In vitro cytokine production and proliferation of T cells from patients with anti‐proteinase 3‐ and antimyeloperoxidase‐associated vasculitis, in response to proteinase 3 and myeloperoxidase

Popa, Elaine R.; Franssen, C. F. M.; Limburg, P. C.; Huitema, Minke G.; Kallenberg, Cees G. M.; Tervaert, Jwc

doi:10.1002/art.10384

Cited by 91 publications

(74 citation statements)

References 41 publications

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“…The notion that tryptophan degradation was due to monocyte/macrophage up-regulation of IDO through the action of proinflammatory cytokines was supported by the presence of elevated levels of serum neopterin in patients with acute disease and patients with disease in remission. Neopterin is a low molecular mass product of monocyte/macrophages, the up-regulation of which is similarly influenced by proinflammatory cytokines such as IFN␥ (13 [8][9][10][11][12][13][14][15][16][17][18][19][20] in healthy controls; P Ͻ 0.001 for patients with acute disease versus controls and P Ͻ 0.05 for patients with disease in remission versus controls, by one-way ANOVA) ( Figure 4C). Serum neopterin levels remained elevated in patients compared with controls when corrected for renal function.…”

Section: Patient Characteristicsmentioning

confidence: 99%

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Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Chavele¹,

Shukla²,

Keteepe-Arachi³

et al. 2010

Arthritis & Rheumatism

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Objective. T lymphocytes have been implicated in the pathogenesis of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Patients with myeloperoxidase (MPO)antineutrophil cytoplasmic antibody (ANCA) experience relapses less frequently than those with proteinase 3 ANCA, suggesting greater immune regulation. This study was undertaken to investigate MPO-specific T cell reactivity during disease remission and the factors regulating their responsiveness.Methods. MPO-specific T cells were quantified by enzyme-linked immunospot assay with additional Treg cell depletion or exogenous interleukin-2. Serum tryptophan and its metabolites were measured. In vivo blockade of indoleamine 2,3-dioxygenase (IDO) was performed, and its effect on MPO reactivity was assessed.Results. During disease remission, MPO-specific interferon-␥-producing T cell frequencies were comparable with those found in healthy controls and significantly lower than those found in patients with acute disease. CD4؉CD25؉ regulatory cells did not play a role in maintaining these low MPO-specific T cell frequencies, since depletion of Treg cells did not augment MPO-specific responses, and FoxP3 levels were diminished in patients compared with controls. Treg cell function, however, was comparable in patients and controls, suggesting numerical rather than functional deficiency. We found diminished serum tryptophan levels and elevated levels of its metabolite kynurenine in patients with MPO AAV as compared with controls. To confirm the effect of tryptophan degradation on MPO responses in vivo, we inhibited degradation in MPOimmunized WKY rats and found greater immune responsiveness to MPO and a tendency to more severe glomerulonephritis.Conclusion. Our findings indicate that MPOspecific T cell frequencies are regulated during disease remission in association with tryptophan degradation. The tryptophan regulatory pathway is induced during active disease and persists during disease remission.The antineutrophil cytoplasmic antibodyassociated vasculitides (AAV) are a group of relapsingremitting systemic diseases that result in considerable morbidity and mortality. Up to 25% of patients develop end-stage renal failure despite optimal immunosuppression. Understanding the immune mechanisms that regulate disease activity is critical for a more successful therapeutic approach to management of the disease. Recent work has highlighted the importance of both humoral and cellular effectors in disease pathogenesis. Pathogenic transplacental transfer of antimyeloperoxidase (anti-MPO) antibody to a neonate has been re-

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Section: Patient Characteristicsmentioning

confidence: 99%

“…Our group and others have shown that T cells responding to the autoantigens MPO and proteinase 3 (PR3) are found in patients with active disease (9)(10)(11), and persistent T cell activation has also been reported (12). Additionally, ANCA are class-switched antibodies, which therefore require T cell help for their generation.…”

mentioning

confidence: 96%

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Chavele¹,

Shukla²,

Keteepe-Arachi³

et al. 2010

Arthritis & Rheumatism

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“…However, these observations are not uniform, and predominance of CD3 ϩ cells, eosinophils, and Th2 cytokines has been reported in a study of nasal biopsies from patients with Wegner's granulomatosis (81). The presence of T cells that respond to the likely target antigens, MPO and PR3, in patients with ANCA-associated GN provides evidence for the involvement of T cell-directed autoimmunity (82)(83)(84)(85)(86). The immunodominant epitopes have not been defined precisely, but for PR3, predominant T cell-reactive residues in three peptide regions involving the C terminal of the propeptide and the signal sequence have been identified (87).…”

