endothelial cells. The interaction of human ANCAs with tumor necrosis factor ␣ (TNF-␣)-primed neutrophils and monocytes results in their strong activation in vitro. 17,18 ANCA-opsonized apoptotic neutrophils enhance the phagocytotic activity of macrophages and production of proinflammatory cytokin...

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Proteinase 3 and dihydrolipoamide dehydrogenase (E3) are major autoantigens in hepatitis C virus (HCV) infection

Cited by 56 publications

References 24 publications

Hypotheses on the Etiology of Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Hypotheses on the Etiology of Antineutrophil Cytoplasmic Autoantibody–Associated Vasculitis

Chronic hepatitis C virus infection: Prevalence of extrahepatic manifestations and association with cryoglobulinemia in Bulgarian patients

Antineutrophil cytoplasmic autoantibodies against the murine homolog of proteinase 3 (Wegener autoantigen) are pathogenic in vivo

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