ANCA and associated diseases: immunodiagnostic and pathogenetic aspects

Gross, Wolfgang L.; Schmitt, Wilhelm H.; Csernok, Elena

doi:10.1111/j.1365-2249.1993.tb03345.x

Cited by 271 publications

(60 citation statements)

References 102 publications

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“…[5][6][7][8] Although antibodies to PR3 and MPO play a pivotal role in AAV, understanding the regulation and consequences of dysregulation of the genes encoding PR3 and MPO may provide unique insight into the disease process.…”

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confidence: 99%

Dysregulation of Autoantigen Genes in ANCA-Associated Vasculitis Involves Alternative Transcripts and New Protein Synthesis

McInnis

Badhwar

Muthigi

et al. 2015

Journal of the American Society of Nephrology

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Proteinase 3 (PR3) and myeloperoxidase (MPO) are two major autoantigens in patients with vasculitis with ANCA. The genes encoding these autoantigens are abnormally expressed in peripheral granulocytes of patients with active ANCA-associated vasculitis. This study provides evidence that this transcriptional dysregulation results in a variety of mRNA processing events from the PRTN3 gene locus. In addition to elevated levels of PR3 message, leukocyte RNA from patients contained PR3 transcripts with an alternative 39 untranslated region. Furthermore, we detected usage of an alternative transcription start site within intron 1 of the PRTN3 gene locus that coincided with active disease (odds ratio, 3.3; 95% confidence interval, 1.3 to 8.4; P=0.01). This promoter may be developmentally regulated, because it was active in normal human bone marrow, multiple leukemia cell lines, MCF-7 cells, and subjects after GM-CSF treatment but not subjects with a neutrophil left shift. This transcript, which lacks exon 1 of PRTN3, encodes a 24-kD protein (p24 PR3/MBN ) with a sequence similar to that previously described for myeloblastin. Notably, PR3, p24 PR3/MBN , and MPO were synthesized in cultured neutrophils from patients with active ANCA-associated vasculitis, indicating that increased transcription results in newly synthesized autoantigens in peripheral neutrophils of patients. The synthesis of p24 PR3/MBN seems to expand the autoantigen repertoire, because immunoblots showed that sera from patients recognized p24 PR3/MBN .These findings emphasize the importance of transcriptional dysregulation of the autoantigen in autoimmune disease.

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confidence: 99%

Dysregulation of Autoantigen Genes in ANCA-Associated Vasculitis Involves Alternative Transcripts and New Protein Synthesis

McInnis

Badhwar

Muthigi

et al. 2015

Journal of the American Society of Nephrology

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“…The ANCA titre was measured by a standard indirect immunofiuorescence test (IIF) on ethanol-fixed human neutrophils [22,23]. Briefly, ethanol-fixed human neutrophils were incubated with patient sera at increasing dilutions, bound antibodies were stained with fluorescein-conjugated rabbit antihuman IgG and read by UV-microscopy.…”

Section: Determination Of Ancamentioning

confidence: 99%

Treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis with high-dose intravenous immunoglobulin

Richter

Schnabel

Csernok

et al. 1995

Clinical and Experimental Immunology

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129

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SUMMARYIn this uncontrolled study 15 patients with ANCA-associated systemic vasculitis, who were poor responders to conventional therapy, were treated with single or multiple courses of intravenous immunoglobulin (IVIG), 30g/day over 5 days. Chnical and serological evaluation was performed before and 4 weeks after IVIG. Six of the 15 patients experienced clinically significant benefit from IVIG. Improvement was confined to single organ manifestations (skin, ENT findings), no improvement was seen with conjunctivitis and scleritis, pericarditis or nephritis. No patient experienced complete remission after IVIG. Repeated courses of IVIG at 4-week intervals were no more effective than single courses. In six anti-proteinase 3 (PR3)-positive patients pretreatment sera were incubated with F(ab')2 fragments of the IVIG preparation in vitro to measure the inhibitory effect of IVIG on anti-PR3 activity. An inhibition of anti-PR3 activity by 25-70% was observed; this did not correlate with clinical effects. Approximately 40% of patients benefited from IVIG treatment, though complete remission of disease activity did not occur. Neither clinical characteristics nor the inhibitory effect of the IVIG preparation on serum anti-PR3 activity in vitro predicted clinical response to this treatment modality.

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“…At one time tubercuiosis was thought to underiie TA, but tiire is no convincing proof, Whiie a high percentage of patients give a positive tubercuiin sidn test, this may oniy indicate increased susceptibiiity to infection in societies where tubercuiosis is common. The diagnostic vaiueof ANCA and its pathogenic impiications proved to beparticuiariy important in systemic vascuiitides such as Wegener" s granuiomatosis (WG), microscopic polyarteritis (mPAN) and the cioseiy related pauci immune necrotizing and crescentic glomerulonephritis [1,2,3]. As soon as ANCA testing became widely avaiiable.…”

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confidence: 99%

“…In addition, it has been shown that the IgG fraction of IVIg that is retained on F('db')^ fragments frt>iTi IVIg by affinity chromatography mainly contains autoantibodies 12], indicating that natural autoantibodies are particularly prone to idiotypic interactions. Studies on the expression and control of the natural autoreactive IgG repertoire showed that iti healthy subjects serum IgG autoreactivity towards a wide spectrumof autoantigens is significantly lower than that of purifiedIgG [3]. The observation thatlgG-depleted serum andpurifiedlgM are capable of inhibiting the binding of IgG to many autoantigens and that IgM can bind to F(ab')j fragments of IVIg [3] indicate that the functional antiUxly network includes not only V region interactions between IgG molecules, but also between IgM and IgG.…”

mentioning

confidence: 99%

“…Studies on the expression and control of the natural autoreactive IgG repertoire showed that iti healthy subjects serum IgG autoreactivity towards a wide spectrumof autoantigens is significantly lower than that of purifiedIgG [3]. The observation thatlgG-depleted serum andpurifiedlgM are capable of inhibiting the binding of IgG to many autoantigens and that IgM can bind to F(ab')j fragments of IVIg [3] indicate that the functional antiUxly network includes not only V region interactions between IgG molecules, but also between IgM and IgG. The role of such interactions in tlie regulation of autoreactivity is also suggested by studies in mice |4| and by the ohservatioti that in humanized SCIH mice, expressing low levels of hujnan IgM, the autoantibody activity of IgG in serum is equivalent to Ihat of purified IgG [3).…”

mentioning

confidence: 99%

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