Section: T Cells In Anca-associated Crescentic Gnmentioning

confidence: 99%

T Cells in Crescentic Glomerulonephritis

Tipping

Holdsworth

2006

Journal of the American Society of Nephrology

162

150

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G lomerulonephritis (GN) is not a single disease but shows a variety of histologic patterns, clinical features, and outcomes that indicate multiple pathogenic mechanisms. A pivotal role for adaptive immune responses in initiation of GN has been demonstrated in experimental models, but across the spectrum of human GN, direct evidence of immune pathogenesis is more variable. The strongest case that adaptive immune responses drive nephritogenic events in glomeruli in humans has been mounted in crescentic GN, and evidence for involvement of autoimmunity, either organspecific autoimmunity to glomerular antigens (e.g., anti-glomerular basement membrane [anti-GBM] GN) or systemic autoimmunity to nonglomerular antigens (e.g., ANCA-associated crescentic GN, lupus nephritis) now is emerging for many forms of human crescentic GN. CD4 ϩ T cells play a central role in adaptive immunity. T cell-independent responses are uncommon. They usually are associated with simple carbohydrate-rich antigens and do not show extensive Ig isotype switching or strong affinity maturation. The known antigens that drive crescentic GN show strong evidence of CD4 ϩ T cell dependence and do not have the characteristics of T-independent antigens. The evidence from glomerular pathology also suggests a prominent role for local CD4 ϩ T cell-driven Th1-type responses in crescentic GN with delayed-type hypersensitivity (DTH)-like cellular effectors (T cells and macrophages) as well as Th1 Ig isotypes in glomeruli.The relative contributions of cellular and humoral CD4 ϩ T cell-driven effectors, particularly in ANCA-associated GN, remains controversial, but it is clear that the nephritogenic immune responses are CD4 ϩ T cell-driven.

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“…IFN-␥ and IL-4 concentrations were determined with the PeliKine Compact IFN-␥-and IL-4 enzyme-linked immunosorbent assay (ELISA) kits in accordance with the guidelines provided by the supplier (Central Laboratory of the Blood Transfusion Service, Amsterdam, The Netherlands). IL-10 concentrations were determined as described previously (14). Optical densities at 450 to 575 nm were measured with SOFTMAX software.…”

Section: Patients and Controls (I) Bud Patientsmentioning

confidence: 99%

Cytokine Responses to Stimulation of Whole Blood from Patients with Buruli Ulcer Disease in Ghana

Westenbrink¹,

Stienstra²,

Huitema³

et al. 2005

Clin Vaccine Immunol

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Buruli ulcer disease (BUD), caused byIL-10 and IL-4 levels did not differ between BUD patients and controls, although active TB patients had significantly higher IL-10 production levels than did treated TB patients. Multivariate analysis showed no confounding factors. In conclusion, Th-1 down regulation in early BUD appears to reverse in later stages of BUD, although an association with IL-10 or IL-4 production does not emerge from our data. Here we show differences in Th-1-type cytokine production between early-and late-stage BUD that might reflect an improved immune defense over time.

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In vitro cytokine production and proliferation of T cells from patients with anti‐proteinase 3‐ and antimyeloperoxidase‐associated vasculitis, in response to proteinase 3 and myeloperoxidase

Abstract: Results.

Cited by 91 publications

References 41 publications

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

Regulation of myeloperoxidase‐specific T cell responses during disease remission in antineutrophil cytoplasmic antibody–associated vasculitis: The role of Treg cells and tryptophan degradation

T Cells in Crescentic Glomerulonephritis

Cytokine Responses to Stimulation of Whole Blood from Patients with Buruli Ulcer Disease in Ghana

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